Hospital Medicine

The safety and the efficacy of shorter durations of antibiotic therapy for uncomplicated pneumonia have been clearly established in the past decade.^1,2 Guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society have been available since 2007. These expert consensus statements recommend that uncomplicated community-acquired pneumonia (CAP) should be treated for 5 to 7 days, as long as the patient exhibits signs and symptoms of clinical stability.³ Similarly, recently updated guidelines for hospital-acquired and ventilator-associated pneumonias call for short-course therapy.⁴ Despite this guidance, pneumonia treatment duration is often discordant.⁵ Unnecessary antimicrobial use is associated with greater selection pressure on pathogens, increased risk of adverse events (AEs), and elevated treatment costs.⁶ The growing burden of antibiotic resistance coupled with limited availability of new antibiotics requires judicious use of these agents.

The IDSA guidelines for Clostridium difficile infection (CDI) note that exposure to antimicrobial agents is the most important modifiable risk factor for the development of CDI.⁷ Longer durations of antibiotics increase the risk of CDI compared with shorter durations.^8,9 Antibiotics are a frequent cause of drug-associated AEs and likely are underestimated.¹⁰ To decrease the unwanted effects of excessive therapy, IDSA and CDC suggest that antimicrobial stewardship interventions should be implemented.^11-13

Antimicrobial stewardship efforts in small community hospitals (also known as district, rural, general, and primary hospitals) are varied and can be challenging due to limited staff and resources.^14,15 The World Health Organization defines a primary care facility as having few specialties, mainly internal medicine and general surgery with limited laboratory services for general (but not specialized) pathologic analysis, and bed size ranging from 30 to 200 beds.¹⁶ Although guidance is available for effective intervention strategies in smaller hospitals, there are limited data in the literature regarding successful outcomes.^17-22

The purpose of this study was to establish the need and evaluate the impact of a pharmacy-initiated 3-part intervention targeting treatment duration in patients hospitalized with uncomplicated pneumonia in a primary hospital setting. The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas, has 50 acute care beds, including 7 intensive care unit beds and excluding 15 mental health beds. The pharmacy is staffed 24 hours a day. Acute-care providers consist of 7 full-time hospitalists, not including nocturnists and contract physicians. The VHSO does not have an infectious disease physician on staff.

The antimicrobial stewardship committee consists of 3 clinical pharmacists, a pulmonologist, a pathologist, and 2 infection-control nurses. There is 1 full-time equivalent allotted for inpatient clinical pharmacy activities in the acute care areas, including enforcement of all antimicrobial stewardship policies, which are conducted by a single pharmacist.

Methods

This was a retrospective chart review of two 12-month periods using a before and after study design. Medical records were reviewed during October 2012 through September 2013 (before the stewardship implementation) and December 2014 through November 2015 (after implementation). Inclusion criteria consisted of a primary discharge diagnosis of pneumonia as documented by the provider (or secondary diagnosis if sepsis was primary), hospitalization for at least 48 hours, administration of antibiotics for a minimum of 24 hours, and survival to discharge.

Exclusion criteria consisted of direct transfer from another facility, inappropriate empiric therapy as evidenced by culture data (isolated pathogens not covered by prescribed antibiotics), pneumonia that developed 48 hours after admission, extrapulmonary sources of infection, hospitalization > 14 days, discharge without a known duration of outpatient antibiotics, discharge for pneumonia within 28 days prior to admission, documented infection caused by Pseudomonas aeruginosa or other nonlactose fermenting Gram-negative rod, and complicated pneumonias defined as lung abscess, empyema, or severe immunosuppression (eg, cancer with chemotherapy within the previous 30 days, transplant recipients, HIV infection, acquired or congenital immunodeficiency, or absolute neutrophil count 1,500 cell/mm³ within past 28 days).

Patients were designated with health care-associated pneumonia (HCAP) if they were hospitalized ≥ 2 days or resided in a skilled nursing or extended-care facility within the previous 90 days; on chronic dialysis; or had wound care, tracheostomy care, or ventilator care from a health care professional within the previous 28 days. Criteria for clinical stability were defined as ≤ 100.4º F temperature, ≤ 100 beats/min heart rate, ≤ 24 breaths/min respiratory rate, ≥ 90 mm Hg systolic blood pressure, ≥ 90% or PaO₂ ≥ 60 mm Hg oxygen saturation on room air (or baseline oxygen requirements), and return to baseline mental status. To compare groups, researchers tabulated the pneumonia severity index on hospital day 1.

The intervention consisted of a 3-part process. First, hospitalists were educated on VHSO’s baseline treatment duration data, and these were compared with current IDSA recommendations. The education was followed by an open-discussion component to solicit feedback from providers on perceived barriers to following guidelines. Provider feedback was used to tailor an antimicrobial stewardship intervention to address perceived barriers to optimal antibiotic treatment duration.

After the education component, prospective intervention and feedback were provided for hospitalized patients by a single clinical pharmacist. This pharmacist interacted verbally and in writing with the patients’ providers, discussing antimicrobial appropriateness, de-escalation, duration of therapy, and intravenous to oral switching. Finally, a stewardship note for the Computerized Patient Record System (CPRS) was generated and included a template with reminders of clinical stability, duration of current therapy, and a request to discontinue therapy if the patient met criteria. For patients who remained hospitalized, this note was entered into CPRS on or about day 7 of antibiotic therapy; this required an electronic signature from the provider.

The VHSO Pharmacy and Therapeutics Committee approved both the provider education and the stewardship note in November 2014, and implementation of the stewardship intervention occurred immediately afterward. The pharmacy staff also was educated on the VHSO baseline data and stewardship efforts.

The primary outcome of the study was the change in days of total antibiotic treatment. Secondary outcomes included days of intravenous antibiotic therapy, days of inpatient oral therapy, mean length of stay (LOS), and number of outpatient antibiotic days once discharged. Incidence of CDI and 28-day readmissions were also evaluated. The VHSO Institutional Review Board approved these methods and the procedures that followed were in accord with the ethical standards of the VHSO Committee on Human Experimentation.

Statistical Analysis

All continuous variables are reported as mean ± standard deviation. Data analysis for significance was performed using a Student t test for continuous variables and a χ² test (or Fisher exact test) for categorical variables in R Foundation for Statistical Computing version 3.1.0. All samples were 2-tailed. A P value < .05 was considered statistically significant. Using the smaller of the 2 study populations, the investigators calculated that the given sample size of 88 in each group would provide 99% power to detect a 2-day difference in the primary endpoint at a 2-sided significance level of 5%.

Results

During the baseline assessment (group 1), 192 cases were reviewed with 103 meeting the inclusion criteria. Group 1 consisted of 85 cases of CAP and 18 cases of HCAP (mean age, 70.7 years). During the follow-up assessment (group 2), 168 cases were reviewed with 88 meeting the inclusion criteria. Group 2 consisted of 68 cases of CAP and 20 cases of HCAP (mean age, 70.8 years).

There was no difference in inpatient mortality rates between groups (3.1% vs 3.0%, P = .99). This mortality rate is consistent with published reports.²³ Empiric antibiotic selection was appropriate because there were no exclusions for drug/pathogen mismatch. Pneumonia severity was similar in both groups (Table).

The total duration of antibiotic treatment decreased significantly for CAP and HCAP (Figure). The observed median treatment days for groups 1 and 2 were 11 days and 8 days, respectively. Outpatient antibiotic days also decreased. Mean LOS was shorter in the follow-up group (4.9 ± 2.6 days vs 4.0 ± 2.6 days, P = .02). Length of IV antibiotic duration decreased. Oral antibiotic days while inpatient were not statistically different (1.5 ± 1.8 days vs 1.1 ± 1.5 days, P = .15). During the follow-up period, 26 stewardship notes were entered into CPRS; antibiotics were stopped in 65% of cases.

There were no recorded cases of CDI in either group. There were eleven 28-day readmissions in group 1, only 3 of which were due to infectious causes. One patient had a primary diagnosis of necrotizing pneumonia, 1 had Pseudomonas pneumonia, and 1 patient had a new lung mass and was diagnosed with postobstructive pneumonia. Of eight 28-day readmissions in group 2, only 2 resulted from infectious causes. One readmission primary diagnosis was sinusitis and 1 was recurrent pneumonia (of note, this patient received a 10-day treatment course for pneumonia on initial admission). Two patients died within 28 days of discharge in each group.

Discussion

Other multifaceted single-center interventions have been shown to be effective in large, teaching hospitals,^24,25 and it has been suggested that smaller, rural hospitals may be underserved in antimicrobial stewardship activities.^26,27 In the global struggle with antimicrobial resistance, McGregor and colleagues highlighted the importance of evaluating successful stewardship methods in an array of clinical settings to help tailor an approach for a specific type of facility.²⁸ To the authors knowledge, this is the first publication showing efficacy of such antimicrobial stewardship interventions specific to pneumonia therapy in a small, primary facility.

The intervention methods used at VHSO are supported by recent IDSA and Society for Healthcare Epidemiology of America guidelines for effective stewardship implementation.²⁹ Prospective audit and feedback is considered a core recommendation, whereas didactic education is recommended only in conjunction with other stewardship activities. Additionally, the guidelines recommend evaluating specific infectious disease syndromes, in this case uncomplicated pneumonia, to focus on specific treatment guidelines. Last, the results of the 3-part intervention can be used to aid in demonstrating facility improvement and encourage continued success.

Of note, VHSO has had established inpatient and outpatient clinical pharmacy roles for several years. Stewardship interventions already in place included an intravenous-to-oral antibiotic switch policy, automatic antibiotic stop dates, as well as pharmacist-driven vancomycin and aminoglycoside dosing. Prior to this multifaceted intervention specific to pneumonia duration, prospective audit and feedback interventions (verbal and written) also were common. The number of interventions specific to this study outside of the stewardship note was not recorded. Using rapid diagnostic testing and biomarkers to aid in stewardship activities at VHSO have been considered, but these tools are not available due to a lab personnel shortage.

Soliciting feedback from providers on their preferred stewardship strategy and perceived barriers was a key component of the educational intervention. Of equal importance was presenting providers with their baseline prescribing data to provide objective evidence of a problem. While all were familiar with existing treatment guidelines, some feedback indicated that it can be difficult to determine accurate antibiotic duration in CPRS. Prescribers reported that identifying antibiotic duration was especially challenging when antibiotics as well as providers change during an admission. Also frequently overlooked were antibiotics given in the emergency department. This could be a key area for clinical pharmacists’ intervention given their familiarity with the CPRS medication sections.

Charani and colleagues suggest that recognizing barriers to implementing best practices and adapting to the local facility culture is paramount for changing prescribing behaviors and developing a successful stewardship intervention.³⁰ At VHSO, the providers were presented with multiple stewardship options but agreed to the new note and template. This process gave providers a voice in selecting their own stewardship intervention. In a culture with no infectious disease physician to champion initiatives, the investigators felt that provider involvement in the intervention selection was unique and may have encouraged provider concurrence.

Although not directly targeted by the intervention strategies, average LOS was shorter in the follow-up group. According to investigators, frequent reminders of clinical stability in the stewardship notes may have influenced this. Even though the note was used only in patients who remained hospitalized for their entire treatment course, investigators felt that it still served as a reminder for prescribing habits as they were also able to show a decrease in outpatient prescription duration.

Limitations

Potential weaknesses of the study include changes in providers. During the transition between group 1 and group 2, 2 hospitalists left and 2 new hospitalists arrived. Given the small size of the staff, this could significantly impact prescribing trends. Another potential weakness is the high exclusion rate, although these rates were similar in both groups (46% group 1, 47% group 2). Furthermore, similar exclusion rates have been reported elsewhere.^24,25,31 The most common reasons for exclusion were complicated pneumonias (36%) and immunocompromised patients (18%). These patient populations were not evaluated in the current study, and optimal treatment durations are unknown. Hospital-acquired and ventilator-associated pneumonias also were excluded. Therefore, limitations in applicability of the results should be noted.

The authors acknowledge that, prior to this publication, the IDSA guidelines have removed the designation of HCAP as a separate clinical entity.⁴ However, this should not affect the significance of the intervention for treatment duration.

The study facility experienced a hiring freeze resulting in a 9.3% decrease in overall admissions from fiscal year 2013 to fiscal year 2015. This is likely why there were fewer admissions for pneumonia in group 2. Regardless, power analysis revealed the study was of adequate sample size to detect its primary outcome. It is possible that patients in either group could have sought health care at other facilities, making the CDI and readmission endpoints less inclusive.

The study was not of a scale to detect changes in antimicrobial resistance pressure or clinical outcomes. Cost savings were not analyzed. However, this study adds to the growing body of evidence that a structured intervention can result in positive outcomes at the facility level. This study shows that interventions targeting pneumonia treatment duration could feasibly be added to the menu of stewardship options available to smaller facilities.

Like other stewardship studies in the literature, the follow-up treatment duration, while improved, still exceeded those recommended in the IDSA guidelines. The investigators noted that not all providers were equal regarding change in prescribing habits, perhaps making the average duration longer. Additionally, the request to discontinue antibiotic therapy through the stewardship note could have been entered earlier (eg, as early as day 5 of therapy) to target the shortest effective date as recommended in the recent stewardship guidelines.²⁹ Future steps include continued feedback to providers on their progress in this area and encouragement to document day of antibiotic treatment in their daily progress notes.

Conclusion

This study showed a significant decrease in antibiotic duration for the treatment of uncomplicated pneumonia using a 3-part pharmacy intervention in a primary hospital setting. The investigators feel that each arm of the strategy was equally important and fewer interventions were not likely to be as effective.³² Although data collection for baseline prescribing and follow-up on outcomes may be a time-consuming task, it can be a valuable component of successful stewardship interventions.

The safety and the efficacy of shorter durations of antibiotic therapy for uncomplicated pneumonia have been clearly established in the past decade.^1,2 Guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society have been available since 2007. These expert consensus statements recommend that uncomplicated community-acquired pneumonia (CAP) should be treated for 5 to 7 days, as long as the patient exhibits signs and symptoms of clinical stability.³ Similarly, recently updated guidelines for hospital-acquired and ventilator-associated pneumonias call for short-course therapy.⁴ Despite this guidance, pneumonia treatment duration is often discordant.⁵ Unnecessary antimicrobial use is associated with greater selection pressure on pathogens, increased risk of adverse events (AEs), and elevated treatment costs.⁶ The growing burden of antibiotic resistance coupled with limited availability of new antibiotics requires judicious use of these agents.

The IDSA guidelines for Clostridium difficile infection (CDI) note that exposure to antimicrobial agents is the most important modifiable risk factor for the development of CDI.⁷ Longer durations of antibiotics increase the risk of CDI compared with shorter durations.^8,9 Antibiotics are a frequent cause of drug-associated AEs and likely are underestimated.¹⁰ To decrease the unwanted effects of excessive therapy, IDSA and CDC suggest that antimicrobial stewardship interventions should be implemented.^11-13

Antimicrobial stewardship efforts in small community hospitals (also known as district, rural, general, and primary hospitals) are varied and can be challenging due to limited staff and resources.^14,15 The World Health Organization defines a primary care facility as having few specialties, mainly internal medicine and general surgery with limited laboratory services for general (but not specialized) pathologic analysis, and bed size ranging from 30 to 200 beds.¹⁶ Although guidance is available for effective intervention strategies in smaller hospitals, there are limited data in the literature regarding successful outcomes.^17-22

The purpose of this study was to establish the need and evaluate the impact of a pharmacy-initiated 3-part intervention targeting treatment duration in patients hospitalized with uncomplicated pneumonia in a primary hospital setting. The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas, has 50 acute care beds, including 7 intensive care unit beds and excluding 15 mental health beds. The pharmacy is staffed 24 hours a day. Acute-care providers consist of 7 full-time hospitalists, not including nocturnists and contract physicians. The VHSO does not have an infectious disease physician on staff.

The antimicrobial stewardship committee consists of 3 clinical pharmacists, a pulmonologist, a pathologist, and 2 infection-control nurses. There is 1 full-time equivalent allotted for inpatient clinical pharmacy activities in the acute care areas, including enforcement of all antimicrobial stewardship policies, which are conducted by a single pharmacist.

Methods

This was a retrospective chart review of two 12-month periods using a before and after study design. Medical records were reviewed during October 2012 through September 2013 (before the stewardship implementation) and December 2014 through November 2015 (after implementation). Inclusion criteria consisted of a primary discharge diagnosis of pneumonia as documented by the provider (or secondary diagnosis if sepsis was primary), hospitalization for at least 48 hours, administration of antibiotics for a minimum of 24 hours, and survival to discharge.

Exclusion criteria consisted of direct transfer from another facility, inappropriate empiric therapy as evidenced by culture data (isolated pathogens not covered by prescribed antibiotics), pneumonia that developed 48 hours after admission, extrapulmonary sources of infection, hospitalization > 14 days, discharge without a known duration of outpatient antibiotics, discharge for pneumonia within 28 days prior to admission, documented infection caused by Pseudomonas aeruginosa or other nonlactose fermenting Gram-negative rod, and complicated pneumonias defined as lung abscess, empyema, or severe immunosuppression (eg, cancer with chemotherapy within the previous 30 days, transplant recipients, HIV infection, acquired or congenital immunodeficiency, or absolute neutrophil count 1,500 cell/mm³ within past 28 days).

Patients were designated with health care-associated pneumonia (HCAP) if they were hospitalized ≥ 2 days or resided in a skilled nursing or extended-care facility within the previous 90 days; on chronic dialysis; or had wound care, tracheostomy care, or ventilator care from a health care professional within the previous 28 days. Criteria for clinical stability were defined as ≤ 100.4º F temperature, ≤ 100 beats/min heart rate, ≤ 24 breaths/min respiratory rate, ≥ 90 mm Hg systolic blood pressure, ≥ 90% or PaO₂ ≥ 60 mm Hg oxygen saturation on room air (or baseline oxygen requirements), and return to baseline mental status. To compare groups, researchers tabulated the pneumonia severity index on hospital day 1.

The intervention consisted of a 3-part process. First, hospitalists were educated on VHSO’s baseline treatment duration data, and these were compared with current IDSA recommendations. The education was followed by an open-discussion component to solicit feedback from providers on perceived barriers to following guidelines. Provider feedback was used to tailor an antimicrobial stewardship intervention to address perceived barriers to optimal antibiotic treatment duration.

After the education component, prospective intervention and feedback were provided for hospitalized patients by a single clinical pharmacist. This pharmacist interacted verbally and in writing with the patients’ providers, discussing antimicrobial appropriateness, de-escalation, duration of therapy, and intravenous to oral switching. Finally, a stewardship note for the Computerized Patient Record System (CPRS) was generated and included a template with reminders of clinical stability, duration of current therapy, and a request to discontinue therapy if the patient met criteria. For patients who remained hospitalized, this note was entered into CPRS on or about day 7 of antibiotic therapy; this required an electronic signature from the provider.

