Matthew Bidwell Goetz, MD

METHODS

RESULTS

DISCUSSION

METHODS

RESULTS

DISCUSSION

METHODS

RESULTS

DISCUSSION

Pneumonia is the leading inpatient infectious diagnosis for which antimicrobials are prescribed in the United States.[1] Supported by moderate‐ to high‐quality evidence, guidelines produced jointly by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) recommend treating pneumonia with the shortest appropriate duration of antimicrobial therapy to minimize risk for antimicrobial‐related adverse events.[2, 3, 4]

Evidence supports short duration of therapy for treatment of uncomplicated pneumonia.[3, 4, 5, 6, 7, 8, 9, 10, 11, 12] IDSA/ATS guidelines state, patients with CAP [community‐acquired pneumonia] should be treated for a minimum of 5 days (level 1 evidence), should be afebrile for 4872 hours, and should have no more than 1 CAP‐associated sign of clinical instabilitybefore discontinuation of therapy (level II evidence). (Moderate recommendation.) A longer duration of therapy may be warranted if initial therapy was not active against the identified pathogen or if it was complicated by [abscess, empyema, severe immunosuppression, or] extra‐pulmonary infection such as meningitis or endocarditis. (Weak recommendation; level III evidence).[3] Recommended therapy duration for patients with uncomplicated healthcare‐associated pneumonia (HCAP) who respond to initial therapy is 7 to 8 days unless gram‐negative nonfermenting rods or complications are identified (level I evidence).[4]

Within the Veterans Health Administration (VHA), the Antimicrobial Stewardship Taskforce (ASTF) was created to optimize care by developing, deploying, and monitoring a national‐level strategic plan for antimicrobial therapy management improvements.[13, 14] Although single‐center studies have found antimicrobial therapy for CAP being frequently prescribed for longer than recommended, the reproducibility of this finding across different facilities has not been assessed.[15, 16] The ASTF collaborated with the VHA Center for Medication Safety to assess total duration of antimicrobial therapy prescribed for veterans hospitalized with uncomplicated pneumonia.[17]

METHODS

This retrospective multicenter evaluation was conducted in 30 VHA facilities that volunteered to participate in this project. Inpatients discharged with a primary International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) diagnosis code for pneumonia (or pneumonia diagnosis secondary to primary sepsis diagnosis) during 2013 were evaluated.[18] Diagnoses, admissions, and patient demographics were identified using Veterans Affairs (VA) integrated databases through the Austin Integrated Technology Center. Up to 200 admissions per facility were randomly selected for review. Clinical pharmacists at each facility performed manual record reviews utilizing a standardized protocol and collection form. Completed cases were uploaded to a central database for analysis. Standardized chart abstraction was facilitated by detailed instructions, a data dictionary, and monthly conference calls.

Inclusion criteria required patient admission to any medical ward including intensive care unit (ICU) wards for 48 hours, receipt of >24 hours inpatient antimicrobial therapy (eg, at least 2 doses of a once‐daily antibiotic), documentation of pneumonia discharge diagnosis, and survival until discharge. Exclusion criteria were: complicated pneumonia (lung abscess, necrotizing pneumonia, thoracentesis performed), significant immunosuppression (cancer chemotherapy or absolute neutrophil count <1500 cell/mm³ within 28 days, organ transplantation, human immunodeficiency virus infection); or extrapulmonary infection (eg, meningitis, endocarditis).[3] Patients were also excluded if directly transferred from another inpatient facility, pneumonia occurred >48 hours after admission, index hospitalization was >14 days, previously hospitalized within 28 days prior to index admission, or discharged without documentation of completing a full course of therapy. In addition, patients who received initial therapy discordant with culture and susceptibility findings, were not clinically stable by discharge, or had gram‐negative nonfermentative bacilli cultured were excluded from analysis because according to the guidelines, either data are lacking to support a short duration of therapy such as initial discordant therapy, or a longer duration of therapy may be warranted such as gram‐negative nonfermentative bacilli and clinical instability at discharge.[4] Our intent for these exclusions was to minimize bias against clinician decision making for cases where a longer duration of therapy may have been appropriate.

Patients meeting all criteria had the following abstracted: demographics; prior healthcare exposures, admitting location (ICU or non‐ICU ward), parameters for calculation of Pneumonia Severity Index (PSI), culture results obtained 48 hours of admission, duration of antimicrobials administered during hospitalization and prescribed upon discharge (or recommendations for outpatient duration in the discharge summary for patients receiving medications from non‐VA sources), daily clinical stability assessment, Clostridium difficile infection (CDI) test results, and readmission or death within 28 days of discharge.[19]

Guideline‐similar CAP therapy duration was defined as a minimum of 5 days of antimicrobials, up to a maximum of 3 additional days beginning the first day the patient was afebrile and exhibited 1 sign of clinical instability (heart rate > 100 beats/minute, respiratory rate >24 breaths/minute, systolic blood pressure <90, oxygen saturation <90% or partial pressure of oxygen <60 mm Hg on room air or baseline O₂ requirements, or not returned to baseline mental status).[3] This definition was made by consensus decision of the investigators and was necessary to operationalize the relationship between clinical stability and appropriate duration of therapy. Guideline‐similar HCAP therapy duration was defined as 8 days.[4] CDI was defined in accordance with VA criteria for hospital onset and community‐onset healthcare‐facilityassociated CDI.[20] All‐cause hospital readmission and all‐cause death were defined as inpatient readmission or any death, respectively, within 28 days after discharge for the pneumonia admission.