The VHSO Pharmacy and Therapeutics Committee approved both the provider education and the stewardship note in November 2014, and implementation of the stewardship intervention occurred immediately afterward. The pharmacy staff also was educated on the VHSO baseline data and stewardship efforts.

The primary outcome of the study was the change in days of total antibiotic treatment. Secondary outcomes included days of intravenous antibiotic therapy, days of inpatient oral therapy, mean length of stay (LOS), and number of outpatient antibiotic days once discharged. Incidence of CDI and 28-day readmissions were also evaluated. The VHSO Institutional Review Board approved these methods and the procedures that followed were in accord with the ethical standards of the VHSO Committee on Human Experimentation.

Statistical Analysis

All continuous variables are reported as mean ± standard deviation. Data analysis for significance was performed using a Student t test for continuous variables and a χ² test (or Fisher exact test) for categorical variables in R Foundation for Statistical Computing version 3.1.0. All samples were 2-tailed. A P value < .05 was considered statistically significant. Using the smaller of the 2 study populations, the investigators calculated that the given sample size of 88 in each group would provide 99% power to detect a 2-day difference in the primary endpoint at a 2-sided significance level of 5%.

Results

During the baseline assessment (group 1), 192 cases were reviewed with 103 meeting the inclusion criteria. Group 1 consisted of 85 cases of CAP and 18 cases of HCAP (mean age, 70.7 years). During the follow-up assessment (group 2), 168 cases were reviewed with 88 meeting the inclusion criteria. Group 2 consisted of 68 cases of CAP and 20 cases of HCAP (mean age, 70.8 years).

There was no difference in inpatient mortality rates between groups (3.1% vs 3.0%, P = .99). This mortality rate is consistent with published reports.²³ Empiric antibiotic selection was appropriate because there were no exclusions for drug/pathogen mismatch. Pneumonia severity was similar in both groups (Table).

The total duration of antibiotic treatment decreased significantly for CAP and HCAP (Figure). The observed median treatment days for groups 1 and 2 were 11 days and 8 days, respectively. Outpatient antibiotic days also decreased. Mean LOS was shorter in the follow-up group (4.9 ± 2.6 days vs 4.0 ± 2.6 days, P = .02). Length of IV antibiotic duration decreased. Oral antibiotic days while inpatient were not statistically different (1.5 ± 1.8 days vs 1.1 ± 1.5 days, P = .15). During the follow-up period, 26 stewardship notes were entered into CPRS; antibiotics were stopped in 65% of cases.

There were no recorded cases of CDI in either group. There were eleven 28-day readmissions in group 1, only 3 of which were due to infectious causes. One patient had a primary diagnosis of necrotizing pneumonia, 1 had Pseudomonas pneumonia, and 1 patient had a new lung mass and was diagnosed with postobstructive pneumonia. Of eight 28-day readmissions in group 2, only 2 resulted from infectious causes. One readmission primary diagnosis was sinusitis and 1 was recurrent pneumonia (of note, this patient received a 10-day treatment course for pneumonia on initial admission). Two patients died within 28 days of discharge in each group.

Discussion

Other multifaceted single-center interventions have been shown to be effective in large, teaching hospitals,^24,25 and it has been suggested that smaller, rural hospitals may be underserved in antimicrobial stewardship activities.^26,27 In the global struggle with antimicrobial resistance, McGregor and colleagues highlighted the importance of evaluating successful stewardship methods in an array of clinical settings to help tailor an approach for a specific type of facility.²⁸ To the authors knowledge, this is the first publication showing efficacy of such antimicrobial stewardship interventions specific to pneumonia therapy in a small, primary facility.

The intervention methods used at VHSO are supported by recent IDSA and Society for Healthcare Epidemiology of America guidelines for effective stewardship implementation.²⁹ Prospective audit and feedback is considered a core recommendation, whereas didactic education is recommended only in conjunction with other stewardship activities. Additionally, the guidelines recommend evaluating specific infectious disease syndromes, in this case uncomplicated pneumonia, to focus on specific treatment guidelines. Last, the results of the 3-part intervention can be used to aid in demonstrating facility improvement and encourage continued success.

Of note, VHSO has had established inpatient and outpatient clinical pharmacy roles for several years. Stewardship interventions already in place included an intravenous-to-oral antibiotic switch policy, automatic antibiotic stop dates, as well as pharmacist-driven vancomycin and aminoglycoside dosing. Prior to this multifaceted intervention specific to pneumonia duration, prospective audit and feedback interventions (verbal and written) also were common. The number of interventions specific to this study outside of the stewardship note was not recorded. Using rapid diagnostic testing and biomarkers to aid in stewardship activities at VHSO have been considered, but these tools are not available due to a lab personnel shortage.

Soliciting feedback from providers on their preferred stewardship strategy and perceived barriers was a key component of the educational intervention. Of equal importance was presenting providers with their baseline prescribing data to provide objective evidence of a problem. While all were familiar with existing treatment guidelines, some feedback indicated that it can be difficult to determine accurate antibiotic duration in CPRS. Prescribers reported that identifying antibiotic duration was especially challenging when antibiotics as well as providers change during an admission. Also frequently overlooked were antibiotics given in the emergency department. This could be a key area for clinical pharmacists’ intervention given their familiarity with the CPRS medication sections.

Charani and colleagues suggest that recognizing barriers to implementing best practices and adapting to the local facility culture is paramount for changing prescribing behaviors and developing a successful stewardship intervention.³⁰ At VHSO, the providers were presented with multiple stewardship options but agreed to the new note and template. This process gave providers a voice in selecting their own stewardship intervention. In a culture with no infectious disease physician to champion initiatives, the investigators felt that provider involvement in the intervention selection was unique and may have encouraged provider concurrence.

Although not directly targeted by the intervention strategies, average LOS was shorter in the follow-up group. According to investigators, frequent reminders of clinical stability in the stewardship notes may have influenced this. Even though the note was used only in patients who remained hospitalized for their entire treatment course, investigators felt that it still served as a reminder for prescribing habits as they were also able to show a decrease in outpatient prescription duration.

Limitations

Potential weaknesses of the study include changes in providers. During the transition between group 1 and group 2, 2 hospitalists left and 2 new hospitalists arrived. Given the small size of the staff, this could significantly impact prescribing trends. Another potential weakness is the high exclusion rate, although these rates were similar in both groups (46% group 1, 47% group 2). Furthermore, similar exclusion rates have been reported elsewhere.^24,25,31 The most common reasons for exclusion were complicated pneumonias (36%) and immunocompromised patients (18%). These patient populations were not evaluated in the current study, and optimal treatment durations are unknown. Hospital-acquired and ventilator-associated pneumonias also were excluded. Therefore, limitations in applicability of the results should be noted.

The authors acknowledge that, prior to this publication, the IDSA guidelines have removed the designation of HCAP as a separate clinical entity.⁴ However, this should not affect the significance of the intervention for treatment duration.

The study facility experienced a hiring freeze resulting in a 9.3% decrease in overall admissions from fiscal year 2013 to fiscal year 2015. This is likely why there were fewer admissions for pneumonia in group 2. Regardless, power analysis revealed the study was of adequate sample size to detect its primary outcome. It is possible that patients in either group could have sought health care at other facilities, making the CDI and readmission endpoints less inclusive.

The study was not of a scale to detect changes in antimicrobial resistance pressure or clinical outcomes. Cost savings were not analyzed. However, this study adds to the growing body of evidence that a structured intervention can result in positive outcomes at the facility level. This study shows that interventions targeting pneumonia treatment duration could feasibly be added to the menu of stewardship options available to smaller facilities.

Like other stewardship studies in the literature, the follow-up treatment duration, while improved, still exceeded those recommended in the IDSA guidelines. The investigators noted that not all providers were equal regarding change in prescribing habits, perhaps making the average duration longer. Additionally, the request to discontinue antibiotic therapy through the stewardship note could have been entered earlier (eg, as early as day 5 of therapy) to target the shortest effective date as recommended in the recent stewardship guidelines.²⁹ Future steps include continued feedback to providers on their progress in this area and encouragement to document day of antibiotic treatment in their daily progress notes.

Conclusion

This study showed a significant decrease in antibiotic duration for the treatment of uncomplicated pneumonia using a 3-part pharmacy intervention in a primary hospital setting. The investigators feel that each arm of the strategy was equally important and fewer interventions were not likely to be as effective.³² Although data collection for baseline prescribing and follow-up on outcomes may be a time-consuming task, it can be a valuable component of successful stewardship interventions.

The safety and the efficacy of shorter durations of antibiotic therapy for uncomplicated pneumonia have been clearly established in the past decade.^1,2 Guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society have been available since 2007. These expert consensus statements recommend that uncomplicated community-acquired pneumonia (CAP) should be treated for 5 to 7 days, as long as the patient exhibits signs and symptoms of clinical stability.³ Similarly, recently updated guidelines for hospital-acquired and ventilator-associated pneumonias call for short-course therapy.⁴ Despite this guidance, pneumonia treatment duration is often discordant.⁵ Unnecessary antimicrobial use is associated with greater selection pressure on pathogens, increased risk of adverse events (AEs), and elevated treatment costs.⁶ The growing burden of antibiotic resistance coupled with limited availability of new antibiotics requires judicious use of these agents.

The IDSA guidelines for Clostridium difficile infection (CDI) note that exposure to antimicrobial agents is the most important modifiable risk factor for the development of CDI.⁷ Longer durations of antibiotics increase the risk of CDI compared with shorter durations.^8,9 Antibiotics are a frequent cause of drug-associated AEs and likely are underestimated.¹⁰ To decrease the unwanted effects of excessive therapy, IDSA and CDC suggest that antimicrobial stewardship interventions should be implemented.^11-13

Antimicrobial stewardship efforts in small community hospitals (also known as district, rural, general, and primary hospitals) are varied and can be challenging due to limited staff and resources.^14,15 The World Health Organization defines a primary care facility as having few specialties, mainly internal medicine and general surgery with limited laboratory services for general (but not specialized) pathologic analysis, and bed size ranging from 30 to 200 beds.¹⁶ Although guidance is available for effective intervention strategies in smaller hospitals, there are limited data in the literature regarding successful outcomes.^17-22

The purpose of this study was to establish the need and evaluate the impact of a pharmacy-initiated 3-part intervention targeting treatment duration in patients hospitalized with uncomplicated pneumonia in a primary hospital setting. The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas, has 50 acute care beds, including 7 intensive care unit beds and excluding 15 mental health beds. The pharmacy is staffed 24 hours a day. Acute-care providers consist of 7 full-time hospitalists, not including nocturnists and contract physicians. The VHSO does not have an infectious disease physician on staff.

The antimicrobial stewardship committee consists of 3 clinical pharmacists, a pulmonologist, a pathologist, and 2 infection-control nurses. There is 1 full-time equivalent allotted for inpatient clinical pharmacy activities in the acute care areas, including enforcement of all antimicrobial stewardship policies, which are conducted by a single pharmacist.

Methods

This was a retrospective chart review of two 12-month periods using a before and after study design. Medical records were reviewed during October 2012 through September 2013 (before the stewardship implementation) and December 2014 through November 2015 (after implementation). Inclusion criteria consisted of a primary discharge diagnosis of pneumonia as documented by the provider (or secondary diagnosis if sepsis was primary), hospitalization for at least 48 hours, administration of antibiotics for a minimum of 24 hours, and survival to discharge.

Exclusion criteria consisted of direct transfer from another facility, inappropriate empiric therapy as evidenced by culture data (isolated pathogens not covered by prescribed antibiotics), pneumonia that developed 48 hours after admission, extrapulmonary sources of infection, hospitalization > 14 days, discharge without a known duration of outpatient antibiotics, discharge for pneumonia within 28 days prior to admission, documented infection caused by Pseudomonas aeruginosa or other nonlactose fermenting Gram-negative rod, and complicated pneumonias defined as lung abscess, empyema, or severe immunosuppression (eg, cancer with chemotherapy within the previous 30 days, transplant recipients, HIV infection, acquired or congenital immunodeficiency, or absolute neutrophil count 1,500 cell/mm³ within past 28 days).

Patients were designated with health care-associated pneumonia (HCAP) if they were hospitalized ≥ 2 days or resided in a skilled nursing or extended-care facility within the previous 90 days; on chronic dialysis; or had wound care, tracheostomy care, or ventilator care from a health care professional within the previous 28 days. Criteria for clinical stability were defined as ≤ 100.4º F temperature, ≤ 100 beats/min heart rate, ≤ 24 breaths/min respiratory rate, ≥ 90 mm Hg systolic blood pressure, ≥ 90% or PaO₂ ≥ 60 mm Hg oxygen saturation on room air (or baseline oxygen requirements), and return to baseline mental status. To compare groups, researchers tabulated the pneumonia severity index on hospital day 1.

The intervention consisted of a 3-part process. First, hospitalists were educated on VHSO’s baseline treatment duration data, and these were compared with current IDSA recommendations. The education was followed by an open-discussion component to solicit feedback from providers on perceived barriers to following guidelines. Provider feedback was used to tailor an antimicrobial stewardship intervention to address perceived barriers to optimal antibiotic treatment duration.

After the education component, prospective intervention and feedback were provided for hospitalized patients by a single clinical pharmacist. This pharmacist interacted verbally and in writing with the patients’ providers, discussing antimicrobial appropriateness, de-escalation, duration of therapy, and intravenous to oral switching. Finally, a stewardship note for the Computerized Patient Record System (CPRS) was generated and included a template with reminders of clinical stability, duration of current therapy, and a request to discontinue therapy if the patient met criteria. For patients who remained hospitalized, this note was entered into CPRS on or about day 7 of antibiotic therapy; this required an electronic signature from the provider.

The VHSO Pharmacy and Therapeutics Committee approved both the provider education and the stewardship note in November 2014, and implementation of the stewardship intervention occurred immediately afterward. The pharmacy staff also was educated on the VHSO baseline data and stewardship efforts.

The primary outcome of the study was the change in days of total antibiotic treatment. Secondary outcomes included days of intravenous antibiotic therapy, days of inpatient oral therapy, mean length of stay (LOS), and number of outpatient antibiotic days once discharged. Incidence of CDI and 28-day readmissions were also evaluated. The VHSO Institutional Review Board approved these methods and the procedures that followed were in accord with the ethical standards of the VHSO Committee on Human Experimentation.

Statistical Analysis

All continuous variables are reported as mean ± standard deviation. Data analysis for significance was performed using a Student t test for continuous variables and a χ² test (or Fisher exact test) for categorical variables in R Foundation for Statistical Computing version 3.1.0. All samples were 2-tailed. A P value < .05 was considered statistically significant. Using the smaller of the 2 study populations, the investigators calculated that the given sample size of 88 in each group would provide 99% power to detect a 2-day difference in the primary endpoint at a 2-sided significance level of 5%.

Results

During the baseline assessment (group 1), 192 cases were reviewed with 103 meeting the inclusion criteria. Group 1 consisted of 85 cases of CAP and 18 cases of HCAP (mean age, 70.7 years). During the follow-up assessment (group 2), 168 cases were reviewed with 88 meeting the inclusion criteria. Group 2 consisted of 68 cases of CAP and 20 cases of HCAP (mean age, 70.8 years).

There was no difference in inpatient mortality rates between groups (3.1% vs 3.0%, P = .99). This mortality rate is consistent with published reports.²³ Empiric antibiotic selection was appropriate because there were no exclusions for drug/pathogen mismatch. Pneumonia severity was similar in both groups (Table).

The total duration of antibiotic treatment decreased significantly for CAP and HCAP (Figure). The observed median treatment days for groups 1 and 2 were 11 days and 8 days, respectively. Outpatient antibiotic days also decreased. Mean LOS was shorter in the follow-up group (4.9 ± 2.6 days vs 4.0 ± 2.6 days, P = .02). Length of IV antibiotic duration decreased. Oral antibiotic days while inpatient were not statistically different (1.5 ± 1.8 days vs 1.1 ± 1.5 days, P = .15). During the follow-up period, 26 stewardship notes were entered into CPRS; antibiotics were stopped in 65% of cases.

There were no recorded cases of CDI in either group. There were eleven 28-day readmissions in group 1, only 3 of which were due to infectious causes. One patient had a primary diagnosis of necrotizing pneumonia, 1 had Pseudomonas pneumonia, and 1 patient had a new lung mass and was diagnosed with postobstructive pneumonia. Of eight 28-day readmissions in group 2, only 2 resulted from infectious causes. One readmission primary diagnosis was sinusitis and 1 was recurrent pneumonia (of note, this patient received a 10-day treatment course for pneumonia on initial admission). Two patients died within 28 days of discharge in each group.

Discussion

Other multifaceted single-center interventions have been shown to be effective in large, teaching hospitals,^24,25 and it has been suggested that smaller, rural hospitals may be underserved in antimicrobial stewardship activities.^26,27 In the global struggle with antimicrobial resistance, McGregor and colleagues highlighted the importance of evaluating successful stewardship methods in an array of clinical settings to help tailor an approach for a specific type of facility.²⁸ To the authors knowledge, this is the first publication showing efficacy of such antimicrobial stewardship interventions specific to pneumonia therapy in a small, primary facility.

The intervention methods used at VHSO are supported by recent IDSA and Society for Healthcare Epidemiology of America guidelines for effective stewardship implementation.²⁹ Prospective audit and feedback is considered a core recommendation, whereas didactic education is recommended only in conjunction with other stewardship activities. Additionally, the guidelines recommend evaluating specific infectious disease syndromes, in this case uncomplicated pneumonia, to focus on specific treatment guidelines. Last, the results of the 3-part intervention can be used to aid in demonstrating facility improvement and encourage continued success.

Of note, VHSO has had established inpatient and outpatient clinical pharmacy roles for several years. Stewardship interventions already in place included an intravenous-to-oral antibiotic switch policy, automatic antibiotic stop dates, as well as pharmacist-driven vancomycin and aminoglycoside dosing. Prior to this multifaceted intervention specific to pneumonia duration, prospective audit and feedback interventions (verbal and written) also were common. The number of interventions specific to this study outside of the stewardship note was not recorded. Using rapid diagnostic testing and biomarkers to aid in stewardship activities at VHSO have been considered, but these tools are not available due to a lab personnel shortage.

Soliciting feedback from providers on their preferred stewardship strategy and perceived barriers was a key component of the educational intervention. Of equal importance was presenting providers with their baseline prescribing data to provide objective evidence of a problem. While all were familiar with existing treatment guidelines, some feedback indicated that it can be difficult to determine accurate antibiotic duration in CPRS. Prescribers reported that identifying antibiotic duration was especially challenging when antibiotics as well as providers change during an admission. Also frequently overlooked were antibiotics given in the emergency department. This could be a key area for clinical pharmacists’ intervention given their familiarity with the CPRS medication sections.