Demographics, comorbidities, microbiology results, antimicrobial utilization, CDI, readmission, and death rates between guideline‐similar and guideline‐excessive duration of antimicrobial therapy groups were characterized with descriptive statistics, Mann‐Whitney U test, or ² test as indicated (significance defined as P < 0.05). Multivariable logistic regression (SAS version 9.3 [SAS Institute, Cary, NC]) was used to assess association between duration of therapy exceeding recommended guidelines with all‐cause readmission and all‐cause death after adjustment for pertinent covariates. Odds ratios (OR) with 95% confidence intervals ( 95% CI) were reported. This medication utilization evaluation (MUE) was reviewed by the Hines VHA Institutional Review Board for Human Subjects Protection. Based on VHA Policy Handbook 1058.05, which defines operations activities that may constitute research, the board determined that the evaluation constituted quality improvement rather than research, and thus was exempt from VHA Human Subjects Research requirements.

RESULTS

There were 3881 admissions eligible for chart review. After manual chart review of inclusion and exclusion criteria, 1739 (44.8%) patients were available for duration of therapy analysis. (Figure 1). Only 1 admission for each patient was analyzed.

Figure 1

The cohort was comprised primarily of elderly male patients (96.6%) of whom more than two‐thirds were hospitalized for CAP (Table 1). Most patients had significant disease severity as indicated by PSI score; however, only 12% were directly admitted to the ICU. Blood cultures were collected in >95% of cases; lower respiratory cultures were obtained in 39.9% of cases.

Commonly administered antimicrobials during hospitalization and at discharge are summarized in Table 2. Anti‐pseudomonal ‐lactams and antimethicillin‐resistant Staphylococcus aureus antimicrobials were more frequently administered to patients with HCAP, whereas third‐generation cephalosporins and macrolides were more likely to be administered to patients with CAP. Fluoroquinolones were prescribed to 55.3% of patients upon discharge.

Overall, 13.9% of patients with uncomplicated pneumonia received guideline‐similar duration of therapy (Table 3). A greater proportion of HCAP patients (29.0%) received guideline‐similar therapy duration as compared to CAP patients (6.9%) (P < 0.01 (Table 3). Median duration of therapy was 7 days (interquartile range [IQR] = 78 days) for guideline‐similar therapy compared to 10 days (913 days) for therapy duration in excess of guideline recommendations. Overall, 97.1 % of patients met clinical stability criteria before day 4 of therapy, yet 50% received 4 days of intravenous (IV) therapy (median was 4 days, IQR = 36 days). Antimicrobial therapy was generally completed after discharge, as only 17.3% received their entire treatment course during hospitalization. Median duration of outpatient oral (PO) antimicrobial therapy was twice as long for guideline‐excessive therapy compared to guideline‐similar therapy (6 vs 3 days), whereas duration of inpatient IV and PO antimicrobial therapy was similar. Patients discharged on a fluoroquinolone were more likely to receive guideline‐similar duration of therapy. The VHA classifies facilities into 3 levels of complexity, with lower scores indicating more complex facilities.[21] Guideline‐similar therapy duration occurred in 10.4% of cases in lower complexity facilities (levels 2 and 3),and 15.1% in more complex facilities (level 1) (P = 0.01). The median duration of therapy was similar for more and less complex facilities, respectively (10 days, IQR = 812 days vs 10 days, IQR = 813 days).

The 28‐day postdischarge all‐cause readmission rate for patients who received guideline‐similar therapy duration was higher (17.4%) than for patients who received therapy duration in excess of guideline recommendations (12.2%) (P = 0.03). After adjustment for covariates associated with readmission (HCAP, age, prior skilled nursing facility residence, PSI score comorbidity elements), we found no evidence that patients who received guideline‐similar therapy duration were more likely to be readmitted than were patients who received guideline‐excessive duration (OR: 1.1 [95% CI: 0.8, 1.7]) (Table 3). Likewise, no difference in 28‐day all‐cause postdischarge mortality was identified between guideline‐similar and guideline‐excessive duration after adjustment for the same covariates (adjusted OR: 0.5 [95% CI: 0.2, 1.2]) (Table 4).

CDI cases (n = 15) were too sparse to adequately perform multivariable logistic regression analysis; however, a higher percentage of patients who received guideline‐similar duration of therapy developed CDI compared to patients who received guideline‐excessive duration of therapy (40.0% vs 13.6%, P < 0.01). The median duration of therapy for patients who did and did not develop CDI was similar (8 days, IQR = 714 days vs 10 days, IQR = 812 days, P = 0.85, respectively). Patients who developed CDI had a higher rate of HCAP diagnosis (1.5% vs 0.6%; P = 0.06), were more likely to have concomitant non‐pneumonia infection (40.0% vs 9.5%, P < 0.01), have chronic comorbidity (86.7% vs 59.1%, P = 0.03), and to have been admitted to the ICU (26.7% vs 12.1%, P = 0.09).