Charani and colleagues suggest that recognizing barriers to implementing best practices and adapting to the local facility culture is paramount for changing prescribing behaviors and developing a successful stewardship intervention.³⁰ At VHSO, the providers were presented with multiple stewardship options but agreed to the new note and template. This process gave providers a voice in selecting their own stewardship intervention. In a culture with no infectious disease physician to champion initiatives, the investigators felt that provider involvement in the intervention selection was unique and may have encouraged provider concurrence.

Although not directly targeted by the intervention strategies, average LOS was shorter in the follow-up group. According to investigators, frequent reminders of clinical stability in the stewardship notes may have influenced this. Even though the note was used only in patients who remained hospitalized for their entire treatment course, investigators felt that it still served as a reminder for prescribing habits as they were also able to show a decrease in outpatient prescription duration.

Limitations

Potential weaknesses of the study include changes in providers. During the transition between group 1 and group 2, 2 hospitalists left and 2 new hospitalists arrived. Given the small size of the staff, this could significantly impact prescribing trends. Another potential weakness is the high exclusion rate, although these rates were similar in both groups (46% group 1, 47% group 2). Furthermore, similar exclusion rates have been reported elsewhere.^24,25,31 The most common reasons for exclusion were complicated pneumonias (36%) and immunocompromised patients (18%). These patient populations were not evaluated in the current study, and optimal treatment durations are unknown. Hospital-acquired and ventilator-associated pneumonias also were excluded. Therefore, limitations in applicability of the results should be noted.

The authors acknowledge that, prior to this publication, the IDSA guidelines have removed the designation of HCAP as a separate clinical entity.⁴ However, this should not affect the significance of the intervention for treatment duration.

The study facility experienced a hiring freeze resulting in a 9.3% decrease in overall admissions from fiscal year 2013 to fiscal year 2015. This is likely why there were fewer admissions for pneumonia in group 2. Regardless, power analysis revealed the study was of adequate sample size to detect its primary outcome. It is possible that patients in either group could have sought health care at other facilities, making the CDI and readmission endpoints less inclusive.

The study was not of a scale to detect changes in antimicrobial resistance pressure or clinical outcomes. Cost savings were not analyzed. However, this study adds to the growing body of evidence that a structured intervention can result in positive outcomes at the facility level. This study shows that interventions targeting pneumonia treatment duration could feasibly be added to the menu of stewardship options available to smaller facilities.

Like other stewardship studies in the literature, the follow-up treatment duration, while improved, still exceeded those recommended in the IDSA guidelines. The investigators noted that not all providers were equal regarding change in prescribing habits, perhaps making the average duration longer. Additionally, the request to discontinue antibiotic therapy through the stewardship note could have been entered earlier (eg, as early as day 5 of therapy) to target the shortest effective date as recommended in the recent stewardship guidelines.²⁹ Future steps include continued feedback to providers on their progress in this area and encouragement to document day of antibiotic treatment in their daily progress notes.

Conclusion

This study showed a significant decrease in antibiotic duration for the treatment of uncomplicated pneumonia using a 3-part pharmacy intervention in a primary hospital setting. The investigators feel that each arm of the strategy was equally important and fewer interventions were not likely to be as effective.³² Although data collection for baseline prescribing and follow-up on outcomes may be a time-consuming task, it can be a valuable component of successful stewardship interventions.

Brain imaging should precede lumbar puncture in patients with focal neurologic deficits or immunodeficiency, or with altered mental status or seizures during the previous week. However, lumbar puncture can be safely done in most patients without first obtaining brain imaging. Empiric antibiotic and corticosteroid therapy must not be delayed; they should be started immediately after the lumber puncture is done, without waiting for the results. If the lumbar puncture is going to be delayed, these treatments should be started immediately after obtaining blood samples for culture.

A MEDICAL EMERGENCY

Bacterial meningitis is a medical emergency and requires prompt recognition and treatment. It is associated with a nearly 15% death rate as well as neurologic effects such as deafness, seizures, and cognitive decline in about the same percentage of patients.¹ Microbiologic information from lumbar puncture and cerebrospinal fluid analysis is an essential part of the initial workup, whenever possible. Lumbar puncture can be done safely at the bedside in most patients and so should not be delayed unless certain contraindications exist, as discussed below.²

INDICATIONS FOR BRAIN IMAGING BEFORE LUMBAR PUNCTURE

Table 1 lists common indications for brain imaging before lumbar puncture. However, there is a lack of good evidence to support them.

Current guidelines on acute bacterial meningitis from the Infectious Diseases Society of America recommend computed tomography (CT) of the brain before lumbar puncture in patients presenting with:

• Altered mental status
• A new focal neurologic deficit (eg, cranial nerve palsy, extremity weakness or drift, dysarthria, aphasia)
• Papilledema
• Seizure within the past week
• History of central nervous system disease (eg, stroke, tumor)
• Age 60 or older (likely because of the association with previous central nervous system disease)
• Immunocompromised state (due to human immunodeficiency virus infection, chemotherapy, or immunosuppressive drugs for transplant or rheumatologic disease)
• A high clinical suspicion for subarachnoid hemorrhage.^3–5

However, a normal result on head CT does not rule out the possibility of increased intracranial pressure and the risk of brain herniation. Actually, patients with acute bacterial meningitis are inherently at higher risk of spontaneous brain herniation even without lumbar puncture, and some cases of brain herniation after lumbar puncture could have represented the natural course of disease. Importantly, lumbar puncture may not be independently associated with the risk of brain herniation in patients with altered mental status (Glasgow Coma Scale score ≤ 8).⁶ A prospective randomized study is needed to better understand when to order brain imaging before lumbar puncture and when it is safe to proceed directly to lumbar puncture.

CONTRAINDICATIONS TO LUMBAR PUNCTURE

General contraindications to lumbar puncture are listed in Table 2.

Gopal et al³ analyzed clinical and radiographic data for 113 adults requiring urgent lumbar puncture and reported that altered mental status (likelihood ratio [LR] 2.2), focal neurologic deficit (LR 4.3), papilledema (LR 11.1), and clinical impression (LR 18.8) were associated with abnormalities on CT.

Hasbun et al⁴ prospectively analyzed whether clinical variables correlated with abnormal results of head CT that would preclude lumbar puncture in 301 patients requiring urgent lumbar puncture. They found that age 60 and older, immunodeficiency, a history of central nervous system disease, recent seizure (within 1 week), and neurologic deficits were associated with abnormal findings on head CT (eg, lesion with mass effect, midline shift). Importantly, absence of these characteristics had a 97% negative predictive value for abnormal findings on head CT. However, neither a normal head CT nor a normal clinical neurologic examination rules out increased intracranial pressure.^4,7

CHIEF CONCERNS ABOUT LUMBAR PUNCTURE

Lumbar puncture is generally well tolerated. Major complications are rare² and can be prevented by checking for contraindications and by using appropriate procedural hygiene and technique. Complications include pain at the puncture site, postprocedural headache, epidural hematoma, meningitis, osteomyelitis or discitis, bleeding, epidermoid tumor, and, most worrisome, brain herniation.

Brain herniation

Concern about causing brain herniation is the reason imaging may be ordered before lumbar puncture. Cerebral edema and increased intracranial pressure are common in patients with bacterial meningitis, as well as in other conditions such as bleeding, tumor, and abscess.¹ If intracranial pressure is elevated, lumbar puncture can cause cerebral herniation with further neurologic compromise and possibly death. Herniation is believed to be due to a sudden decrease in pressure in the spinal cord caused by removal of cerebrospinal fluid. However, the only information we have about this complication comes from case reports and case series, so we don’t really know how often it happens.

On the other hand, ordering ancillary tests before lumbar puncture and starting empiric antibiotics in patients with suspected bacterial meningitis may delay treatment and lead to worse clinical outcomes and thus should be discouraged.⁸

Also important to note is the lack of good data regarding the safety of lumbar puncture in patients with potential hemostatic problems (thrombocytopenia, coagulopathy). The recommendation not to do lumbar puncture in these situations (Table 1) is taken from neuraxial anesthesia guidelines.⁹ Further, a small retrospective study of thrombocytopenic oncology patients requiring lumbar puncture did not demonstrate an increased risk of complications.¹⁰

ADDITIONAL CONSIDERATIONS

In a retrospective study in 2015, Glimåker et al⁶ demonstrated that lumbar puncture without prior brain CT was safe in patients with suspected acute bacterial meningitis with moderate to severe impairment of mental status, and that it led to a shorter “door-to-antibiotic time.” Lumbar puncture before imaging was also associated with a concomitant decrease in the risk of death, with no increase in the rate of complications.⁶

If brain imaging is to be done before lumbar puncture, then blood cultures (and cultures of other fluids, whenever appropriate) should be collected and the patient should be started on empiric management for central nervous system infection first. CT evidence of diffuse cerebral edema, focal lesions with mass effect, and ventriculomegaly should be viewed as further contraindications to lumbar puncture.¹

Antibiotic therapy

When contraindications to lumbar puncture exist, the choice of antibiotic and the duration of therapy should be based on the patient’s history, demographics, risk factors, and microbiologic data from blood culture, urine culture, sputum culture, and detection of microbiological antigens.¹ The choice of antibiotic is beyond the scope of this article. However, empiric antibiotic therapy with a third-generation cephalosporin (eg, ceftriaxone) and vancomycin and anti-inflammatory therapy (dexamethasone) should in most cases be started immediately after collecting samples for blood culture and must not be delayed by neuroimaging and lumbar puncture with cerebrospinal fluid sampling, given the high rates of mortality and morbidity if treatment is delayed.^5,8

Consultation with the neurosurgery service regarding alternative brain ventricular fluid sampling should be considered.¹¹

Brain imaging should precede lumbar puncture in patients with focal neurologic deficits or immunodeficiency, or with altered mental status or seizures during the previous week. However, lumbar puncture can be safely done in most patients without first obtaining brain imaging. Empiric antibiotic and corticosteroid therapy must not be delayed; they should be started immediately after the lumber puncture is done, without waiting for the results. If the lumbar puncture is going to be delayed, these treatments should be started immediately after obtaining blood samples for culture.

A MEDICAL EMERGENCY

Bacterial meningitis is a medical emergency and requires prompt recognition and treatment. It is associated with a nearly 15% death rate as well as neurologic effects such as deafness, seizures, and cognitive decline in about the same percentage of patients.¹ Microbiologic information from lumbar puncture and cerebrospinal fluid analysis is an essential part of the initial workup, whenever possible. Lumbar puncture can be done safely at the bedside in most patients and so should not be delayed unless certain contraindications exist, as discussed below.²

INDICATIONS FOR BRAIN IMAGING BEFORE LUMBAR PUNCTURE

Table 1 lists common indications for brain imaging before lumbar puncture. However, there is a lack of good evidence to support them.

Current guidelines on acute bacterial meningitis from the Infectious Diseases Society of America recommend computed tomography (CT) of the brain before lumbar puncture in patients presenting with:

• Altered mental status
• A new focal neurologic deficit (eg, cranial nerve palsy, extremity weakness or drift, dysarthria, aphasia)
• Papilledema
• Seizure within the past week
• History of central nervous system disease (eg, stroke, tumor)
• Age 60 or older (likely because of the association with previous central nervous system disease)
• Immunocompromised state (due to human immunodeficiency virus infection, chemotherapy, or immunosuppressive drugs for transplant or rheumatologic disease)
• A high clinical suspicion for subarachnoid hemorrhage.^3–5

However, a normal result on head CT does not rule out the possibility of increased intracranial pressure and the risk of brain herniation. Actually, patients with acute bacterial meningitis are inherently at higher risk of spontaneous brain herniation even without lumbar puncture, and some cases of brain herniation after lumbar puncture could have represented the natural course of disease. Importantly, lumbar puncture may not be independently associated with the risk of brain herniation in patients with altered mental status (Glasgow Coma Scale score ≤ 8).⁶ A prospective randomized study is needed to better understand when to order brain imaging before lumbar puncture and when it is safe to proceed directly to lumbar puncture.

CONTRAINDICATIONS TO LUMBAR PUNCTURE

General contraindications to lumbar puncture are listed in Table 2.

Gopal et al³ analyzed clinical and radiographic data for 113 adults requiring urgent lumbar puncture and reported that altered mental status (likelihood ratio [LR] 2.2), focal neurologic deficit (LR 4.3), papilledema (LR 11.1), and clinical impression (LR 18.8) were associated with abnormalities on CT.

Hasbun et al⁴ prospectively analyzed whether clinical variables correlated with abnormal results of head CT that would preclude lumbar puncture in 301 patients requiring urgent lumbar puncture. They found that age 60 and older, immunodeficiency, a history of central nervous system disease, recent seizure (within 1 week), and neurologic deficits were associated with abnormal findings on head CT (eg, lesion with mass effect, midline shift). Importantly, absence of these characteristics had a 97% negative predictive value for abnormal findings on head CT. However, neither a normal head CT nor a normal clinical neurologic examination rules out increased intracranial pressure.^4,7

CHIEF CONCERNS ABOUT LUMBAR PUNCTURE

Lumbar puncture is generally well tolerated. Major complications are rare² and can be prevented by checking for contraindications and by using appropriate procedural hygiene and technique. Complications include pain at the puncture site, postprocedural headache, epidural hematoma, meningitis, osteomyelitis or discitis, bleeding, epidermoid tumor, and, most worrisome, brain herniation.

Brain herniation

Concern about causing brain herniation is the reason imaging may be ordered before lumbar puncture. Cerebral edema and increased intracranial pressure are common in patients with bacterial meningitis, as well as in other conditions such as bleeding, tumor, and abscess.¹ If intracranial pressure is elevated, lumbar puncture can cause cerebral herniation with further neurologic compromise and possibly death. Herniation is believed to be due to a sudden decrease in pressure in the spinal cord caused by removal of cerebrospinal fluid. However, the only information we have about this complication comes from case reports and case series, so we don’t really know how often it happens.

On the other hand, ordering ancillary tests before lumbar puncture and starting empiric antibiotics in patients with suspected bacterial meningitis may delay treatment and lead to worse clinical outcomes and thus should be discouraged.⁸

Also important to note is the lack of good data regarding the safety of lumbar puncture in patients with potential hemostatic problems (thrombocytopenia, coagulopathy). The recommendation not to do lumbar puncture in these situations (Table 1) is taken from neuraxial anesthesia guidelines.⁹ Further, a small retrospective study of thrombocytopenic oncology patients requiring lumbar puncture did not demonstrate an increased risk of complications.¹⁰

ADDITIONAL CONSIDERATIONS

In a retrospective study in 2015, Glimåker et al⁶ demonstrated that lumbar puncture without prior brain CT was safe in patients with suspected acute bacterial meningitis with moderate to severe impairment of mental status, and that it led to a shorter “door-to-antibiotic time.” Lumbar puncture before imaging was also associated with a concomitant decrease in the risk of death, with no increase in the rate of complications.⁶

If brain imaging is to be done before lumbar puncture, then blood cultures (and cultures of other fluids, whenever appropriate) should be collected and the patient should be started on empiric management for central nervous system infection first. CT evidence of diffuse cerebral edema, focal lesions with mass effect, and ventriculomegaly should be viewed as further contraindications to lumbar puncture.¹

Antibiotic therapy

When contraindications to lumbar puncture exist, the choice of antibiotic and the duration of therapy should be based on the patient’s history, demographics, risk factors, and microbiologic data from blood culture, urine culture, sputum culture, and detection of microbiological antigens.¹ The choice of antibiotic is beyond the scope of this article. However, empiric antibiotic therapy with a third-generation cephalosporin (eg, ceftriaxone) and vancomycin and anti-inflammatory therapy (dexamethasone) should in most cases be started immediately after collecting samples for blood culture and must not be delayed by neuroimaging and lumbar puncture with cerebrospinal fluid sampling, given the high rates of mortality and morbidity if treatment is delayed.^5,8

Consultation with the neurosurgery service regarding alternative brain ventricular fluid sampling should be considered.¹¹

Brain imaging should precede lumbar puncture in patients with focal neurologic deficits or immunodeficiency, or with altered mental status or seizures during the previous week. However, lumbar puncture can be safely done in most patients without first obtaining brain imaging. Empiric antibiotic and corticosteroid therapy must not be delayed; they should be started immediately after the lumber puncture is done, without waiting for the results. If the lumbar puncture is going to be delayed, these treatments should be started immediately after obtaining blood samples for culture.

A MEDICAL EMERGENCY

Bacterial meningitis is a medical emergency and requires prompt recognition and treatment. It is associated with a nearly 15% death rate as well as neurologic effects such as deafness, seizures, and cognitive decline in about the same percentage of patients.¹ Microbiologic information from lumbar puncture and cerebrospinal fluid analysis is an essential part of the initial workup, whenever possible. Lumbar puncture can be done safely at the bedside in most patients and so should not be delayed unless certain contraindications exist, as discussed below.²

INDICATIONS FOR BRAIN IMAGING BEFORE LUMBAR PUNCTURE

Table 1 lists common indications for brain imaging before lumbar puncture. However, there is a lack of good evidence to support them.

Current guidelines on acute bacterial meningitis from the Infectious Diseases Society of America recommend computed tomography (CT) of the brain before lumbar puncture in patients presenting with:

• Altered mental status
• A new focal neurologic deficit (eg, cranial nerve palsy, extremity weakness or drift, dysarthria, aphasia)
• Papilledema
• Seizure within the past week
• History of central nervous system disease (eg, stroke, tumor)
• Age 60 or older (likely because of the association with previous central nervous system disease)
• Immunocompromised state (due to human immunodeficiency virus infection, chemotherapy, or immunosuppressive drugs for transplant or rheumatologic disease)
• A high clinical suspicion for subarachnoid hemorrhage.^3–5

However, a normal result on head CT does not rule out the possibility of increased intracranial pressure and the risk of brain herniation. Actually, patients with acute bacterial meningitis are inherently at higher risk of spontaneous brain herniation even without lumbar puncture, and some cases of brain herniation after lumbar puncture could have represented the natural course of disease. Importantly, lumbar puncture may not be independently associated with the risk of brain herniation in patients with altered mental status (Glasgow Coma Scale score ≤ 8).⁶ A prospective randomized study is needed to better understand when to order brain imaging before lumbar puncture and when it is safe to proceed directly to lumbar puncture.

CONTRAINDICATIONS TO LUMBAR PUNCTURE

General contraindications to lumbar puncture are listed in Table 2.

Gopal et al³ analyzed clinical and radiographic data for 113 adults requiring urgent lumbar puncture and reported that altered mental status (likelihood ratio [LR] 2.2), focal neurologic deficit (LR 4.3), papilledema (LR 11.1), and clinical impression (LR 18.8) were associated with abnormalities on CT.