DISCUSSION

IDSA/ATS guidelines for pneumonia duration of therapy generally agree with other professional society guidelines including the British Thoracic Society and National Institute for Health and Care Excellence.[22, 23] In contrast to existing evidence and guideline recommendations, this multi‐centered evaluation identified prolonged durations of antimicrobial therapy prescribed in 93% and 71% of patients with uncomplicated CAP and HCAP (Table 3), respectively.[3, 4, 5, 6, 7, 8, 9, 10, 11, 12] Almost all (97.1%) uncomplicated CAP and HCAP patients met clinical stability criteria before day 4 of hospitalization, yet the median duration of IV therapy was 4 days. Because criteria for IV to PO conversion and the clinical stability definition utilized in this analysis were similar, many patients may have been eligible for PO therapy earlier, favorably impacting length of stay, cost, and adverse effects.[3, 12, 24, 25, 26] Although median days of inpatient PO therapy administered was 1 day (IQR = 03 days), inpatient observation after PO conversion may not be necessary. The duration of PO therapy was based on calendar days, where if a patient received 1 dose of a once daily antibiotic (ie, levofloxacin), they were considered to have received 1 day of inpatient PO antibiotics even if discharged the same day.

Approximately half of all days of therapy occurred after discharge. Although the median therapy duration for inpatients was similar, the median duration of antimicrobials administered upon hospital discharge was twice as long for patients receiving guideline‐excessive compared to guideline‐similar duration of therapy. The median excess in antibiotic duration is almost entirely accounted for by excess outpatient days of therapy. This is an important consideration for antimicrobial stewardship programs that tend to focus on inpatient antimicrobial use.

Noteworthy observations include the low rate of respiratory tract culture collection (41%) and frequent use of fluoroquinolones upon discharge. Collection of respiratory tract cultures is recommended for all patients with HCAP and patients with CAP who have risk factors for resistant pathogens, characteristics that were common in this cohort.[3, 4] Recently, we identified that respiratory culture collection is associated with increased de‐escalation rates in HCAP, and that culture‐negative patients frequently receive fluoroquinolones.[27] IDSA/ATS CAP guidelines discourage empirically switching to PO fluoroquinolone therapy based on bioavailability considerations alone.[3] Further, fluoroquinolones are considered to be associated with high risk of CDI.[28, 29] Prescription of fluoroquinolone upon discharge was associated with guideline‐similar duration of therapy and was not shown to be associated with CDI; however, power to detect differences between exposures to specific antimicrobials and CDI was low.

CDI was more common in patients with CAP (1.2% vs 0.5%) and HCAP (3.2% vs 0.8%) who received duration of therapy similar with guideline recommendations. This observation is confounded, as patients with CDI had significantly greater comorbidity as well as secondary infections and tended to more frequently receive ICU care. There were no differences in adjusted rates of readmission or death between patients receiving guideline‐similar and guideline‐excessive duration of therapy.

Evaluation strengths included exclusion of patients with complicating conditions possibly requiring prolonged antimicrobial treatment courses, which allowed the evaluation to focus on patients most likely to benefit from shorter course therapy. The definition of appropriate therapy duration was based upon daily assessment of clinical stability criteria that paralleled the CAP guidelines. The definition utilized objective parameters while accounting for patient variability in achieving clinical stability criteria. Finally, the analyses of clinical end points suggest that shorter duration of therapy may be as safe and effective as longer duration of therapy in uncomplicated pneumonia.

Limitations include those common to other analyses conducted within the VHA, including a predominantly elderly male cohort.[30] Only ICD‐9‐CM codes consistent with a discharge diagnosis of pneumonia were used to identify the cohort, and clinical impressions not documented in the medical record may have impacted the clinician's treatment duration decisions. The upper limit of appropriate duration of therapy for CAP was arbitrarily set at up to 3 days beyond meeting clinical stability criteria to provide a reasonable duration of appropriate therapy beyond clinical stability to operationalize the duration of therapy recommendations within the context of the IDSA/ATS guidelines. Additionally, CIs for the ORs of readmission and mortality were broad, and thus too imprecise to determine whether guideline‐similar durations increased or decreased readmission or mortality in comparison with therapy that exceeded guideline recommendations. We could not fully assess the potential for association between guideline‐excessive therapy duration and risk for CDI due to sparse cases. Finally, non‐VA prescription data were not available for all patients, and we relied on intended duration of therapy as recommended by the discharging provider in 4.1% of cases.

Most quality assessments of pneumonia treatment have focused on antimicrobial selection and timely administration or conversion from IV to PO therapy.[31, 32] This evaluation identified potential opportunities for expansion of antimicrobial stewardship activities during the transition of care setting. The efficacy of short‐course ‐lactam, macrolide, or fluoroquinolone therapy for CAP appears equivalent to longer treatment regimens with no difference in adverse event rates, suggesting that optimal duration of therapy may be a rational target for quality improvement.[5, 6, 7, 8, 9, 10, 11, 12, 15, 31] Recommendations for HCAP duration of therapy are extrapolated from a prospective multicentered study, which randomized patients with hospital‐acquired pneumonia to receive 8 versus 15 days of therapy, that identified similar outcomes to ours.[4, 12]

Single‐center studies have identified that antimicrobial therapy for pneumonia is frequently prescribed for longer than recommended by guidelines, which found a similar median duration of therapy as our evaluation.[15, 16] Similar to Jenkins et al., we observed a high rate of fluoroquinolone prescriptions upon discharge.[16]

There are few published examples of interventions designed to limit excessive duration of therapy, particularly for antimicrobials prescribed upon hospital discharge.[15, 33, 34] Serial procalcitonin measurements have been used to guide duration of therapy for pneumonia; however, the costbenefit ratio of procalcitonin measurement is unclear.[35, 36] Procalcitonin use was uncommon, and none of the participating facilities in our evaluation utilized a specific algorithm to guide therapy duration. Limited data suggest that patient‐level prospective audit with feedback may be effective. Advic et al. evaluated management of presumed CAP before and after education and prospective feedback to medical teams concerning antimicrobial selection and duration of therapy.[15] The intervention led to a decrease in median duration of therapy from 10 days (IQR = 813 days) to 7 days (IQR = 78 days) without increasing clinical failure or readmission rates. We recently reported a single‐center evaluation in which pharmacists utilizing a decision support tool while performing discharge medication reconciliation were able to reduce excessive mean duration of therapy from 9.5 days ( 2.4 days) to 8.3 days ( 2.9 days) in patients without complicated pneumonia, with a 19.2% reduction in duration of therapy prescribed at discharge.[37] A similar approach utilizing pharmacists performing discharge review has recently been reported in a community hospital.[38]

Future work should recognize that few patients complete their entire course of therapy as inpatients, and the majority of treatment is prescribed upon discharge. Pivotal time points for antimicrobial stewardship intervention include day 2 to 3 of hospitalization when conveying suggestions for antimicrobial de‐escalation and/or IV to PO conversion, and toward the end of hospitalization during discharge planning. Although it may not be feasible for antimicrobial stewards to review all uncomplicated cases of pneumonia during hospitalization, most facilities have a systematic process for reviewing medications during transitions of care. We believe that interventions intended to assess and recommend shortened courses of therapy are appropriate. These interventions should include a mechanism for support by stewardship personnel or other infectious diseases specialists. Based on our evaluation, the ASTF produced and disseminated clinical guidance documents and tools to triage pneumonia case severity and assess response to therapy. Qualified personnel are encouraged to use this information to make recommendations to providers regarding excessive duration of therapy for uncomplicated cases where appropriate. Other work should include an in‐depth assessment of clinical outcomes related to treatment duration, investigation of provider rationale for prolonged treatment, and duration of antimicrobial therapy prescribed upon discharge for other common disease states. Finally, manual chart review to classify uncomplicated cases and related outcomes was laborious, and automated case identification is technologically plausible and should be explored.[39]

In conclusion, this national VHA MUE found that patients with uncomplicated pneumonia were commonly prescribed antimicrobials for the duration of therapy in excess of guideline recommendations. Patients with uncomplicated pneumonia who received therapy duration consistent with guideline recommendations did not have significantly different all‐cause readmission and death rates compared to patients receiving prolonged treatment. Approximately half of all therapy was prescribed upon hospital discharge, and clinicians as well as antimicrobial stewardship programs should consider these findings to address excessive duration of antimicrobial therapy upon hospital discharge.

Disclosures: Karl Madaras‐Kelly is employed full time by Idaho State University and has a without compensation appointment as a clinical pharmacist at the Boise VA Medical Center. He receives grant support unrelated to this work through the Department of Veterans Affairs subcontracted to Idaho State University. Muriel Burk is employed full time through the Department of Veterans Affairs as clinical pharmacy specialist in outcomes and medication safety evaluation. Christina Caplinger was employed by the Department of Veterans Affairs as an infectious diseases fellow at the time this work was completed. She is currently employed by Micromedex. Jefferson Bohan is employed full time by the Department of Veterans Affairs as an infectious diseases fellow. Melinda Neuhauser is employed full time through the Department of Veterans Affairs as a clinical pharmacy specialistinfectious diseases. Matthew Goetz is employed full time through the Department of Veterans Affairs as an infectious diseases physician. Rhongping Zhang is employed full time through the Department of Veterans Affairs as a data analyst. Francesca Cunningham is employed full time through the Department of Veterans Affairs as the director of the VA Center for Medication Safety. This work was supported with resources and use of the Department of Veterans Affairs healthcare system. The views expressed in this article are solely those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The authors report no conflicts of interest.