Hasbun et al⁴ prospectively analyzed whether clinical variables correlated with abnormal results of head CT that would preclude lumbar puncture in 301 patients requiring urgent lumbar puncture. They found that age 60 and older, immunodeficiency, a history of central nervous system disease, recent seizure (within 1 week), and neurologic deficits were associated with abnormal findings on head CT (eg, lesion with mass effect, midline shift). Importantly, absence of these characteristics had a 97% negative predictive value for abnormal findings on head CT. However, neither a normal head CT nor a normal clinical neurologic examination rules out increased intracranial pressure.^4,7

CHIEF CONCERNS ABOUT LUMBAR PUNCTURE

Lumbar puncture is generally well tolerated. Major complications are rare² and can be prevented by checking for contraindications and by using appropriate procedural hygiene and technique. Complications include pain at the puncture site, postprocedural headache, epidural hematoma, meningitis, osteomyelitis or discitis, bleeding, epidermoid tumor, and, most worrisome, brain herniation.

Brain herniation

Concern about causing brain herniation is the reason imaging may be ordered before lumbar puncture. Cerebral edema and increased intracranial pressure are common in patients with bacterial meningitis, as well as in other conditions such as bleeding, tumor, and abscess.¹ If intracranial pressure is elevated, lumbar puncture can cause cerebral herniation with further neurologic compromise and possibly death. Herniation is believed to be due to a sudden decrease in pressure in the spinal cord caused by removal of cerebrospinal fluid. However, the only information we have about this complication comes from case reports and case series, so we don’t really know how often it happens.

On the other hand, ordering ancillary tests before lumbar puncture and starting empiric antibiotics in patients with suspected bacterial meningitis may delay treatment and lead to worse clinical outcomes and thus should be discouraged.⁸

Also important to note is the lack of good data regarding the safety of lumbar puncture in patients with potential hemostatic problems (thrombocytopenia, coagulopathy). The recommendation not to do lumbar puncture in these situations (Table 1) is taken from neuraxial anesthesia guidelines.⁹ Further, a small retrospective study of thrombocytopenic oncology patients requiring lumbar puncture did not demonstrate an increased risk of complications.¹⁰

ADDITIONAL CONSIDERATIONS

In a retrospective study in 2015, Glimåker et al⁶ demonstrated that lumbar puncture without prior brain CT was safe in patients with suspected acute bacterial meningitis with moderate to severe impairment of mental status, and that it led to a shorter “door-to-antibiotic time.” Lumbar puncture before imaging was also associated with a concomitant decrease in the risk of death, with no increase in the rate of complications.⁶

If brain imaging is to be done before lumbar puncture, then blood cultures (and cultures of other fluids, whenever appropriate) should be collected and the patient should be started on empiric management for central nervous system infection first. CT evidence of diffuse cerebral edema, focal lesions with mass effect, and ventriculomegaly should be viewed as further contraindications to lumbar puncture.¹

Antibiotic therapy

When contraindications to lumbar puncture exist, the choice of antibiotic and the duration of therapy should be based on the patient’s history, demographics, risk factors, and microbiologic data from blood culture, urine culture, sputum culture, and detection of microbiological antigens.¹ The choice of antibiotic is beyond the scope of this article. However, empiric antibiotic therapy with a third-generation cephalosporin (eg, ceftriaxone) and vancomycin and anti-inflammatory therapy (dexamethasone) should in most cases be started immediately after collecting samples for blood culture and must not be delayed by neuroimaging and lumbar puncture with cerebrospinal fluid sampling, given the high rates of mortality and morbidity if treatment is delayed.^5,8

Consultation with the neurosurgery service regarding alternative brain ventricular fluid sampling should be considered.¹¹

A 39-year-old woman with a history of human immunodeficiency virus (HIV) and hepatitis B virus infection was brought to the emergency department for evaluation of seizures, which had started a few days earlier. She was born and raised in a state bordering the Ohio River, an area where Histoplasma capsulatum is endemic. She denied any recent travel.

Her vital signs and neurologic examination were normal. Computed tomography of the head showed two areas of increased attenuation anterior to the frontal horns. To better characterize those lesions, magnetic resonance imaging (MRI) with contrast was done, which showed about a dozen 1-cm ring-enhancing lesions in the right cerebellum and both cerebral hemispheres (Figure 1).

Results of a complete blood cell count, metabolic profile, and chest radiography were normal. Her CD4 count was 428/μL (reference range 533–1,674) and 20% (60%–89%); her HIV viral load was 326,000 copies/mL.

She was initially treated empirically with sulfadiazine, pyrimethamine, and leukovorin for possible toxoplasmosis, which is the most common cause of ring-enhancing brain lesions in HIV patients. In the meantime, cerebrospinal fluid, blood, and urine were sent for a detailed workup for fungi, including Histoplasma. Results of the Histoplasma antibody and antigen studies of the serum, urine, and cerebrospinal fluid were positive, while cerebrospinal fluid testing for Toxoplasma by polymerase chain reaction testing was negative. Empirical treatment for toxoplasmosis was stopped and amphotericin B was started to treat disseminated histoplasmosis.

During her hospital course, she underwent brain biopsy via right frontotemporal craniotomy with resection of right frontal lesions. Pathologic study showed partially organizing abscesses with central necrosis (Figure 2), microscopy with Grocott-Gomori methenamine silver stain was positive for budding yeast forms consistent with H capsulatum (Figure 3), and special stain for acid-fast bacilli was negative for mycobacteria. Cultures of the brain biopsy specimen, blood, and cerebrospinal fluid for fungi, acid-fast bacilli, and bacteria did not reveal any growth after 28 days.

The patient was discharged home with instructions to take amphotericin B for a total of 6 weeks and then itraconazole. About 1 year later, she remained free of symptoms, although repeat MRI did not show any significant change in the size or number of histoplasmomas.

She did not comply well with her HIV treatment, and her immune status did not improve, so we decided to continue her itraconazole treatment for more than 1 year.

CEREBRAL HISTOPLASMOMA

The term “histoplasmoma” was introduced by Shapiro et al¹ in 1955, when they first described numerous focal areas of softening, up to 1 cm in diameter, scattered throughout the brain at autopsy in a 41-year-old man who had died of disseminated histoplasmosis. They coined the word to describe these discrete areas of necrosis that might resemble tumors on the basis of their size, location, and capability of causing increased intracranial pressure.

Central nervous system involvement can either be a manifestation of disseminated disease or present as an isolated illness.² It occurs in 5% to 10% of cases of disseminated histoplasmosis.³ Histoplasmosis of the central nervous system can have different manifestations; the most common presentation is chronic meningitis.⁴

Laboratory diagnosis is based on detecting H capsulatum antigen and antibody in the urine, blood, and cerebrospinal fluid. Tissue biopsy (histopathology) as well as cultures of tissue samples or body fluids may also establish the diagnosis.⁴

Toxoplasmosis and primary central nervous system lymphoma are the most common causes of brain ring-enhancing lesions in HIV patients in developed countries, while in the developing world neurocysticercosis and tuberculomas are more common.^5,6 Much less common causes include brain abscesses secondary to bacterial infections (pyogenic abscess),⁷ cryptococcomas,⁸ syphilitic cerebral gummata,⁹ primary brain tumors (gliomas), and metastases.¹⁰

Compared with other forms of the disease, histoplasmosis of the central nervous system has higher rates of treatment failure and relapse, so treatment should be prolonged and aggressive.^2,3 The cure rate with amphotericin B ranges from 33% to 61%, and higher doses produce better response rates.³

Current treatment recommendations are based on 2007 guidelines of the Infectious Diseases Society of America.¹¹ Liposomal amphotericin B is the drug of choice because it achieves higher concentrations in the central nervous system than other drugs and is less toxic. It is given for 4 to 6 weeks, followed by itraconazole for at least 1 year and until the cerebrospinal fluid Histoplasma antigen test is negative and other cerebrospinal fluid abnormalities are resolved.

In patients who have primary disseminated histoplasmosis that includes the central nervous system, itraconazole can be given for more than 1 year or until immune recovery is achieved—or lifelong if necessary.^2,12 Long-term suppressive antifungal therapy also should be considered in patients for whom appropriate initial therapy fails.²

Nephrotoxicity (acute kidney injury, hypokalemia, and hypomagnesemia), infusion-related drug reactions, and rash are among the well-described side effects of amphotericin B. Maintenance of intravascular volume and replacement of electrolytes should be an integral part of the amphotericin B treatment regimen.¹³

TAKE-AWAY POINTS

• Histoplasmomas should be considered in the differential diagnosis of ring-enhancing lesions of the central nervous system, along with toxoplasmosis and primary central nervous system lymphoma. This will allow timely initiation of the diagnostic workup, avoiding unnecessary and potentially risky interventions and delays in starting targeted antifungal therapy.
• There is no single gold standard test for central nervous system histoplasmosis. Rather, the final diagnosis is based on the combination of clinical, laboratory, and radiologic findings.

Acknowledgment: Library research assistance provided by HSHS St. John’s Hospital Health Sciences Library staff.

A 39-year-old woman with a history of human immunodeficiency virus (HIV) and hepatitis B virus infection was brought to the emergency department for evaluation of seizures, which had started a few days earlier. She was born and raised in a state bordering the Ohio River, an area where Histoplasma capsulatum is endemic. She denied any recent travel.

Her vital signs and neurologic examination were normal. Computed tomography of the head showed two areas of increased attenuation anterior to the frontal horns. To better characterize those lesions, magnetic resonance imaging (MRI) with contrast was done, which showed about a dozen 1-cm ring-enhancing lesions in the right cerebellum and both cerebral hemispheres (Figure 1).

Results of a complete blood cell count, metabolic profile, and chest radiography were normal. Her CD4 count was 428/μL (reference range 533–1,674) and 20% (60%–89%); her HIV viral load was 326,000 copies/mL.

She was initially treated empirically with sulfadiazine, pyrimethamine, and leukovorin for possible toxoplasmosis, which is the most common cause of ring-enhancing brain lesions in HIV patients. In the meantime, cerebrospinal fluid, blood, and urine were sent for a detailed workup for fungi, including Histoplasma. Results of the Histoplasma antibody and antigen studies of the serum, urine, and cerebrospinal fluid were positive, while cerebrospinal fluid testing for Toxoplasma by polymerase chain reaction testing was negative. Empirical treatment for toxoplasmosis was stopped and amphotericin B was started to treat disseminated histoplasmosis.

During her hospital course, she underwent brain biopsy via right frontotemporal craniotomy with resection of right frontal lesions. Pathologic study showed partially organizing abscesses with central necrosis (Figure 2), microscopy with Grocott-Gomori methenamine silver stain was positive for budding yeast forms consistent with H capsulatum (Figure 3), and special stain for acid-fast bacilli was negative for mycobacteria. Cultures of the brain biopsy specimen, blood, and cerebrospinal fluid for fungi, acid-fast bacilli, and bacteria did not reveal any growth after 28 days.

The patient was discharged home with instructions to take amphotericin B for a total of 6 weeks and then itraconazole. About 1 year later, she remained free of symptoms, although repeat MRI did not show any significant change in the size or number of histoplasmomas.

She did not comply well with her HIV treatment, and her immune status did not improve, so we decided to continue her itraconazole treatment for more than 1 year.

CEREBRAL HISTOPLASMOMA

The term “histoplasmoma” was introduced by Shapiro et al¹ in 1955, when they first described numerous focal areas of softening, up to 1 cm in diameter, scattered throughout the brain at autopsy in a 41-year-old man who had died of disseminated histoplasmosis. They coined the word to describe these discrete areas of necrosis that might resemble tumors on the basis of their size, location, and capability of causing increased intracranial pressure.

Central nervous system involvement can either be a manifestation of disseminated disease or present as an isolated illness.² It occurs in 5% to 10% of cases of disseminated histoplasmosis.³ Histoplasmosis of the central nervous system can have different manifestations; the most common presentation is chronic meningitis.⁴

Laboratory diagnosis is based on detecting H capsulatum antigen and antibody in the urine, blood, and cerebrospinal fluid. Tissue biopsy (histopathology) as well as cultures of tissue samples or body fluids may also establish the diagnosis.⁴

Toxoplasmosis and primary central nervous system lymphoma are the most common causes of brain ring-enhancing lesions in HIV patients in developed countries, while in the developing world neurocysticercosis and tuberculomas are more common.^5,6 Much less common causes include brain abscesses secondary to bacterial infections (pyogenic abscess),⁷ cryptococcomas,⁸ syphilitic cerebral gummata,⁹ primary brain tumors (gliomas), and metastases.¹⁰

Compared with other forms of the disease, histoplasmosis of the central nervous system has higher rates of treatment failure and relapse, so treatment should be prolonged and aggressive.^2,3 The cure rate with amphotericin B ranges from 33% to 61%, and higher doses produce better response rates.³

Current treatment recommendations are based on 2007 guidelines of the Infectious Diseases Society of America.¹¹ Liposomal amphotericin B is the drug of choice because it achieves higher concentrations in the central nervous system than other drugs and is less toxic. It is given for 4 to 6 weeks, followed by itraconazole for at least 1 year and until the cerebrospinal fluid Histoplasma antigen test is negative and other cerebrospinal fluid abnormalities are resolved.

In patients who have primary disseminated histoplasmosis that includes the central nervous system, itraconazole can be given for more than 1 year or until immune recovery is achieved—or lifelong if necessary.^2,12 Long-term suppressive antifungal therapy also should be considered in patients for whom appropriate initial therapy fails.²

Nephrotoxicity (acute kidney injury, hypokalemia, and hypomagnesemia), infusion-related drug reactions, and rash are among the well-described side effects of amphotericin B. Maintenance of intravascular volume and replacement of electrolytes should be an integral part of the amphotericin B treatment regimen.¹³

TAKE-AWAY POINTS

• Histoplasmomas should be considered in the differential diagnosis of ring-enhancing lesions of the central nervous system, along with toxoplasmosis and primary central nervous system lymphoma. This will allow timely initiation of the diagnostic workup, avoiding unnecessary and potentially risky interventions and delays in starting targeted antifungal therapy.
• There is no single gold standard test for central nervous system histoplasmosis. Rather, the final diagnosis is based on the combination of clinical, laboratory, and radiologic findings.

Acknowledgment: Library research assistance provided by HSHS St. John’s Hospital Health Sciences Library staff.

A 39-year-old woman with a history of human immunodeficiency virus (HIV) and hepatitis B virus infection was brought to the emergency department for evaluation of seizures, which had started a few days earlier. She was born and raised in a state bordering the Ohio River, an area where Histoplasma capsulatum is endemic. She denied any recent travel.

Her vital signs and neurologic examination were normal. Computed tomography of the head showed two areas of increased attenuation anterior to the frontal horns. To better characterize those lesions, magnetic resonance imaging (MRI) with contrast was done, which showed about a dozen 1-cm ring-enhancing lesions in the right cerebellum and both cerebral hemispheres (Figure 1).

Results of a complete blood cell count, metabolic profile, and chest radiography were normal. Her CD4 count was 428/μL (reference range 533–1,674) and 20% (60%–89%); her HIV viral load was 326,000 copies/mL.

She was initially treated empirically with sulfadiazine, pyrimethamine, and leukovorin for possible toxoplasmosis, which is the most common cause of ring-enhancing brain lesions in HIV patients. In the meantime, cerebrospinal fluid, blood, and urine were sent for a detailed workup for fungi, including Histoplasma. Results of the Histoplasma antibody and antigen studies of the serum, urine, and cerebrospinal fluid were positive, while cerebrospinal fluid testing for Toxoplasma by polymerase chain reaction testing was negative. Empirical treatment for toxoplasmosis was stopped and amphotericin B was started to treat disseminated histoplasmosis.

During her hospital course, she underwent brain biopsy via right frontotemporal craniotomy with resection of right frontal lesions. Pathologic study showed partially organizing abscesses with central necrosis (Figure 2), microscopy with Grocott-Gomori methenamine silver stain was positive for budding yeast forms consistent with H capsulatum (Figure 3), and special stain for acid-fast bacilli was negative for mycobacteria. Cultures of the brain biopsy specimen, blood, and cerebrospinal fluid for fungi, acid-fast bacilli, and bacteria did not reveal any growth after 28 days.

The patient was discharged home with instructions to take amphotericin B for a total of 6 weeks and then itraconazole. About 1 year later, she remained free of symptoms, although repeat MRI did not show any significant change in the size or number of histoplasmomas.

She did not comply well with her HIV treatment, and her immune status did not improve, so we decided to continue her itraconazole treatment for more than 1 year.

CEREBRAL HISTOPLASMOMA

The term “histoplasmoma” was introduced by Shapiro et al¹ in 1955, when they first described numerous focal areas of softening, up to 1 cm in diameter, scattered throughout the brain at autopsy in a 41-year-old man who had died of disseminated histoplasmosis. They coined the word to describe these discrete areas of necrosis that might resemble tumors on the basis of their size, location, and capability of causing increased intracranial pressure.

Central nervous system involvement can either be a manifestation of disseminated disease or present as an isolated illness.² It occurs in 5% to 10% of cases of disseminated histoplasmosis.³ Histoplasmosis of the central nervous system can have different manifestations; the most common presentation is chronic meningitis.⁴

Laboratory diagnosis is based on detecting H capsulatum antigen and antibody in the urine, blood, and cerebrospinal fluid. Tissue biopsy (histopathology) as well as cultures of tissue samples or body fluids may also establish the diagnosis.⁴

Toxoplasmosis and primary central nervous system lymphoma are the most common causes of brain ring-enhancing lesions in HIV patients in developed countries, while in the developing world neurocysticercosis and tuberculomas are more common.^5,6 Much less common causes include brain abscesses secondary to bacterial infections (pyogenic abscess),⁷ cryptococcomas,⁸ syphilitic cerebral gummata,⁹ primary brain tumors (gliomas), and metastases.¹⁰

Compared with other forms of the disease, histoplasmosis of the central nervous system has higher rates of treatment failure and relapse, so treatment should be prolonged and aggressive.^2,3 The cure rate with amphotericin B ranges from 33% to 61%, and higher doses produce better response rates.³

Current treatment recommendations are based on 2007 guidelines of the Infectious Diseases Society of America.¹¹ Liposomal amphotericin B is the drug of choice because it achieves higher concentrations in the central nervous system than other drugs and is less toxic. It is given for 4 to 6 weeks, followed by itraconazole for at least 1 year and until the cerebrospinal fluid Histoplasma antigen test is negative and other cerebrospinal fluid abnormalities are resolved.

In patients who have primary disseminated histoplasmosis that includes the central nervous system, itraconazole can be given for more than 1 year or until immune recovery is achieved—or lifelong if necessary.^2,12 Long-term suppressive antifungal therapy also should be considered in patients for whom appropriate initial therapy fails.²

Nephrotoxicity (acute kidney injury, hypokalemia, and hypomagnesemia), infusion-related drug reactions, and rash are among the well-described side effects of amphotericin B. Maintenance of intravascular volume and replacement of electrolytes should be an integral part of the amphotericin B treatment regimen.¹³

TAKE-AWAY POINTS

• Histoplasmomas should be considered in the differential diagnosis of ring-enhancing lesions of the central nervous system, along with toxoplasmosis and primary central nervous system lymphoma. This will allow timely initiation of the diagnostic workup, avoiding unnecessary and potentially risky interventions and delays in starting targeted antifungal therapy.
• There is no single gold standard test for central nervous system histoplasmosis. Rather, the final diagnosis is based on the combination of clinical, laboratory, and radiologic findings.