Pneumonia is the leading inpatient infectious diagnosis for which antimicrobials are prescribed in the United States.[1] Supported by moderate‐ to high‐quality evidence, guidelines produced jointly by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) recommend treating pneumonia with the shortest appropriate duration of antimicrobial therapy to minimize risk for antimicrobial‐related adverse events.[2, 3, 4]

Evidence supports short duration of therapy for treatment of uncomplicated pneumonia.[3, 4, 5, 6, 7, 8, 9, 10, 11, 12] IDSA/ATS guidelines state, patients with CAP [community‐acquired pneumonia] should be treated for a minimum of 5 days (level 1 evidence), should be afebrile for 4872 hours, and should have no more than 1 CAP‐associated sign of clinical instabilitybefore discontinuation of therapy (level II evidence). (Moderate recommendation.) A longer duration of therapy may be warranted if initial therapy was not active against the identified pathogen or if it was complicated by [abscess, empyema, severe immunosuppression, or] extra‐pulmonary infection such as meningitis or endocarditis. (Weak recommendation; level III evidence).[3] Recommended therapy duration for patients with uncomplicated healthcare‐associated pneumonia (HCAP) who respond to initial therapy is 7 to 8 days unless gram‐negative nonfermenting rods or complications are identified (level I evidence).[4]

Within the Veterans Health Administration (VHA), the Antimicrobial Stewardship Taskforce (ASTF) was created to optimize care by developing, deploying, and monitoring a national‐level strategic plan for antimicrobial therapy management improvements.[13, 14] Although single‐center studies have found antimicrobial therapy for CAP being frequently prescribed for longer than recommended, the reproducibility of this finding across different facilities has not been assessed.[15, 16] The ASTF collaborated with the VHA Center for Medication Safety to assess total duration of antimicrobial therapy prescribed for veterans hospitalized with uncomplicated pneumonia.[17]

METHODS

This retrospective multicenter evaluation was conducted in 30 VHA facilities that volunteered to participate in this project. Inpatients discharged with a primary International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) diagnosis code for pneumonia (or pneumonia diagnosis secondary to primary sepsis diagnosis) during 2013 were evaluated.[18] Diagnoses, admissions, and patient demographics were identified using Veterans Affairs (VA) integrated databases through the Austin Integrated Technology Center. Up to 200 admissions per facility were randomly selected for review. Clinical pharmacists at each facility performed manual record reviews utilizing a standardized protocol and collection form. Completed cases were uploaded to a central database for analysis. Standardized chart abstraction was facilitated by detailed instructions, a data dictionary, and monthly conference calls.

Inclusion criteria required patient admission to any medical ward including intensive care unit (ICU) wards for 48 hours, receipt of >24 hours inpatient antimicrobial therapy (eg, at least 2 doses of a once‐daily antibiotic), documentation of pneumonia discharge diagnosis, and survival until discharge. Exclusion criteria were: complicated pneumonia (lung abscess, necrotizing pneumonia, thoracentesis performed), significant immunosuppression (cancer chemotherapy or absolute neutrophil count <1500 cell/mm³ within 28 days, organ transplantation, human immunodeficiency virus infection); or extrapulmonary infection (eg, meningitis, endocarditis).[3] Patients were also excluded if directly transferred from another inpatient facility, pneumonia occurred >48 hours after admission, index hospitalization was >14 days, previously hospitalized within 28 days prior to index admission, or discharged without documentation of completing a full course of therapy. In addition, patients who received initial therapy discordant with culture and susceptibility findings, were not clinically stable by discharge, or had gram‐negative nonfermentative bacilli cultured were excluded from analysis because according to the guidelines, either data are lacking to support a short duration of therapy such as initial discordant therapy, or a longer duration of therapy may be warranted such as gram‐negative nonfermentative bacilli and clinical instability at discharge.[4] Our intent for these exclusions was to minimize bias against clinician decision making for cases where a longer duration of therapy may have been appropriate.

Patients meeting all criteria had the following abstracted: demographics; prior healthcare exposures, admitting location (ICU or non‐ICU ward), parameters for calculation of Pneumonia Severity Index (PSI), culture results obtained 48 hours of admission, duration of antimicrobials administered during hospitalization and prescribed upon discharge (or recommendations for outpatient duration in the discharge summary for patients receiving medications from non‐VA sources), daily clinical stability assessment, Clostridium difficile infection (CDI) test results, and readmission or death within 28 days of discharge.[19]

Guideline‐similar CAP therapy duration was defined as a minimum of 5 days of antimicrobials, up to a maximum of 3 additional days beginning the first day the patient was afebrile and exhibited 1 sign of clinical instability (heart rate > 100 beats/minute, respiratory rate >24 breaths/minute, systolic blood pressure <90, oxygen saturation <90% or partial pressure of oxygen <60 mm Hg on room air or baseline O₂ requirements, or not returned to baseline mental status).[3] This definition was made by consensus decision of the investigators and was necessary to operationalize the relationship between clinical stability and appropriate duration of therapy. Guideline‐similar HCAP therapy duration was defined as 8 days.[4] CDI was defined in accordance with VA criteria for hospital onset and community‐onset healthcare‐facilityassociated CDI.[20] All‐cause hospital readmission and all‐cause death were defined as inpatient readmission or any death, respectively, within 28 days after discharge for the pneumonia admission.

Demographics, comorbidities, microbiology results, antimicrobial utilization, CDI, readmission, and death rates between guideline‐similar and guideline‐excessive duration of antimicrobial therapy groups were characterized with descriptive statistics, Mann‐Whitney U test, or ² test as indicated (significance defined as P < 0.05). Multivariable logistic regression (SAS version 9.3 [SAS Institute, Cary, NC]) was used to assess association between duration of therapy exceeding recommended guidelines with all‐cause readmission and all‐cause death after adjustment for pertinent covariates. Odds ratios (OR) with 95% confidence intervals ( 95% CI) were reported. This medication utilization evaluation (MUE) was reviewed by the Hines VHA Institutional Review Board for Human Subjects Protection. Based on VHA Policy Handbook 1058.05, which defines operations activities that may constitute research, the board determined that the evaluation constituted quality improvement rather than research, and thus was exempt from VHA Human Subjects Research requirements.

RESULTS

There were 3881 admissions eligible for chart review. After manual chart review of inclusion and exclusion criteria, 1739 (44.8%) patients were available for duration of therapy analysis. (Figure 1). Only 1 admission for each patient was analyzed.

Figure 1

The cohort was comprised primarily of elderly male patients (96.6%) of whom more than two‐thirds were hospitalized for CAP (Table 1). Most patients had significant disease severity as indicated by PSI score; however, only 12% were directly admitted to the ICU. Blood cultures were collected in >95% of cases; lower respiratory cultures were obtained in 39.9% of cases.

Commonly administered antimicrobials during hospitalization and at discharge are summarized in Table 2. Anti‐pseudomonal ‐lactams and antimethicillin‐resistant Staphylococcus aureus antimicrobials were more frequently administered to patients with HCAP, whereas third‐generation cephalosporins and macrolides were more likely to be administered to patients with CAP. Fluoroquinolones were prescribed to 55.3% of patients upon discharge.

Overall, 13.9% of patients with uncomplicated pneumonia received guideline‐similar duration of therapy (Table 3). A greater proportion of HCAP patients (29.0%) received guideline‐similar therapy duration as compared to CAP patients (6.9%) (P < 0.01 (Table 3). Median duration of therapy was 7 days (interquartile range [IQR] = 78 days) for guideline‐similar therapy compared to 10 days (913 days) for therapy duration in excess of guideline recommendations. Overall, 97.1 % of patients met clinical stability criteria before day 4 of therapy, yet 50% received 4 days of intravenous (IV) therapy (median was 4 days, IQR = 36 days). Antimicrobial therapy was generally completed after discharge, as only 17.3% received their entire treatment course during hospitalization. Median duration of outpatient oral (PO) antimicrobial therapy was twice as long for guideline‐excessive therapy compared to guideline‐similar therapy (6 vs 3 days), whereas duration of inpatient IV and PO antimicrobial therapy was similar. Patients discharged on a fluoroquinolone were more likely to receive guideline‐similar duration of therapy. The VHA classifies facilities into 3 levels of complexity, with lower scores indicating more complex facilities.[21] Guideline‐similar therapy duration occurred in 10.4% of cases in lower complexity facilities (levels 2 and 3),and 15.1% in more complex facilities (level 1) (P = 0.01). The median duration of therapy was similar for more and less complex facilities, respectively (10 days, IQR = 812 days vs 10 days, IQR = 813 days).

The 28‐day postdischarge all‐cause readmission rate for patients who received guideline‐similar therapy duration was higher (17.4%) than for patients who received therapy duration in excess of guideline recommendations (12.2%) (P = 0.03). After adjustment for covariates associated with readmission (HCAP, age, prior skilled nursing facility residence, PSI score comorbidity elements), we found no evidence that patients who received guideline‐similar therapy duration were more likely to be readmitted than were patients who received guideline‐excessive duration (OR: 1.1 [95% CI: 0.8, 1.7]) (Table 3). Likewise, no difference in 28‐day all‐cause postdischarge mortality was identified between guideline‐similar and guideline‐excessive duration after adjustment for the same covariates (adjusted OR: 0.5 [95% CI: 0.2, 1.2]) (Table 4).

CDI cases (n = 15) were too sparse to adequately perform multivariable logistic regression analysis; however, a higher percentage of patients who received guideline‐similar duration of therapy developed CDI compared to patients who received guideline‐excessive duration of therapy (40.0% vs 13.6%, P < 0.01). The median duration of therapy for patients who did and did not develop CDI was similar (8 days, IQR = 714 days vs 10 days, IQR = 812 days, P = 0.85, respectively). Patients who developed CDI had a higher rate of HCAP diagnosis (1.5% vs 0.6%; P = 0.06), were more likely to have concomitant non‐pneumonia infection (40.0% vs 9.5%, P < 0.01), have chronic comorbidity (86.7% vs 59.1%, P = 0.03), and to have been admitted to the ICU (26.7% vs 12.1%, P = 0.09).

DISCUSSION

IDSA/ATS guidelines for pneumonia duration of therapy generally agree with other professional society guidelines including the British Thoracic Society and National Institute for Health and Care Excellence.[22, 23] In contrast to existing evidence and guideline recommendations, this multi‐centered evaluation identified prolonged durations of antimicrobial therapy prescribed in 93% and 71% of patients with uncomplicated CAP and HCAP (Table 3), respectively.[3, 4, 5, 6, 7, 8, 9, 10, 11, 12] Almost all (97.1%) uncomplicated CAP and HCAP patients met clinical stability criteria before day 4 of hospitalization, yet the median duration of IV therapy was 4 days. Because criteria for IV to PO conversion and the clinical stability definition utilized in this analysis were similar, many patients may have been eligible for PO therapy earlier, favorably impacting length of stay, cost, and adverse effects.[3, 12, 24, 25, 26] Although median days of inpatient PO therapy administered was 1 day (IQR = 03 days), inpatient observation after PO conversion may not be necessary. The duration of PO therapy was based on calendar days, where if a patient received 1 dose of a once daily antibiotic (ie, levofloxacin), they were considered to have received 1 day of inpatient PO antibiotics even if discharged the same day.