Acknowledgment: Library research assistance provided by HSHS St. John’s Hospital Health Sciences Library staff.

Despite advances in therapy, more than 10% of patients with acute bacterial meningitis still die of it, and more suffer significant morbidity, including cognitive dysfunction and deafness. Well-defined protocols that include empiric antibiotics and systemic corticosteroids have improved the outcomes of patients with meningitis. But, as with other closed-space infections such as septic arthritis, any delay in providing appropriate antibiotic treatment is associated with a worse prognosis. In the case of bacterial meningitis, a retrospective analysis concluded that each hour of delay in delivering antibiotics and a corticosteroid can be associated with a relative (not absolute) increase in mortality of 13%.¹

The precise diagnosis of bacterial meningitis depends entirely on obtaining cerebrospinal fluid for analysis, including culture and antibiotic sensitivity testing. But that simple statement belies several current and historical complexities. From my experience, getting a prompt diagnostic lumbar puncture is not as simple as it once was.

Many hospitals have imposed patient safety initiatives, which overall have been beneficial but have had the effect that medical residents and probably even hospitalists in some medical centers are less frequently the ones doing interventional procedures. Some procedures, such as placement of pulmonary arterial catheters in the medical intensive care unit, have been shown to be less useful and to pose more risk than once believed. The tasks of placing other central lines and performing thoracenteses have been relegated to special procedure teams trained in using ultrasound guidance. Interventional radiologists now often do the visceral biopsies and lumbar punctures, and as a result, it is hoped that procedural complication rates will decline. On the other hand, these changes mean that medical residents and future staff are less experienced in performing these procedures, even though there are times that they are the only ones available to perform them. The result is a potential delay in performing a necessary lumbar puncture.

Another reason that a lumbar puncture may be delayed is concern over iatrogenic herniation if the procedure is done in a patient who has elevated intracranial pressure. We do not know precisely how often this occurs if there is an undiagnosed brain mass lesion such as an abscess, which can mimic bacterial meningitis, or a malignancy, and meningitis itself may be associated with herniation. Yet, for years physicians have hesitated to perform lumbar punctures in some patients without first ruling out a brain mass by computed tomography (CT), a diagnostic flow algorithm that often introduces at least an hour of delay in performing the procedure and in obtaining cultures before starting antibiotics.

When I was in training, we were perhaps more cavalier, appropriately or not. If the history and examination did not suggest a brain mass and the patient had retinal vein pulsations without papilledema, we did the lumbar puncture. It was a different time, and there was a different perspective on risks and benefits. More recently, the trend has been to obtain a CT scan before a lumbar puncture in several subsets of patients.

A 2015 analysis from Sweden¹ showed that we can probably do a lumbar puncture for suspected bacterial meningitis without first doing a CT scan in most patients, even in patients with moderately impaired mentation. Perhaps some other concerns can also be assuaged if evaluated, but we don’t have data. Mirrakhimov et al, in this issue of the Journal, review the current evidence on when to do CT before a lumbar puncture, even if it may significantly delay the procedure and the timely delivery of antibiotics. A perfect algorithm that balances the risks of delaying treatment, initiating less-than-ideal empiric antibiotics potentially without definitive culture, and inducing complications from a procedure done promptly may well be impossible to develop. Evidence helps us refine the diagnostic approach, but with limited data, some important decisions unfortunately remain within the “art” rather than the science of medicine.

Despite advances in therapy, more than 10% of patients with acute bacterial meningitis still die of it, and more suffer significant morbidity, including cognitive dysfunction and deafness. Well-defined protocols that include empiric antibiotics and systemic corticosteroids have improved the outcomes of patients with meningitis. But, as with other closed-space infections such as septic arthritis, any delay in providing appropriate antibiotic treatment is associated with a worse prognosis. In the case of bacterial meningitis, a retrospective analysis concluded that each hour of delay in delivering antibiotics and a corticosteroid can be associated with a relative (not absolute) increase in mortality of 13%.¹

The precise diagnosis of bacterial meningitis depends entirely on obtaining cerebrospinal fluid for analysis, including culture and antibiotic sensitivity testing. But that simple statement belies several current and historical complexities. From my experience, getting a prompt diagnostic lumbar puncture is not as simple as it once was.

Many hospitals have imposed patient safety initiatives, which overall have been beneficial but have had the effect that medical residents and probably even hospitalists in some medical centers are less frequently the ones doing interventional procedures. Some procedures, such as placement of pulmonary arterial catheters in the medical intensive care unit, have been shown to be less useful and to pose more risk than once believed. The tasks of placing other central lines and performing thoracenteses have been relegated to special procedure teams trained in using ultrasound guidance. Interventional radiologists now often do the visceral biopsies and lumbar punctures, and as a result, it is hoped that procedural complication rates will decline. On the other hand, these changes mean that medical residents and future staff are less experienced in performing these procedures, even though there are times that they are the only ones available to perform them. The result is a potential delay in performing a necessary lumbar puncture.

Another reason that a lumbar puncture may be delayed is concern over iatrogenic herniation if the procedure is done in a patient who has elevated intracranial pressure. We do not know precisely how often this occurs if there is an undiagnosed brain mass lesion such as an abscess, which can mimic bacterial meningitis, or a malignancy, and meningitis itself may be associated with herniation. Yet, for years physicians have hesitated to perform lumbar punctures in some patients without first ruling out a brain mass by computed tomography (CT), a diagnostic flow algorithm that often introduces at least an hour of delay in performing the procedure and in obtaining cultures before starting antibiotics.

When I was in training, we were perhaps more cavalier, appropriately or not. If the history and examination did not suggest a brain mass and the patient had retinal vein pulsations without papilledema, we did the lumbar puncture. It was a different time, and there was a different perspective on risks and benefits. More recently, the trend has been to obtain a CT scan before a lumbar puncture in several subsets of patients.

A 2015 analysis from Sweden¹ showed that we can probably do a lumbar puncture for suspected bacterial meningitis without first doing a CT scan in most patients, even in patients with moderately impaired mentation. Perhaps some other concerns can also be assuaged if evaluated, but we don’t have data. Mirrakhimov et al, in this issue of the Journal, review the current evidence on when to do CT before a lumbar puncture, even if it may significantly delay the procedure and the timely delivery of antibiotics. A perfect algorithm that balances the risks of delaying treatment, initiating less-than-ideal empiric antibiotics potentially without definitive culture, and inducing complications from a procedure done promptly may well be impossible to develop. Evidence helps us refine the diagnostic approach, but with limited data, some important decisions unfortunately remain within the “art” rather than the science of medicine.

Despite advances in therapy, more than 10% of patients with acute bacterial meningitis still die of it, and more suffer significant morbidity, including cognitive dysfunction and deafness. Well-defined protocols that include empiric antibiotics and systemic corticosteroids have improved the outcomes of patients with meningitis. But, as with other closed-space infections such as septic arthritis, any delay in providing appropriate antibiotic treatment is associated with a worse prognosis. In the case of bacterial meningitis, a retrospective analysis concluded that each hour of delay in delivering antibiotics and a corticosteroid can be associated with a relative (not absolute) increase in mortality of 13%.¹

The precise diagnosis of bacterial meningitis depends entirely on obtaining cerebrospinal fluid for analysis, including culture and antibiotic sensitivity testing. But that simple statement belies several current and historical complexities. From my experience, getting a prompt diagnostic lumbar puncture is not as simple as it once was.

Many hospitals have imposed patient safety initiatives, which overall have been beneficial but have had the effect that medical residents and probably even hospitalists in some medical centers are less frequently the ones doing interventional procedures. Some procedures, such as placement of pulmonary arterial catheters in the medical intensive care unit, have been shown to be less useful and to pose more risk than once believed. The tasks of placing other central lines and performing thoracenteses have been relegated to special procedure teams trained in using ultrasound guidance. Interventional radiologists now often do the visceral biopsies and lumbar punctures, and as a result, it is hoped that procedural complication rates will decline. On the other hand, these changes mean that medical residents and future staff are less experienced in performing these procedures, even though there are times that they are the only ones available to perform them. The result is a potential delay in performing a necessary lumbar puncture.

Another reason that a lumbar puncture may be delayed is concern over iatrogenic herniation if the procedure is done in a patient who has elevated intracranial pressure. We do not know precisely how often this occurs if there is an undiagnosed brain mass lesion such as an abscess, which can mimic bacterial meningitis, or a malignancy, and meningitis itself may be associated with herniation. Yet, for years physicians have hesitated to perform lumbar punctures in some patients without first ruling out a brain mass by computed tomography (CT), a diagnostic flow algorithm that often introduces at least an hour of delay in performing the procedure and in obtaining cultures before starting antibiotics.

When I was in training, we were perhaps more cavalier, appropriately or not. If the history and examination did not suggest a brain mass and the patient had retinal vein pulsations without papilledema, we did the lumbar puncture. It was a different time, and there was a different perspective on risks and benefits. More recently, the trend has been to obtain a CT scan before a lumbar puncture in several subsets of patients.

A 2015 analysis from Sweden¹ showed that we can probably do a lumbar puncture for suspected bacterial meningitis without first doing a CT scan in most patients, even in patients with moderately impaired mentation. Perhaps some other concerns can also be assuaged if evaluated, but we don’t have data. Mirrakhimov et al, in this issue of the Journal, review the current evidence on when to do CT before a lumbar puncture, even if it may significantly delay the procedure and the timely delivery of antibiotics. A perfect algorithm that balances the risks of delaying treatment, initiating less-than-ideal empiric antibiotics potentially without definitive culture, and inducing complications from a procedure done promptly may well be impossible to develop. Evidence helps us refine the diagnostic approach, but with limited data, some important decisions unfortunately remain within the “art” rather than the science of medicine.

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

Click here to access the February 2017 Digital Edition.

Table of Contents

• The VA Is Not Just a Hospital, It Is a Community
• Minimizing Postdisaster Fatalities
• A Primary Hospital Antimicrobial Stewardship Intervention on Pneumonia Treatment Duration
• Review of the Long-Term Effects of Proton Pump Inhibitors
• Malnutrition as a Fall Risk Factor
• Sleep-Disordered Breathing in the Active-Duty Military Population and Its Civilian Care Cost
• Anticoagulation Management Outcomes in Veterans: Office vs Telephone Visits
• Allergic Reaction to Phenylephrine
• FDA Updates
• COVER to COVER: Connecting Older Veterans (Especially Rural) to Community or Veteran-Eligible Resources

Click here to access the February 2017 Digital Edition.

Table of Contents

• The VA Is Not Just a Hospital, It Is a Community
• Minimizing Postdisaster Fatalities
• A Primary Hospital Antimicrobial Stewardship Intervention on Pneumonia Treatment Duration
• Review of the Long-Term Effects of Proton Pump Inhibitors
• Malnutrition as a Fall Risk Factor
• Sleep-Disordered Breathing in the Active-Duty Military Population and Its Civilian Care Cost
• Anticoagulation Management Outcomes in Veterans: Office vs Telephone Visits
• Allergic Reaction to Phenylephrine
• FDA Updates
• COVER to COVER: Connecting Older Veterans (Especially Rural) to Community or Veteran-Eligible Resources

Click here to access the February 2017 Digital Edition.

Table of Contents

• The VA Is Not Just a Hospital, It Is a Community
• Minimizing Postdisaster Fatalities
• A Primary Hospital Antimicrobial Stewardship Intervention on Pneumonia Treatment Duration
• Review of the Long-Term Effects of Proton Pump Inhibitors
• Malnutrition as a Fall Risk Factor
• Sleep-Disordered Breathing in the Active-Duty Military Population and Its Civilian Care Cost
• Anticoagulation Management Outcomes in Veterans: Office vs Telephone Visits
• Allergic Reaction to Phenylephrine
• FDA Updates
• COVER to COVER: Connecting Older Veterans (Especially Rural) to Community or Veteran-Eligible Resources

A single cough can propel as many as 3,000 droplets into the air at a velocity of 6 to 28 m/s. The droplets travel in what classic fluid mechanics calls a “2-stage jet”: the starting jet (when the cough starts) and interrupted jet (when the cough stops). After the original cough ends, a “leading vortex” carries particles forward, but as the momentum slows, particles fall out of the jet according to researchers from the University of Hong Kong and Shenzhen Institute of Research and Innovation, both in China, who studied cough trajectories and the implications for disease transmission in buildings.

Once the penetration velocity drops below 0.01 m/s, environmental factors, such as ventilation and human body temperature, begin to influence the flow. Beyond 1 to 2 m, the exhaled air stream dissolves into the room airflow, and the pathogen-containing droplets or droplet nuclei are dispersed according to the global airflow in the room.

When a cough doesn’t last long, the researchers say, the velocity of fine particles decays significantly after the jet is interrupted. However, even short coughs have consequences: Pathogen-containing droplets as large as ≥ 5 µm in diameter can be directly deposited on the nasal or oral mucosa of a nearby “new host.”

But coughs differ in many ways, including how far and wide they send the droplets. The researchers conducted experiments to help determine spread by discharging dyed or particle-filled water into a water tank.  They examined 3 different temporal exit velocity profiles: pulsation, sinusoidal, and real-cough.

The “most striking phenomenon,” the researchers say, is that the particle clouds of all 3 sizes of particles (small [8-14 µm], medium [57-68 µm], large [96-114 µm]) penetrated almost the same distance at different time steps. In other words, large particles can travel as far as fine particles.

The cough flow’s maximum penetration distance was 53.4 to 69.7 opening diameter. That is, for a mouth opening to a diameter of 2 cm, the large particles could penetrate 1 to 1.4 m in a “real cough case,” they note. Cough duration was important in determining the spread range of particles. Their maximum travel distance was “much enhanced” in a long starting jet, especially for small particles.

Source:
Wei J, Li Y. PLoS One. 2017;12(1): e0169235.
doi:  10.1371/journal.pone.0169235.

A single cough can propel as many as 3,000 droplets into the air at a velocity of 6 to 28 m/s. The droplets travel in what classic fluid mechanics calls a “2-stage jet”: the starting jet (when the cough starts) and interrupted jet (when the cough stops). After the original cough ends, a “leading vortex” carries particles forward, but as the momentum slows, particles fall out of the jet according to researchers from the University of Hong Kong and Shenzhen Institute of Research and Innovation, both in China, who studied cough trajectories and the implications for disease transmission in buildings.

Once the penetration velocity drops below 0.01 m/s, environmental factors, such as ventilation and human body temperature, begin to influence the flow. Beyond 1 to 2 m, the exhaled air stream dissolves into the room airflow, and the pathogen-containing droplets or droplet nuclei are dispersed according to the global airflow in the room.

When a cough doesn’t last long, the researchers say, the velocity of fine particles decays significantly after the jet is interrupted. However, even short coughs have consequences: Pathogen-containing droplets as large as ≥ 5 µm in diameter can be directly deposited on the nasal or oral mucosa of a nearby “new host.”

But coughs differ in many ways, including how far and wide they send the droplets. The researchers conducted experiments to help determine spread by discharging dyed or particle-filled water into a water tank.  They examined 3 different temporal exit velocity profiles: pulsation, sinusoidal, and real-cough.

The “most striking phenomenon,” the researchers say, is that the particle clouds of all 3 sizes of particles (small [8-14 µm], medium [57-68 µm], large [96-114 µm]) penetrated almost the same distance at different time steps. In other words, large particles can travel as far as fine particles.

The cough flow’s maximum penetration distance was 53.4 to 69.7 opening diameter. That is, for a mouth opening to a diameter of 2 cm, the large particles could penetrate 1 to 1.4 m in a “real cough case,” they note. Cough duration was important in determining the spread range of particles. Their maximum travel distance was “much enhanced” in a long starting jet, especially for small particles.

Source:
Wei J, Li Y. PLoS One. 2017;12(1): e0169235.
doi:  10.1371/journal.pone.0169235.

A single cough can propel as many as 3,000 droplets into the air at a velocity of 6 to 28 m/s. The droplets travel in what classic fluid mechanics calls a “2-stage jet”: the starting jet (when the cough starts) and interrupted jet (when the cough stops). After the original cough ends, a “leading vortex” carries particles forward, but as the momentum slows, particles fall out of the jet according to researchers from the University of Hong Kong and Shenzhen Institute of Research and Innovation, both in China, who studied cough trajectories and the implications for disease transmission in buildings.

Once the penetration velocity drops below 0.01 m/s, environmental factors, such as ventilation and human body temperature, begin to influence the flow. Beyond 1 to 2 m, the exhaled air stream dissolves into the room airflow, and the pathogen-containing droplets or droplet nuclei are dispersed according to the global airflow in the room.

When a cough doesn’t last long, the researchers say, the velocity of fine particles decays significantly after the jet is interrupted. However, even short coughs have consequences: Pathogen-containing droplets as large as ≥ 5 µm in diameter can be directly deposited on the nasal or oral mucosa of a nearby “new host.”

But coughs differ in many ways, including how far and wide they send the droplets. The researchers conducted experiments to help determine spread by discharging dyed or particle-filled water into a water tank.  They examined 3 different temporal exit velocity profiles: pulsation, sinusoidal, and real-cough.

The “most striking phenomenon,” the researchers say, is that the particle clouds of all 3 sizes of particles (small [8-14 µm], medium [57-68 µm], large [96-114 µm]) penetrated almost the same distance at different time steps. In other words, large particles can travel as far as fine particles.

The cough flow’s maximum penetration distance was 53.4 to 69.7 opening diameter. That is, for a mouth opening to a diameter of 2 cm, the large particles could penetrate 1 to 1.4 m in a “real cough case,” they note. Cough duration was important in determining the spread range of particles. Their maximum travel distance was “much enhanced” in a long starting jet, especially for small particles.

Source:
Wei J, Li Y. PLoS One. 2017;12(1): e0169235.
doi:  10.1371/journal.pone.0169235.

Empiric antimicrobial therapy often consists of the combination of gram-positive coverage with vancomycin (VAN) and gram-negative coverage, specifically an antipseudomonal beta-lactam such as piperacillin-tazobactam (PTZ). Literature from a variety of patient populations reports nephrotoxicity associated with VAN, targeting troughs greater than 15 µg/mL, that occur in 5% to 43% of patients.¹ In a study of critically ill patients, acute kidney injury (AKI) was found in 21% of patients receiving VAN, with increasing duration of VAN treatment, greater VAN levels, concomitant vasoactive medication administration, and intermittent infusion methods being associated with higher odds of AKI.² A recent report from adult internal medicine patients estimated the incidence of VAN-associated nephrotoxicity at 13.6% and implicated concomitant PTZ therapy as a key factor in these patients.³

Further studies have explored the interaction between empiric beta-lactam and VAN therapy, showing mixed results. Reports of AKI associated with the combination of VAN and PTZ range from 16.3% to 34.8%,^4-8 while the cefepime-VAN combination is reported to range from 12.5% to 13.3%.^5,6 While VAN monotherapy groups were well represented, only 1 study⁷ compared the PTZ-VAN combination to a control group of PTZ monotherapy.

The primary objective of this study was to evaluate the differences in AKI incidence between patients treated with VAN and with PTZ, alone and in combination.

This is a retrospective cohort study of adult patients conducted at the University of Kentucky Chandler Medical Center (UKMC) from September 1, 2010 through August 31, 2014. Patients were included if they were at least 18 years of age on admission; remained hospitalized for at least 48 hours; received VAN combined with PTZ (VAN/PTZ), VAN alone, or PTZ alone; and had at least 48 hours of therapy (and 48 hours of overlapping therapy in the VAN/PTZ group). Patients were excluded if they had underlying diagnosis of chronic kidney disease according to the International Classification of Diseases 9 (ICD-9) code, were receiving renal replacement therapy before admission, had a diagnosis of cystic fibrosis, or were pregnant. Additionally, patients were excluded if they presented with AKI, defined as an initial creatinine clearance less than 30 mL/min, or if baseline creatinine clearance was greater than 4 times the standard deviation from the mean; serum creatinine values were not obtained during admission; and if AKI occurred prior to therapy initiation, within 48 hours of initiation, or more than 7 days after treatment was discontinued. Patients were followed throughout their stay until time of discharge.

Data Source

Patient data were collected from the University of Kentucky Center for Clinical and Translational Science Enterprise Data Trust (EDT). The EDT contains clinical data from the inpatient population of UKMC from 2006 to present. Data stored and updated nightly by the EDT includes: demographics, financial classification (Medicare, Medicaid, private insurance), provider-level detail (service line), medical diagnosis (ICD-9 codes), medical procedures (Current Procedural Terminology [CPT] codes), lab tests and results, medication administration details, visit details (age, length of stay, etc), and vital signs. This study was approved by the UKMC Institutional Review Board.

Data collected for each patient included: demographic data, visit details (length of stay, admitting and primary diagnosis codes, etc.), severity of underlying illness as defined by the Charlson Comorbidity Index (CCI), all serum creatinine levels drawn per visit, medication administration information (dose, date, and time administered), all VAN trough levels, receipt of other nephrotoxic agents, blood pressures, and receipt of vasopressors.

Outcome Ascertainment

The definition of AKI was based on the RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria,⁹ with risk defined as a 25% to 50% decrease in estimated glomerular filtration rate (GFR), injury as a 50% to 75% decrease in estimated GFR, and failure defined as a greater than 75% decrease in estimated GFR. Loss and end-stage classifications were not assessed because of this study’s follow-up period. The adjusted Cockcroft and Gault equation¹⁰ was used to estimate GFR due to the inconsistency of weight availability in the dataset and concordance with the institution’s practice. Baseline creatinine clearance was calculated with the first serum creatinine obtained, and the minimum creatinine clearance was calculated using the maximum serum creatinine during each patient’s visit. The percent decrease in creatinine clearance was calculated from these 2 values. AKI status was defined as meeting any of the RIFLE criteria. Mortality was assessed for all patients and defined as the composite of inhospital mortality and discharge or transfer to hospice care.

Exposure Ascertainment

Hypotension exposure was defined as experiencing 1 of the following: mean arterial blood pressure less than 60 mm Hg, a diagnosis of hypotension by a physician, or receipt of vasopressors or inotropic agents. Days of therapy for each drug were obtained and combination days of therapy were calculated by including only those days in which the patient received both medications. Total days of therapy were calculated by the sum of all days receiving at least 1 study agent. Exposure to other nephrotoxic agents (eg, acyclovir, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aminoglycosides, amphotericin B, cyclosporine, foscarnet, loop diuretics, nonsteroidal anti-inflammatory drugs, sulfonamides, tacrolimus, and tenofovir) were defined as receipt of at least 1 dose of the agent during hospitalization.

Statistical Analysis

Characteristics between groups were described with basic descriptive statistics. Continuous variables were compared with 1-way analysis of variance (ANOVA) or the Kruskal-Wallis test. Categorical variables were compared with chi-square or Fisher exact test. Yearly AKI trends were assessed with Pearson correlation coefficient. To control for differences in underlying severity of illness between groups, a subanalysis was performed in which the cohort was split into 4 groups (0, 1, 2 to 4, and ≥5 points) based on CCI. Univariate models for all covariates were created with probability of AKI as the outcome. Covariates significant after univariate were incorporated into the multivariate model, which was subsequently adjusted to achieve the highest predictive accuracy by minimizing the Akaike information criterion (AIC). Nephrotoxic agent exposures were included in the final multivariate model regardless of statistical significance in univariate analysis. Model fit was assessed with a standardized Hosmer-Lemeshow goodness-of-fit test.¹¹ All statistical analyses were completed with RStudio v 0.98 running R v 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria).¹² All tests were 2-tailed and significance was defined at an alpha of 0.05.

Of 17,879 patients initially screened, 11,650 patients were evaluated, of which 5,497 received VAN and PTZ (VAN/PTZ), 3,055 received VAN alone, and 3,098 received PTZ alone. Table 1 contains basic demographic information. The mean age of patients was 52.5 years ± 16.8 years with 6,242 (53.6%) males. Patients receiving VAN/PTZ had higher CCIs than either monotherapy group and had significantly increased length of hospitalization. While patients in the combination therapy group were more likely to experience hypotension, concomitant nephrotoxic agent exposure was more common in the VAN monotherapy group.

RIFLE-defined AKI occurred in 1,647 (14.1%) across the entire cohort. AKI occurred in 21% of VAN/PTZ patients, 8.3% of VAN patients, and 7.8% of PTZ patients (P < 0.0001). RIFLE-defined risk, injury, and failure occurred more frequently in the VAN/PTZ cohort compared to the VAN and PTZ monotherapy groups (Figure). There were no differences in AKI rates between years studied (r² = 0.4732, P = 0.2). Patients in the VAN/PTZ group experienced AKI on average of 8.0 days after treatment initiation, compared to 8.7 days and 5.2 days for VAN and PTZ monotherapy groups, respectively. The composite of inhospital mortality and transfer-to-hospice care was more common in VAN/PTZ patients (9.6%) compared to monotherapy groups (VAN, 3.9%; PTZ, 3.4%), most likely due to the increased severity of illness.

Acute kidney injury secondary to VAN therapy is a well-characterized adverse effect, while AKI incidence secondary to PTZ is less understood. Additionally, there appears to be an additive effect when these agents are used in combination. This is the largest review of AKI in patients receiving VAN,PTZ, or the combination of both agents.

There is increasing evidence suggesting greater nephrotoxicity in patients treated with the combination of VAN and antipseudomonal beta-lactams. The mechanism for the apparent increase in nephrotoxicity with this drug combination is not well understood and needs further study in both animal models and humans.

Acute kidney injury rates related to VAN vary widely, with recent studies in critically ill and internal medicine patients estimated at 21% and 13.6%, respectively.^2,3 In our VAN monotherapy cohort, the AKI rate was 8.3%, with 2.3% of patients experiencing a greater than 50% decrease in creatinine clearance. Piperacillin-tazobactam-related AKI rates are not well characterized; however, a small retrospective analysis estimated that 11.1% of PTZ patients experienced acute renal failure (defined as either increase in serum creatinine greater than 0.5 mg/dL or 50% increase from baseline).¹³ In the present study, we found the PTZ-related AKI rate to be 7.8%, which may be due to a more stringent definition of AKI. Additionally, Hellwig et al¹³ found that PTZ monotherapy was associated with higher AKI rates compared to VAN monotherapy (11.1% vs 4.9%; P = 0.014). This was not replicated in our study, with VAN and PTZ monotherapy having similar AKI rates (8.3% and 7.8%, respectively) and an adjusted aOR of 0.88 (95% CI 0.0.73-1.08) for AKI in PTZ- compared to VAN-treated patients. The estimated AKI incidence of 21% in the combination therapy group at our institution is consistent with literature that ranges from 16.3% to 34.8%.^4-8,13

To control for differences in baseline severity of illness, we performed a subgroup analysis of patients with similar CCI scores. The finding of increased AKI in patients receiving combination VAN and PTZ was consistent in each subgroup, suggesting that the increase in AKI is independent of illness severity.

This study is not without limitations. As with all retrospective studies, it is difficult to determine a causal link between VAN and PTZ combination therapy and increased AKI incidence due to confounding. We employed a rigorous study design that controlled for major confounders of AKI, such as concomitant nephrotoxic exposure, hypotension, and renal disease. Severity of illness was measured with CCI, which may not accurately capture the severity of illness at treatment initiation. Alternatives, such as acute physiology and chronic health evaluation (APACHE) and sequential organ failure assessment (SOFA) scores, may more accurately reflect critical illness on presentation; however, this study was not focused specifically on critically ill patients. In addition to baseline comorbidity, we controlled for hypotension and dehydration as a surrogate marker for critical illness. In the subgroup analysis of patients with similar CCI, the effect of VAN/PTZ on AKI compared to VAN or PTZ monotherapy was consistent in each group. Nephrotoxic potential of agents was assumed to be equal, which is not necessarily true. Additionally, the binary representation of nephrotoxic exposure does not describe the amount of the agent received; as such, our estimations of AKI odds may be artificially elevated. Approximately one-quarter of the patients in this study were transferred from an outside hospital, for which no data regarding initial treatment are available. This may lead to exposure misclassification. We attempted to control for this factor in the regression model and found that, after controlling for other covariates, hospital transfer was associated with increasing odds of AKI. Finally, data were collected retrospectively from the electronic medical record and are subject to inaccuracies documented in the chart; however, any bias introduced should be nondifferential.

In our large retrospective study of combination empiric therapy with VAN and PTZ, we found that combination therapy was associated with more than double the odds of AKI occurring compared to either monotherapy with VAN or PTZ. Increasing duration of therapy was also associated with increases in AKI. These findings demonstrate the need for judicious use of combination therapy and strengthen the need for antimicrobial de-escalation when appropriate to avoid deleterious effects.

Acknowledgments

The authors thank Chantal Le Rutter, MPA, for copyediting services.

Disclosures

This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant numbers UL1TR000117 and UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no conflicts of interest.

Empiric antimicrobial therapy often consists of the combination of gram-positive coverage with vancomycin (VAN) and gram-negative coverage, specifically an antipseudomonal beta-lactam such as piperacillin-tazobactam (PTZ). Literature from a variety of patient populations reports nephrotoxicity associated with VAN, targeting troughs greater than 15 µg/mL, that occur in 5% to 43% of patients.¹ In a study of critically ill patients, acute kidney injury (AKI) was found in 21% of patients receiving VAN, with increasing duration of VAN treatment, greater VAN levels, concomitant vasoactive medication administration, and intermittent infusion methods being associated with higher odds of AKI.² A recent report from adult internal medicine patients estimated the incidence of VAN-associated nephrotoxicity at 13.6% and implicated concomitant PTZ therapy as a key factor in these patients.³

Further studies have explored the interaction between empiric beta-lactam and VAN therapy, showing mixed results. Reports of AKI associated with the combination of VAN and PTZ range from 16.3% to 34.8%,^4-8 while the cefepime-VAN combination is reported to range from 12.5% to 13.3%.^5,6 While VAN monotherapy groups were well represented, only 1 study⁷ compared the PTZ-VAN combination to a control group of PTZ monotherapy.

The primary objective of this study was to evaluate the differences in AKI incidence between patients treated with VAN and with PTZ, alone and in combination.

This is a retrospective cohort study of adult patients conducted at the University of Kentucky Chandler Medical Center (UKMC) from September 1, 2010 through August 31, 2014. Patients were included if they were at least 18 years of age on admission; remained hospitalized for at least 48 hours; received VAN combined with PTZ (VAN/PTZ), VAN alone, or PTZ alone; and had at least 48 hours of therapy (and 48 hours of overlapping therapy in the VAN/PTZ group). Patients were excluded if they had underlying diagnosis of chronic kidney disease according to the International Classification of Diseases 9 (ICD-9) code, were receiving renal replacement therapy before admission, had a diagnosis of cystic fibrosis, or were pregnant. Additionally, patients were excluded if they presented with AKI, defined as an initial creatinine clearance less than 30 mL/min, or if baseline creatinine clearance was greater than 4 times the standard deviation from the mean; serum creatinine values were not obtained during admission; and if AKI occurred prior to therapy initiation, within 48 hours of initiation, or more than 7 days after treatment was discontinued. Patients were followed throughout their stay until time of discharge.

Data Source

Patient data were collected from the University of Kentucky Center for Clinical and Translational Science Enterprise Data Trust (EDT). The EDT contains clinical data from the inpatient population of UKMC from 2006 to present. Data stored and updated nightly by the EDT includes: demographics, financial classification (Medicare, Medicaid, private insurance), provider-level detail (service line), medical diagnosis (ICD-9 codes), medical procedures (Current Procedural Terminology [CPT] codes), lab tests and results, medication administration details, visit details (age, length of stay, etc), and vital signs. This study was approved by the UKMC Institutional Review Board.

Data collected for each patient included: demographic data, visit details (length of stay, admitting and primary diagnosis codes, etc.), severity of underlying illness as defined by the Charlson Comorbidity Index (CCI), all serum creatinine levels drawn per visit, medication administration information (dose, date, and time administered), all VAN trough levels, receipt of other nephrotoxic agents, blood pressures, and receipt of vasopressors.

Outcome Ascertainment

The definition of AKI was based on the RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria,⁹ with risk defined as a 25% to 50% decrease in estimated glomerular filtration rate (GFR), injury as a 50% to 75% decrease in estimated GFR, and failure defined as a greater than 75% decrease in estimated GFR. Loss and end-stage classifications were not assessed because of this study’s follow-up period. The adjusted Cockcroft and Gault equation¹⁰ was used to estimate GFR due to the inconsistency of weight availability in the dataset and concordance with the institution’s practice. Baseline creatinine clearance was calculated with the first serum creatinine obtained, and the minimum creatinine clearance was calculated using the maximum serum creatinine during each patient’s visit. The percent decrease in creatinine clearance was calculated from these 2 values. AKI status was defined as meeting any of the RIFLE criteria. Mortality was assessed for all patients and defined as the composite of inhospital mortality and discharge or transfer to hospice care.

Exposure Ascertainment

Hypotension exposure was defined as experiencing 1 of the following: mean arterial blood pressure less than 60 mm Hg, a diagnosis of hypotension by a physician, or receipt of vasopressors or inotropic agents. Days of therapy for each drug were obtained and combination days of therapy were calculated by including only those days in which the patient received both medications. Total days of therapy were calculated by the sum of all days receiving at least 1 study agent. Exposure to other nephrotoxic agents (eg, acyclovir, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aminoglycosides, amphotericin B, cyclosporine, foscarnet, loop diuretics, nonsteroidal anti-inflammatory drugs, sulfonamides, tacrolimus, and tenofovir) were defined as receipt of at least 1 dose of the agent during hospitalization.

Statistical Analysis

Characteristics between groups were described with basic descriptive statistics. Continuous variables were compared with 1-way analysis of variance (ANOVA) or the Kruskal-Wallis test. Categorical variables were compared with chi-square or Fisher exact test. Yearly AKI trends were assessed with Pearson correlation coefficient. To control for differences in underlying severity of illness between groups, a subanalysis was performed in which the cohort was split into 4 groups (0, 1, 2 to 4, and ≥5 points) based on CCI. Univariate models for all covariates were created with probability of AKI as the outcome. Covariates significant after univariate were incorporated into the multivariate model, which was subsequently adjusted to achieve the highest predictive accuracy by minimizing the Akaike information criterion (AIC). Nephrotoxic agent exposures were included in the final multivariate model regardless of statistical significance in univariate analysis. Model fit was assessed with a standardized Hosmer-Lemeshow goodness-of-fit test.¹¹ All statistical analyses were completed with RStudio v 0.98 running R v 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria).¹² All tests were 2-tailed and significance was defined at an alpha of 0.05.

Of 17,879 patients initially screened, 11,650 patients were evaluated, of which 5,497 received VAN and PTZ (VAN/PTZ), 3,055 received VAN alone, and 3,098 received PTZ alone. Table 1 contains basic demographic information. The mean age of patients was 52.5 years ± 16.8 years with 6,242 (53.6%) males. Patients receiving VAN/PTZ had higher CCIs than either monotherapy group and had significantly increased length of hospitalization. While patients in the combination therapy group were more likely to experience hypotension, concomitant nephrotoxic agent exposure was more common in the VAN monotherapy group.

RIFLE-defined AKI occurred in 1,647 (14.1%) across the entire cohort. AKI occurred in 21% of VAN/PTZ patients, 8.3% of VAN patients, and 7.8% of PTZ patients (P < 0.0001). RIFLE-defined risk, injury, and failure occurred more frequently in the VAN/PTZ cohort compared to the VAN and PTZ monotherapy groups (Figure). There were no differences in AKI rates between years studied (r² = 0.4732, P = 0.2). Patients in the VAN/PTZ group experienced AKI on average of 8.0 days after treatment initiation, compared to 8.7 days and 5.2 days for VAN and PTZ monotherapy groups, respectively. The composite of inhospital mortality and transfer-to-hospice care was more common in VAN/PTZ patients (9.6%) compared to monotherapy groups (VAN, 3.9%; PTZ, 3.4%), most likely due to the increased severity of illness.

Acute kidney injury secondary to VAN therapy is a well-characterized adverse effect, while AKI incidence secondary to PTZ is less understood. Additionally, there appears to be an additive effect when these agents are used in combination. This is the largest review of AKI in patients receiving VAN,PTZ, or the combination of both agents.

There is increasing evidence suggesting greater nephrotoxicity in patients treated with the combination of VAN and antipseudomonal beta-lactams. The mechanism for the apparent increase in nephrotoxicity with this drug combination is not well understood and needs further study in both animal models and humans.

Acute kidney injury rates related to VAN vary widely, with recent studies in critically ill and internal medicine patients estimated at 21% and 13.6%, respectively.^2,3 In our VAN monotherapy cohort, the AKI rate was 8.3%, with 2.3% of patients experiencing a greater than 50% decrease in creatinine clearance. Piperacillin-tazobactam-related AKI rates are not well characterized; however, a small retrospective analysis estimated that 11.1% of PTZ patients experienced acute renal failure (defined as either increase in serum creatinine greater than 0.5 mg/dL or 50% increase from baseline).¹³ In the present study, we found the PTZ-related AKI rate to be 7.8%, which may be due to a more stringent definition of AKI. Additionally, Hellwig et al¹³ found that PTZ monotherapy was associated with higher AKI rates compared to VAN monotherapy (11.1% vs 4.9%; P = 0.014). This was not replicated in our study, with VAN and PTZ monotherapy having similar AKI rates (8.3% and 7.8%, respectively) and an adjusted aOR of 0.88 (95% CI 0.0.73-1.08) for AKI in PTZ- compared to VAN-treated patients. The estimated AKI incidence of 21% in the combination therapy group at our institution is consistent with literature that ranges from 16.3% to 34.8%.^4-8,13

To control for differences in baseline severity of illness, we performed a subgroup analysis of patients with similar CCI scores. The finding of increased AKI in patients receiving combination VAN and PTZ was consistent in each subgroup, suggesting that the increase in AKI is independent of illness severity.