Approximately half of all days of therapy occurred after discharge. Although the median therapy duration for inpatients was similar, the median duration of antimicrobials administered upon hospital discharge was twice as long for patients receiving guideline‐excessive compared to guideline‐similar duration of therapy. The median excess in antibiotic duration is almost entirely accounted for by excess outpatient days of therapy. This is an important consideration for antimicrobial stewardship programs that tend to focus on inpatient antimicrobial use.

Noteworthy observations include the low rate of respiratory tract culture collection (41%) and frequent use of fluoroquinolones upon discharge. Collection of respiratory tract cultures is recommended for all patients with HCAP and patients with CAP who have risk factors for resistant pathogens, characteristics that were common in this cohort.[3, 4] Recently, we identified that respiratory culture collection is associated with increased de‐escalation rates in HCAP, and that culture‐negative patients frequently receive fluoroquinolones.[27] IDSA/ATS CAP guidelines discourage empirically switching to PO fluoroquinolone therapy based on bioavailability considerations alone.[3] Further, fluoroquinolones are considered to be associated with high risk of CDI.[28, 29] Prescription of fluoroquinolone upon discharge was associated with guideline‐similar duration of therapy and was not shown to be associated with CDI; however, power to detect differences between exposures to specific antimicrobials and CDI was low.

CDI was more common in patients with CAP (1.2% vs 0.5%) and HCAP (3.2% vs 0.8%) who received duration of therapy similar with guideline recommendations. This observation is confounded, as patients with CDI had significantly greater comorbidity as well as secondary infections and tended to more frequently receive ICU care. There were no differences in adjusted rates of readmission or death between patients receiving guideline‐similar and guideline‐excessive duration of therapy.

Evaluation strengths included exclusion of patients with complicating conditions possibly requiring prolonged antimicrobial treatment courses, which allowed the evaluation to focus on patients most likely to benefit from shorter course therapy. The definition of appropriate therapy duration was based upon daily assessment of clinical stability criteria that paralleled the CAP guidelines. The definition utilized objective parameters while accounting for patient variability in achieving clinical stability criteria. Finally, the analyses of clinical end points suggest that shorter duration of therapy may be as safe and effective as longer duration of therapy in uncomplicated pneumonia.

Limitations include those common to other analyses conducted within the VHA, including a predominantly elderly male cohort.[30] Only ICD‐9‐CM codes consistent with a discharge diagnosis of pneumonia were used to identify the cohort, and clinical impressions not documented in the medical record may have impacted the clinician's treatment duration decisions. The upper limit of appropriate duration of therapy for CAP was arbitrarily set at up to 3 days beyond meeting clinical stability criteria to provide a reasonable duration of appropriate therapy beyond clinical stability to operationalize the duration of therapy recommendations within the context of the IDSA/ATS guidelines. Additionally, CIs for the ORs of readmission and mortality were broad, and thus too imprecise to determine whether guideline‐similar durations increased or decreased readmission or mortality in comparison with therapy that exceeded guideline recommendations. We could not fully assess the potential for association between guideline‐excessive therapy duration and risk for CDI due to sparse cases. Finally, non‐VA prescription data were not available for all patients, and we relied on intended duration of therapy as recommended by the discharging provider in 4.1% of cases.

Most quality assessments of pneumonia treatment have focused on antimicrobial selection and timely administration or conversion from IV to PO therapy.[31, 32] This evaluation identified potential opportunities for expansion of antimicrobial stewardship activities during the transition of care setting. The efficacy of short‐course ‐lactam, macrolide, or fluoroquinolone therapy for CAP appears equivalent to longer treatment regimens with no difference in adverse event rates, suggesting that optimal duration of therapy may be a rational target for quality improvement.[5, 6, 7, 8, 9, 10, 11, 12, 15, 31] Recommendations for HCAP duration of therapy are extrapolated from a prospective multicentered study, which randomized patients with hospital‐acquired pneumonia to receive 8 versus 15 days of therapy, that identified similar outcomes to ours.[4, 12]

Single‐center studies have identified that antimicrobial therapy for pneumonia is frequently prescribed for longer than recommended by guidelines, which found a similar median duration of therapy as our evaluation.[15, 16] Similar to Jenkins et al., we observed a high rate of fluoroquinolone prescriptions upon discharge.[16]