This study is not without limitations. As with all retrospective studies, it is difficult to determine a causal link between VAN and PTZ combination therapy and increased AKI incidence due to confounding. We employed a rigorous study design that controlled for major confounders of AKI, such as concomitant nephrotoxic exposure, hypotension, and renal disease. Severity of illness was measured with CCI, which may not accurately capture the severity of illness at treatment initiation. Alternatives, such as acute physiology and chronic health evaluation (APACHE) and sequential organ failure assessment (SOFA) scores, may more accurately reflect critical illness on presentation; however, this study was not focused specifically on critically ill patients. In addition to baseline comorbidity, we controlled for hypotension and dehydration as a surrogate marker for critical illness. In the subgroup analysis of patients with similar CCI, the effect of VAN/PTZ on AKI compared to VAN or PTZ monotherapy was consistent in each group. Nephrotoxic potential of agents was assumed to be equal, which is not necessarily true. Additionally, the binary representation of nephrotoxic exposure does not describe the amount of the agent received; as such, our estimations of AKI odds may be artificially elevated. Approximately one-quarter of the patients in this study were transferred from an outside hospital, for which no data regarding initial treatment are available. This may lead to exposure misclassification. We attempted to control for this factor in the regression model and found that, after controlling for other covariates, hospital transfer was associated with increasing odds of AKI. Finally, data were collected retrospectively from the electronic medical record and are subject to inaccuracies documented in the chart; however, any bias introduced should be nondifferential.

In our large retrospective study of combination empiric therapy with VAN and PTZ, we found that combination therapy was associated with more than double the odds of AKI occurring compared to either monotherapy with VAN or PTZ. Increasing duration of therapy was also associated with increases in AKI. These findings demonstrate the need for judicious use of combination therapy and strengthen the need for antimicrobial de-escalation when appropriate to avoid deleterious effects.

Acknowledgments

The authors thank Chantal Le Rutter, MPA, for copyediting services.

Disclosures

This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant numbers UL1TR000117 and UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no conflicts of interest.

Empiric antimicrobial therapy often consists of the combination of gram-positive coverage with vancomycin (VAN) and gram-negative coverage, specifically an antipseudomonal beta-lactam such as piperacillin-tazobactam (PTZ). Literature from a variety of patient populations reports nephrotoxicity associated with VAN, targeting troughs greater than 15 µg/mL, that occur in 5% to 43% of patients.¹ In a study of critically ill patients, acute kidney injury (AKI) was found in 21% of patients receiving VAN, with increasing duration of VAN treatment, greater VAN levels, concomitant vasoactive medication administration, and intermittent infusion methods being associated with higher odds of AKI.² A recent report from adult internal medicine patients estimated the incidence of VAN-associated nephrotoxicity at 13.6% and implicated concomitant PTZ therapy as a key factor in these patients.³

Further studies have explored the interaction between empiric beta-lactam and VAN therapy, showing mixed results. Reports of AKI associated with the combination of VAN and PTZ range from 16.3% to 34.8%,^4-8 while the cefepime-VAN combination is reported to range from 12.5% to 13.3%.^5,6 While VAN monotherapy groups were well represented, only 1 study⁷ compared the PTZ-VAN combination to a control group of PTZ monotherapy.

The primary objective of this study was to evaluate the differences in AKI incidence between patients treated with VAN and with PTZ, alone and in combination.

This is a retrospective cohort study of adult patients conducted at the University of Kentucky Chandler Medical Center (UKMC) from September 1, 2010 through August 31, 2014. Patients were included if they were at least 18 years of age on admission; remained hospitalized for at least 48 hours; received VAN combined with PTZ (VAN/PTZ), VAN alone, or PTZ alone; and had at least 48 hours of therapy (and 48 hours of overlapping therapy in the VAN/PTZ group). Patients were excluded if they had underlying diagnosis of chronic kidney disease according to the International Classification of Diseases 9 (ICD-9) code, were receiving renal replacement therapy before admission, had a diagnosis of cystic fibrosis, or were pregnant. Additionally, patients were excluded if they presented with AKI, defined as an initial creatinine clearance less than 30 mL/min, or if baseline creatinine clearance was greater than 4 times the standard deviation from the mean; serum creatinine values were not obtained during admission; and if AKI occurred prior to therapy initiation, within 48 hours of initiation, or more than 7 days after treatment was discontinued. Patients were followed throughout their stay until time of discharge.

Data Source

Patient data were collected from the University of Kentucky Center for Clinical and Translational Science Enterprise Data Trust (EDT). The EDT contains clinical data from the inpatient population of UKMC from 2006 to present. Data stored and updated nightly by the EDT includes: demographics, financial classification (Medicare, Medicaid, private insurance), provider-level detail (service line), medical diagnosis (ICD-9 codes), medical procedures (Current Procedural Terminology [CPT] codes), lab tests and results, medication administration details, visit details (age, length of stay, etc), and vital signs. This study was approved by the UKMC Institutional Review Board.

Data collected for each patient included: demographic data, visit details (length of stay, admitting and primary diagnosis codes, etc.), severity of underlying illness as defined by the Charlson Comorbidity Index (CCI), all serum creatinine levels drawn per visit, medication administration information (dose, date, and time administered), all VAN trough levels, receipt of other nephrotoxic agents, blood pressures, and receipt of vasopressors.

Outcome Ascertainment

The definition of AKI was based on the RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria,⁹ with risk defined as a 25% to 50% decrease in estimated glomerular filtration rate (GFR), injury as a 50% to 75% decrease in estimated GFR, and failure defined as a greater than 75% decrease in estimated GFR. Loss and end-stage classifications were not assessed because of this study’s follow-up period. The adjusted Cockcroft and Gault equation¹⁰ was used to estimate GFR due to the inconsistency of weight availability in the dataset and concordance with the institution’s practice. Baseline creatinine clearance was calculated with the first serum creatinine obtained, and the minimum creatinine clearance was calculated using the maximum serum creatinine during each patient’s visit. The percent decrease in creatinine clearance was calculated from these 2 values. AKI status was defined as meeting any of the RIFLE criteria. Mortality was assessed for all patients and defined as the composite of inhospital mortality and discharge or transfer to hospice care.

Exposure Ascertainment

Hypotension exposure was defined as experiencing 1 of the following: mean arterial blood pressure less than 60 mm Hg, a diagnosis of hypotension by a physician, or receipt of vasopressors or inotropic agents. Days of therapy for each drug were obtained and combination days of therapy were calculated by including only those days in which the patient received both medications. Total days of therapy were calculated by the sum of all days receiving at least 1 study agent. Exposure to other nephrotoxic agents (eg, acyclovir, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aminoglycosides, amphotericin B, cyclosporine, foscarnet, loop diuretics, nonsteroidal anti-inflammatory drugs, sulfonamides, tacrolimus, and tenofovir) were defined as receipt of at least 1 dose of the agent during hospitalization.

Statistical Analysis

Characteristics between groups were described with basic descriptive statistics. Continuous variables were compared with 1-way analysis of variance (ANOVA) or the Kruskal-Wallis test. Categorical variables were compared with chi-square or Fisher exact test. Yearly AKI trends were assessed with Pearson correlation coefficient. To control for differences in underlying severity of illness between groups, a subanalysis was performed in which the cohort was split into 4 groups (0, 1, 2 to 4, and ≥5 points) based on CCI. Univariate models for all covariates were created with probability of AKI as the outcome. Covariates significant after univariate were incorporated into the multivariate model, which was subsequently adjusted to achieve the highest predictive accuracy by minimizing the Akaike information criterion (AIC). Nephrotoxic agent exposures were included in the final multivariate model regardless of statistical significance in univariate analysis. Model fit was assessed with a standardized Hosmer-Lemeshow goodness-of-fit test.¹¹ All statistical analyses were completed with RStudio v 0.98 running R v 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria).¹² All tests were 2-tailed and significance was defined at an alpha of 0.05.

Of 17,879 patients initially screened, 11,650 patients were evaluated, of which 5,497 received VAN and PTZ (VAN/PTZ), 3,055 received VAN alone, and 3,098 received PTZ alone. Table 1 contains basic demographic information. The mean age of patients was 52.5 years ± 16.8 years with 6,242 (53.6%) males. Patients receiving VAN/PTZ had higher CCIs than either monotherapy group and had significantly increased length of hospitalization. While patients in the combination therapy group were more likely to experience hypotension, concomitant nephrotoxic agent exposure was more common in the VAN monotherapy group.

RIFLE-defined AKI occurred in 1,647 (14.1%) across the entire cohort. AKI occurred in 21% of VAN/PTZ patients, 8.3% of VAN patients, and 7.8% of PTZ patients (P < 0.0001). RIFLE-defined risk, injury, and failure occurred more frequently in the VAN/PTZ cohort compared to the VAN and PTZ monotherapy groups (Figure). There were no differences in AKI rates between years studied (r² = 0.4732, P = 0.2). Patients in the VAN/PTZ group experienced AKI on average of 8.0 days after treatment initiation, compared to 8.7 days and 5.2 days for VAN and PTZ monotherapy groups, respectively. The composite of inhospital mortality and transfer-to-hospice care was more common in VAN/PTZ patients (9.6%) compared to monotherapy groups (VAN, 3.9%; PTZ, 3.4%), most likely due to the increased severity of illness.

Acute kidney injury secondary to VAN therapy is a well-characterized adverse effect, while AKI incidence secondary to PTZ is less understood. Additionally, there appears to be an additive effect when these agents are used in combination. This is the largest review of AKI in patients receiving VAN,PTZ, or the combination of both agents.

There is increasing evidence suggesting greater nephrotoxicity in patients treated with the combination of VAN and antipseudomonal beta-lactams. The mechanism for the apparent increase in nephrotoxicity with this drug combination is not well understood and needs further study in both animal models and humans.

Acute kidney injury rates related to VAN vary widely, with recent studies in critically ill and internal medicine patients estimated at 21% and 13.6%, respectively.^2,3 In our VAN monotherapy cohort, the AKI rate was 8.3%, with 2.3% of patients experiencing a greater than 50% decrease in creatinine clearance. Piperacillin-tazobactam-related AKI rates are not well characterized; however, a small retrospective analysis estimated that 11.1% of PTZ patients experienced acute renal failure (defined as either increase in serum creatinine greater than 0.5 mg/dL or 50% increase from baseline).¹³ In the present study, we found the PTZ-related AKI rate to be 7.8%, which may be due to a more stringent definition of AKI. Additionally, Hellwig et al¹³ found that PTZ monotherapy was associated with higher AKI rates compared to VAN monotherapy (11.1% vs 4.9%; P = 0.014). This was not replicated in our study, with VAN and PTZ monotherapy having similar AKI rates (8.3% and 7.8%, respectively) and an adjusted aOR of 0.88 (95% CI 0.0.73-1.08) for AKI in PTZ- compared to VAN-treated patients. The estimated AKI incidence of 21% in the combination therapy group at our institution is consistent with literature that ranges from 16.3% to 34.8%.^4-8,13

To control for differences in baseline severity of illness, we performed a subgroup analysis of patients with similar CCI scores. The finding of increased AKI in patients receiving combination VAN and PTZ was consistent in each subgroup, suggesting that the increase in AKI is independent of illness severity.

This study is not without limitations. As with all retrospective studies, it is difficult to determine a causal link between VAN and PTZ combination therapy and increased AKI incidence due to confounding. We employed a rigorous study design that controlled for major confounders of AKI, such as concomitant nephrotoxic exposure, hypotension, and renal disease. Severity of illness was measured with CCI, which may not accurately capture the severity of illness at treatment initiation. Alternatives, such as acute physiology and chronic health evaluation (APACHE) and sequential organ failure assessment (SOFA) scores, may more accurately reflect critical illness on presentation; however, this study was not focused specifically on critically ill patients. In addition to baseline comorbidity, we controlled for hypotension and dehydration as a surrogate marker for critical illness. In the subgroup analysis of patients with similar CCI, the effect of VAN/PTZ on AKI compared to VAN or PTZ monotherapy was consistent in each group. Nephrotoxic potential of agents was assumed to be equal, which is not necessarily true. Additionally, the binary representation of nephrotoxic exposure does not describe the amount of the agent received; as such, our estimations of AKI odds may be artificially elevated. Approximately one-quarter of the patients in this study were transferred from an outside hospital, for which no data regarding initial treatment are available. This may lead to exposure misclassification. We attempted to control for this factor in the regression model and found that, after controlling for other covariates, hospital transfer was associated with increasing odds of AKI. Finally, data were collected retrospectively from the electronic medical record and are subject to inaccuracies documented in the chart; however, any bias introduced should be nondifferential.

In our large retrospective study of combination empiric therapy with VAN and PTZ, we found that combination therapy was associated with more than double the odds of AKI occurring compared to either monotherapy with VAN or PTZ. Increasing duration of therapy was also associated with increases in AKI. These findings demonstrate the need for judicious use of combination therapy and strengthen the need for antimicrobial de-escalation when appropriate to avoid deleterious effects.

Acknowledgments

The authors thank Chantal Le Rutter, MPA, for copyediting services.

Disclosures

This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant numbers UL1TR000117 and UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no conflicts of interest.

Clostridium difficile (C difficile) infection (CDI) is a leading cause of infectious diarrhea among hospitalized patients and, increasingly, in ambulatory patients.^1,2 The high prevalence of CDI and the high recurrence rates (15%-30%) led the CDC to categorize C difficile as an "urgent" threat (the highest category) in its 2013 Antimicrobial Resistance Threat Report.^3-5 The Infectious Diseases Society of America guideline recommended treatment for CDI is vancomycin or metronidazole; more recent studies also support fidaxomicin use.^4,6,7  

Patients experiencing recurrent CDI are at risk for further recurrences, such that after the third CDI episode, the risk of subsequent recurrences exceeds 50%.⁸ This recurrence rate has stimulated research into other treatments, including fecal microbiota transplantation (FMT). A recent systematic  review of FMT reports that 85% of patients have resolution of symptoms without recurrence after FMT, although this is based on data from case series and 2 small randomized clinical trials.⁹

A commonly cited barrier to FMT is patient acceptance. In response to this concern, a previous survey demonstrated that 81% of respondents would opt for FMT to treat a hypothetical case of recurrent CDI.¹⁰ However, the surveyed population did not have CDI, and the 48% response rate is concerning, since those with a favorable opinion of FMT might be more willing to complete a survey than would other patients. Accordingly, the authors systematically surveyed hospitalized veterans with active CDI to assess their knowledge, attitudes, and opinions about FMT as a treatment for CDI.

Methods

In-person patient interviews were conducted by one of the study authors at the Minneapolis VA Health Care System (MVAHCS), consisting of 13 to 18 questions. Questions addressed any prior CDI episodes and knowledge of the following: CDI, recurrence risk, and FMT; preferred route and location of FMT administration; concerns regarding FMT; likelihood of agreeing to undergo FMT (if available); and likelihood of enrollment in a hypothetical study comparing FMT to standard antibiotic treatment. The survey was developed internally and was not validated. Questions used the Likert-scale (Survey).

Patients with CDI were identified by monitoring for positive C difficile polymerase chain reaction (PCR) stool tests and then screened for inclusion by medical record review. Inclusion criteria were (1) MVAHCS hospitalization; and (2) written informed consent. Exclusion criteria were the inability to communicate or participate in an interview. Patient responses regarding their likelihood of agreeing to FMT for CDI treatment under different circumstances were compared using Wilcoxon rank sum test. These circumstances included FMT for their current episode of CDI, FMT for a subsequent episode, and FMT if recommended by their physician. Possible concerns regarding FMT also were solicited, including infection risk, effectiveness, and procedural aesthetics. The MVAHCS institutional review board approved the study.

Results

Stool PCR tests for CDI were monitored for 158 days from 2013 to 2014 (based on availability of study staff), yielding 106 positive results. Of those, 31 (29%) were from outpatients and not addressed further. Of the 75 positive CDI tests from 66 hospitalized patients (9 patients had duplicate tests), 18 of 66 (27%) were not able to provide consent and were excluded, leaving 48 eligible patients. Six (13%) were missed for logistic reasons (patient at a test or procedure, discharged before approached, etc), leaving 42 patients who were approached for participation. Among these, 34 (81%) consented to participate in the survey. Two subjects (6%) found the topic so unappealing that they terminated the interview.

The majority of enrolled subjects were men (32/34, 94%), with a mean age of 65.3 years (range, 31-89). Eleven subjects (32%) reported a prior CDI episode, with 10 reporting 1 such episode, and the other 2 episodes. Those with prior CDI reported the effect of CDI on their overall quality of life as 5.1 (1 = no limitation, 10 = severe limitation). Respondents were fairly accurate regarding the risk of recurrence after an initial episode of CDI, with the average expectedrecurrence rate estimated at 33%. In contrast, their estimation of the risk of recurrence after a second CDI episode was lower (28%), although the risk of recurrent episodes increases with each CDI recurrence.

Regarding FMT, 5 subjects indicated awareness of the procedure: 2 learning of it from a news source, 1 from family, 1 from a health care provider, and 1 was unsure of the source. After subjects received a description of FMT, their opinions regarding the procedure were elicited. When asked which route of delivery they would prefer if they were to undergo FMT, the 33 subjects who provided a response indicated a strong preference for either enema (15, 45%) or colonoscopy (10, 30%), compared with just 4 (12%) indicating no preference, 2 (6%) choosing nasogastric tube administration, and 2 (6%) indicating that they would not undergo FMT by any route (P < .001).

Regarding the location of FMT administration (hospital setting vs self-administered at home), 31 of 33 respondents (94%) indicated they would prefer FMT to occur in the hospital vs 2 (6%) preferring self-administration at home (P < .001). The preferred source of donor stool was more evenly distributed, with 14 of 32 respondents (44%) indicating a preference for an anonymous donor, 11 preferring a family member (34%), and 7 (21%) with no preference (P = .21).

Subjects were asked about concerns regarding FMT, and asked to rate each on a 5-point Likert scale (1 = not at all concerning; 5 = overwhelming concern). Concerns regarding risk of infection and effectiveness received an average score of 2.74 and 2.72, respectively, whereas concern regarding the aesthetics, or "yuck factor" was slightly lower (2.1: P = NS for all comparisons). Subjects also were asked to rate the likelihood of undergoing FMT, if it were available, for their current episode of CDI, a subsequent episode of CDI, or if their physician recommended undergoing FMT (10 point scale: 1 = not at all likely; 10 = certainly agree to FMT). The mean scores (SD) for agreeing to FMT for the current or a subsequent episode were 4.8 (SD 2.7) and 5.6 (SD 3.0); P = .12, but increased to 7.1 (SD 3.23) if FMT were recommended by their physician (P < .001 for FMT if physician recommended vs FMT for current episode; P = .001 for FMT if physician recommended vs FMT for a subsequent episode). Finally, subjects were asked about the likelihood of enrolling in a study comparing FMT to standard antimicrobial treatment, with answers ranging from 1 (almost certainly would not enroll) to 5 (almost certainly would enroll). Among the 32 respondents to this question, 17 (53%) answered either "probably would enroll" or "almost certainly would enroll," with a mean score of 3.2.  

Discussion

Overall, VA patients with a current episode of CDI were not aware of FMT, with just 15% knowing about the procedure. However, after learning about FMT, patients expressed clear opinions regarding the route and setting of FMT administration, with enema or colonoscopy being the preferred routes, and a hospital the preferred setting. In contrast, subjects expressed ambivalence with regard to the source of donor stool, with no clear preference for stool from an anonymous donor vs from a family member.

When asked about concerns regarding FMT, none of the presented options (risk of infection, uncertain effectiveness, or procedural aesthetics) emerged as significantly more important than did others, although the oft-cited concern regarding FMT aesthetics engendered the lowest overall level of concern. In terms of FMT acceptance, 4 subjects (12%) were opposed to the procedure, indicating that they were not at all likely to agree to FMT for all scenarios (defined as a score of 1 or 2 on the 10-point Likert scale) or by terminating the survey because of the questions. However, 15 (44%) indicated that they would certainly agree to FMT (defined as a score of 9 or 10 on the 10-point Likert scale) if their physician recommended it. Physician recommendation for FMT resulted in the highest overall likelihood of agreeing to FMT, a finding in agreement with a previous survey of FMT for CDI.¹⁰ Most subjects indicated likely enrollment in a potential study comparing FMT with standard antimicrobial therapy.

Strengths/Limitations

Study strengths included surveying patients with current CDI, such that patients had personal experience with the disease in question. Use of in-person interviews also resulted in a robust response rate of 81% and allowed subjects to clarify any unclear questions with study personnel. Weaknesses included a relatively small sample size, underrepresentation of women, and lack of detail regarding respondent characteristics. Additionally, capsule delivery of FMT was not assessed since this method of delivery had not been published at the time of survey administration.

Conclusion

This survey of VA patients with CDI suggests that aesthetic concerns are not a critical deterrent for this population, and interest in FMT for the treatment of recurrent CDI exists. Physician recommendation to undergo FMT seems to be the most influential factor affecting the likelihood of agreeing to undergo FMT. These results support the feasibility of conducting clinical trials of FMT in the VA system.

Clostridium difficile (C difficile) infection (CDI) is a leading cause of infectious diarrhea among hospitalized patients and, increasingly, in ambulatory patients.^1,2 The high prevalence of CDI and the high recurrence rates (15%-30%) led the CDC to categorize C difficile as an "urgent" threat (the highest category) in its 2013 Antimicrobial Resistance Threat Report.^3-5 The Infectious Diseases Society of America guideline recommended treatment for CDI is vancomycin or metronidazole; more recent studies also support fidaxomicin use.^4,6,7  

Patients experiencing recurrent CDI are at risk for further recurrences, such that after the third CDI episode, the risk of subsequent recurrences exceeds 50%.⁸ This recurrence rate has stimulated research into other treatments, including fecal microbiota transplantation (FMT). A recent systematic  review of FMT reports that 85% of patients have resolution of symptoms without recurrence after FMT, although this is based on data from case series and 2 small randomized clinical trials.⁹

A commonly cited barrier to FMT is patient acceptance. In response to this concern, a previous survey demonstrated that 81% of respondents would opt for FMT to treat a hypothetical case of recurrent CDI.¹⁰ However, the surveyed population did not have CDI, and the 48% response rate is concerning, since those with a favorable opinion of FMT might be more willing to complete a survey than would other patients. Accordingly, the authors systematically surveyed hospitalized veterans with active CDI to assess their knowledge, attitudes, and opinions about FMT as a treatment for CDI.

Methods

In-person patient interviews were conducted by one of the study authors at the Minneapolis VA Health Care System (MVAHCS), consisting of 13 to 18 questions. Questions addressed any prior CDI episodes and knowledge of the following: CDI, recurrence risk, and FMT; preferred route and location of FMT administration; concerns regarding FMT; likelihood of agreeing to undergo FMT (if available); and likelihood of enrollment in a hypothetical study comparing FMT to standard antibiotic treatment. The survey was developed internally and was not validated. Questions used the Likert-scale (Survey).

Patients with CDI were identified by monitoring for positive C difficile polymerase chain reaction (PCR) stool tests and then screened for inclusion by medical record review. Inclusion criteria were (1) MVAHCS hospitalization; and (2) written informed consent. Exclusion criteria were the inability to communicate or participate in an interview. Patient responses regarding their likelihood of agreeing to FMT for CDI treatment under different circumstances were compared using Wilcoxon rank sum test. These circumstances included FMT for their current episode of CDI, FMT for a subsequent episode, and FMT if recommended by their physician. Possible concerns regarding FMT also were solicited, including infection risk, effectiveness, and procedural aesthetics. The MVAHCS institutional review board approved the study.

Results

Stool PCR tests for CDI were monitored for 158 days from 2013 to 2014 (based on availability of study staff), yielding 106 positive results. Of those, 31 (29%) were from outpatients and not addressed further. Of the 75 positive CDI tests from 66 hospitalized patients (9 patients had duplicate tests), 18 of 66 (27%) were not able to provide consent and were excluded, leaving 48 eligible patients. Six (13%) were missed for logistic reasons (patient at a test or procedure, discharged before approached, etc), leaving 42 patients who were approached for participation. Among these, 34 (81%) consented to participate in the survey. Two subjects (6%) found the topic so unappealing that they terminated the interview.

The majority of enrolled subjects were men (32/34, 94%), with a mean age of 65.3 years (range, 31-89). Eleven subjects (32%) reported a prior CDI episode, with 10 reporting 1 such episode, and the other 2 episodes. Those with prior CDI reported the effect of CDI on their overall quality of life as 5.1 (1 = no limitation, 10 = severe limitation). Respondents were fairly accurate regarding the risk of recurrence after an initial episode of CDI, with the average expectedrecurrence rate estimated at 33%. In contrast, their estimation of the risk of recurrence after a second CDI episode was lower (28%), although the risk of recurrent episodes increases with each CDI recurrence.

Regarding FMT, 5 subjects indicated awareness of the procedure: 2 learning of it from a news source, 1 from family, 1 from a health care provider, and 1 was unsure of the source. After subjects received a description of FMT, their opinions regarding the procedure were elicited. When asked which route of delivery they would prefer if they were to undergo FMT, the 33 subjects who provided a response indicated a strong preference for either enema (15, 45%) or colonoscopy (10, 30%), compared with just 4 (12%) indicating no preference, 2 (6%) choosing nasogastric tube administration, and 2 (6%) indicating that they would not undergo FMT by any route (P < .001).

Regarding the location of FMT administration (hospital setting vs self-administered at home), 31 of 33 respondents (94%) indicated they would prefer FMT to occur in the hospital vs 2 (6%) preferring self-administration at home (P < .001). The preferred source of donor stool was more evenly distributed, with 14 of 32 respondents (44%) indicating a preference for an anonymous donor, 11 preferring a family member (34%), and 7 (21%) with no preference (P = .21).

Subjects were asked about concerns regarding FMT, and asked to rate each on a 5-point Likert scale (1 = not at all concerning; 5 = overwhelming concern). Concerns regarding risk of infection and effectiveness received an average score of 2.74 and 2.72, respectively, whereas concern regarding the aesthetics, or "yuck factor" was slightly lower (2.1: P = NS for all comparisons). Subjects also were asked to rate the likelihood of undergoing FMT, if it were available, for their current episode of CDI, a subsequent episode of CDI, or if their physician recommended undergoing FMT (10 point scale: 1 = not at all likely; 10 = certainly agree to FMT). The mean scores (SD) for agreeing to FMT for the current or a subsequent episode were 4.8 (SD 2.7) and 5.6 (SD 3.0); P = .12, but increased to 7.1 (SD 3.23) if FMT were recommended by their physician (P < .001 for FMT if physician recommended vs FMT for current episode; P = .001 for FMT if physician recommended vs FMT for a subsequent episode). Finally, subjects were asked about the likelihood of enrolling in a study comparing FMT to standard antimicrobial treatment, with answers ranging from 1 (almost certainly would not enroll) to 5 (almost certainly would enroll). Among the 32 respondents to this question, 17 (53%) answered either "probably would enroll" or "almost certainly would enroll," with a mean score of 3.2.  

Discussion

Overall, VA patients with a current episode of CDI were not aware of FMT, with just 15% knowing about the procedure. However, after learning about FMT, patients expressed clear opinions regarding the route and setting of FMT administration, with enema or colonoscopy being the preferred routes, and a hospital the preferred setting. In contrast, subjects expressed ambivalence with regard to the source of donor stool, with no clear preference for stool from an anonymous donor vs from a family member.

When asked about concerns regarding FMT, none of the presented options (risk of infection, uncertain effectiveness, or procedural aesthetics) emerged as significantly more important than did others, although the oft-cited concern regarding FMT aesthetics engendered the lowest overall level of concern. In terms of FMT acceptance, 4 subjects (12%) were opposed to the procedure, indicating that they were not at all likely to agree to FMT for all scenarios (defined as a score of 1 or 2 on the 10-point Likert scale) or by terminating the survey because of the questions. However, 15 (44%) indicated that they would certainly agree to FMT (defined as a score of 9 or 10 on the 10-point Likert scale) if their physician recommended it. Physician recommendation for FMT resulted in the highest overall likelihood of agreeing to FMT, a finding in agreement with a previous survey of FMT for CDI.¹⁰ Most subjects indicated likely enrollment in a potential study comparing FMT with standard antimicrobial therapy.

Strengths/Limitations

Study strengths included surveying patients with current CDI, such that patients had personal experience with the disease in question. Use of in-person interviews also resulted in a robust response rate of 81% and allowed subjects to clarify any unclear questions with study personnel. Weaknesses included a relatively small sample size, underrepresentation of women, and lack of detail regarding respondent characteristics. Additionally, capsule delivery of FMT was not assessed since this method of delivery had not been published at the time of survey administration.

Conclusion

This survey of VA patients with CDI suggests that aesthetic concerns are not a critical deterrent for this population, and interest in FMT for the treatment of recurrent CDI exists. Physician recommendation to undergo FMT seems to be the most influential factor affecting the likelihood of agreeing to undergo FMT. These results support the feasibility of conducting clinical trials of FMT in the VA system.

Clostridium difficile (C difficile) infection (CDI) is a leading cause of infectious diarrhea among hospitalized patients and, increasingly, in ambulatory patients.^1,2 The high prevalence of CDI and the high recurrence rates (15%-30%) led the CDC to categorize C difficile as an "urgent" threat (the highest category) in its 2013 Antimicrobial Resistance Threat Report.^3-5 The Infectious Diseases Society of America guideline recommended treatment for CDI is vancomycin or metronidazole; more recent studies also support fidaxomicin use.^4,6,7  

Patients experiencing recurrent CDI are at risk for further recurrences, such that after the third CDI episode, the risk of subsequent recurrences exceeds 50%.⁸ This recurrence rate has stimulated research into other treatments, including fecal microbiota transplantation (FMT). A recent systematic  review of FMT reports that 85% of patients have resolution of symptoms without recurrence after FMT, although this is based on data from case series and 2 small randomized clinical trials.⁹

A commonly cited barrier to FMT is patient acceptance. In response to this concern, a previous survey demonstrated that 81% of respondents would opt for FMT to treat a hypothetical case of recurrent CDI.¹⁰ However, the surveyed population did not have CDI, and the 48% response rate is concerning, since those with a favorable opinion of FMT might be more willing to complete a survey than would other patients. Accordingly, the authors systematically surveyed hospitalized veterans with active CDI to assess their knowledge, attitudes, and opinions about FMT as a treatment for CDI.

Methods

In-person patient interviews were conducted by one of the study authors at the Minneapolis VA Health Care System (MVAHCS), consisting of 13 to 18 questions. Questions addressed any prior CDI episodes and knowledge of the following: CDI, recurrence risk, and FMT; preferred route and location of FMT administration; concerns regarding FMT; likelihood of agreeing to undergo FMT (if available); and likelihood of enrollment in a hypothetical study comparing FMT to standard antibiotic treatment. The survey was developed internally and was not validated. Questions used the Likert-scale (Survey).

Patients with CDI were identified by monitoring for positive C difficile polymerase chain reaction (PCR) stool tests and then screened for inclusion by medical record review. Inclusion criteria were (1) MVAHCS hospitalization; and (2) written informed consent. Exclusion criteria were the inability to communicate or participate in an interview. Patient responses regarding their likelihood of agreeing to FMT for CDI treatment under different circumstances were compared using Wilcoxon rank sum test. These circumstances included FMT for their current episode of CDI, FMT for a subsequent episode, and FMT if recommended by their physician. Possible concerns regarding FMT also were solicited, including infection risk, effectiveness, and procedural aesthetics. The MVAHCS institutional review board approved the study.

Results

Stool PCR tests for CDI were monitored for 158 days from 2013 to 2014 (based on availability of study staff), yielding 106 positive results. Of those, 31 (29%) were from outpatients and not addressed further. Of the 75 positive CDI tests from 66 hospitalized patients (9 patients had duplicate tests), 18 of 66 (27%) were not able to provide consent and were excluded, leaving 48 eligible patients. Six (13%) were missed for logistic reasons (patient at a test or procedure, discharged before approached, etc), leaving 42 patients who were approached for participation. Among these, 34 (81%) consented to participate in the survey. Two subjects (6%) found the topic so unappealing that they terminated the interview.

The majority of enrolled subjects were men (32/34, 94%), with a mean age of 65.3 years (range, 31-89). Eleven subjects (32%) reported a prior CDI episode, with 10 reporting 1 such episode, and the other 2 episodes. Those with prior CDI reported the effect of CDI on their overall quality of life as 5.1 (1 = no limitation, 10 = severe limitation). Respondents were fairly accurate regarding the risk of recurrence after an initial episode of CDI, with the average expectedrecurrence rate estimated at 33%. In contrast, their estimation of the risk of recurrence after a second CDI episode was lower (28%), although the risk of recurrent episodes increases with each CDI recurrence.

Regarding FMT, 5 subjects indicated awareness of the procedure: 2 learning of it from a news source, 1 from family, 1 from a health care provider, and 1 was unsure of the source. After subjects received a description of FMT, their opinions regarding the procedure were elicited. When asked which route of delivery they would prefer if they were to undergo FMT, the 33 subjects who provided a response indicated a strong preference for either enema (15, 45%) or colonoscopy (10, 30%), compared with just 4 (12%) indicating no preference, 2 (6%) choosing nasogastric tube administration, and 2 (6%) indicating that they would not undergo FMT by any route (P < .001).

Regarding the location of FMT administration (hospital setting vs self-administered at home), 31 of 33 respondents (94%) indicated they would prefer FMT to occur in the hospital vs 2 (6%) preferring self-administration at home (P < .001). The preferred source of donor stool was more evenly distributed, with 14 of 32 respondents (44%) indicating a preference for an anonymous donor, 11 preferring a family member (34%), and 7 (21%) with no preference (P = .21).

Subjects were asked about concerns regarding FMT, and asked to rate each on a 5-point Likert scale (1 = not at all concerning; 5 = overwhelming concern). Concerns regarding risk of infection and effectiveness received an average score of 2.74 and 2.72, respectively, whereas concern regarding the aesthetics, or "yuck factor" was slightly lower (2.1: P = NS for all comparisons). Subjects also were asked to rate the likelihood of undergoing FMT, if it were available, for their current episode of CDI, a subsequent episode of CDI, or if their physician recommended undergoing FMT (10 point scale: 1 = not at all likely; 10 = certainly agree to FMT). The mean scores (SD) for agreeing to FMT for the current or a subsequent episode were 4.8 (SD 2.7) and 5.6 (SD 3.0); P = .12, but increased to 7.1 (SD 3.23) if FMT were recommended by their physician (P < .001 for FMT if physician recommended vs FMT for current episode; P = .001 for FMT if physician recommended vs FMT for a subsequent episode). Finally, subjects were asked about the likelihood of enrolling in a study comparing FMT to standard antimicrobial treatment, with answers ranging from 1 (almost certainly would not enroll) to 5 (almost certainly would enroll). Among the 32 respondents to this question, 17 (53%) answered either "probably would enroll" or "almost certainly would enroll," with a mean score of 3.2.  

Discussion

Overall, VA patients with a current episode of CDI were not aware of FMT, with just 15% knowing about the procedure. However, after learning about FMT, patients expressed clear opinions regarding the route and setting of FMT administration, with enema or colonoscopy being the preferred routes, and a hospital the preferred setting. In contrast, subjects expressed ambivalence with regard to the source of donor stool, with no clear preference for stool from an anonymous donor vs from a family member.

When asked about concerns regarding FMT, none of the presented options (risk of infection, uncertain effectiveness, or procedural aesthetics) emerged as significantly more important than did others, although the oft-cited concern regarding FMT aesthetics engendered the lowest overall level of concern. In terms of FMT acceptance, 4 subjects (12%) were opposed to the procedure, indicating that they were not at all likely to agree to FMT for all scenarios (defined as a score of 1 or 2 on the 10-point Likert scale) or by terminating the survey because of the questions. However, 15 (44%) indicated that they would certainly agree to FMT (defined as a score of 9 or 10 on the 10-point Likert scale) if their physician recommended it. Physician recommendation for FMT resulted in the highest overall likelihood of agreeing to FMT, a finding in agreement with a previous survey of FMT for CDI.¹⁰ Most subjects indicated likely enrollment in a potential study comparing FMT with standard antimicrobial therapy.

Strengths/Limitations

Study strengths included surveying patients with current CDI, such that patients had personal experience with the disease in question. Use of in-person interviews also resulted in a robust response rate of 81% and allowed subjects to clarify any unclear questions with study personnel. Weaknesses included a relatively small sample size, underrepresentation of women, and lack of detail regarding respondent characteristics. Additionally, capsule delivery of FMT was not assessed since this method of delivery had not been published at the time of survey administration.

Conclusion

This survey of VA patients with CDI suggests that aesthetic concerns are not a critical deterrent for this population, and interest in FMT for the treatment of recurrent CDI exists. Physician recommendation to undergo FMT seems to be the most influential factor affecting the likelihood of agreeing to undergo FMT. These results support the feasibility of conducting clinical trials of FMT in the VA system.