There are few published examples of interventions designed to limit excessive duration of therapy, particularly for antimicrobials prescribed upon hospital discharge.[15, 33, 34] Serial procalcitonin measurements have been used to guide duration of therapy for pneumonia; however, the costbenefit ratio of procalcitonin measurement is unclear.[35, 36] Procalcitonin use was uncommon, and none of the participating facilities in our evaluation utilized a specific algorithm to guide therapy duration. Limited data suggest that patient‐level prospective audit with feedback may be effective. Advic et al. evaluated management of presumed CAP before and after education and prospective feedback to medical teams concerning antimicrobial selection and duration of therapy.[15] The intervention led to a decrease in median duration of therapy from 10 days (IQR = 813 days) to 7 days (IQR = 78 days) without increasing clinical failure or readmission rates. We recently reported a single‐center evaluation in which pharmacists utilizing a decision support tool while performing discharge medication reconciliation were able to reduce excessive mean duration of therapy from 9.5 days ( 2.4 days) to 8.3 days ( 2.9 days) in patients without complicated pneumonia, with a 19.2% reduction in duration of therapy prescribed at discharge.[37] A similar approach utilizing pharmacists performing discharge review has recently been reported in a community hospital.[38]

Future work should recognize that few patients complete their entire course of therapy as inpatients, and the majority of treatment is prescribed upon discharge. Pivotal time points for antimicrobial stewardship intervention include day 2 to 3 of hospitalization when conveying suggestions for antimicrobial de‐escalation and/or IV to PO conversion, and toward the end of hospitalization during discharge planning. Although it may not be feasible for antimicrobial stewards to review all uncomplicated cases of pneumonia during hospitalization, most facilities have a systematic process for reviewing medications during transitions of care. We believe that interventions intended to assess and recommend shortened courses of therapy are appropriate. These interventions should include a mechanism for support by stewardship personnel or other infectious diseases specialists. Based on our evaluation, the ASTF produced and disseminated clinical guidance documents and tools to triage pneumonia case severity and assess response to therapy. Qualified personnel are encouraged to use this information to make recommendations to providers regarding excessive duration of therapy for uncomplicated cases where appropriate. Other work should include an in‐depth assessment of clinical outcomes related to treatment duration, investigation of provider rationale for prolonged treatment, and duration of antimicrobial therapy prescribed upon discharge for other common disease states. Finally, manual chart review to classify uncomplicated cases and related outcomes was laborious, and automated case identification is technologically plausible and should be explored.[39]

In conclusion, this national VHA MUE found that patients with uncomplicated pneumonia were commonly prescribed antimicrobials for the duration of therapy in excess of guideline recommendations. Patients with uncomplicated pneumonia who received therapy duration consistent with guideline recommendations did not have significantly different all‐cause readmission and death rates compared to patients receiving prolonged treatment. Approximately half of all therapy was prescribed upon hospital discharge, and clinicians as well as antimicrobial stewardship programs should consider these findings to address excessive duration of antimicrobial therapy upon hospital discharge.

Disclosures: Karl Madaras‐Kelly is employed full time by Idaho State University and has a without compensation appointment as a clinical pharmacist at the Boise VA Medical Center. He receives grant support unrelated to this work through the Department of Veterans Affairs subcontracted to Idaho State University. Muriel Burk is employed full time through the Department of Veterans Affairs as clinical pharmacy specialist in outcomes and medication safety evaluation. Christina Caplinger was employed by the Department of Veterans Affairs as an infectious diseases fellow at the time this work was completed. She is currently employed by Micromedex. Jefferson Bohan is employed full time by the Department of Veterans Affairs as an infectious diseases fellow. Melinda Neuhauser is employed full time through the Department of Veterans Affairs as a clinical pharmacy specialistinfectious diseases. Matthew Goetz is employed full time through the Department of Veterans Affairs as an infectious diseases physician. Rhongping Zhang is employed full time through the Department of Veterans Affairs as a data analyst. Francesca Cunningham is employed full time through the Department of Veterans Affairs as the director of the VA Center for Medication Safety. This work was supported with resources and use of the Department of Veterans Affairs healthcare system. The views expressed in this article are solely those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The authors report no conflicts of interest.

Pneumonia is the leading inpatient infectious diagnosis for which antimicrobials are prescribed in the United States.[1] Supported by moderate‐ to high‐quality evidence, guidelines produced jointly by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) recommend treating pneumonia with the shortest appropriate duration of antimicrobial therapy to minimize risk for antimicrobial‐related adverse events.[2, 3, 4]

Evidence supports short duration of therapy for treatment of uncomplicated pneumonia.[3, 4, 5, 6, 7, 8, 9, 10, 11, 12] IDSA/ATS guidelines state, patients with CAP [community‐acquired pneumonia] should be treated for a minimum of 5 days (level 1 evidence), should be afebrile for 4872 hours, and should have no more than 1 CAP‐associated sign of clinical instabilitybefore discontinuation of therapy (level II evidence). (Moderate recommendation.) A longer duration of therapy may be warranted if initial therapy was not active against the identified pathogen or if it was complicated by [abscess, empyema, severe immunosuppression, or] extra‐pulmonary infection such as meningitis or endocarditis. (Weak recommendation; level III evidence).[3] Recommended therapy duration for patients with uncomplicated healthcare‐associated pneumonia (HCAP) who respond to initial therapy is 7 to 8 days unless gram‐negative nonfermenting rods or complications are identified (level I evidence).[4]

Within the Veterans Health Administration (VHA), the Antimicrobial Stewardship Taskforce (ASTF) was created to optimize care by developing, deploying, and monitoring a national‐level strategic plan for antimicrobial therapy management improvements.[13, 14] Although single‐center studies have found antimicrobial therapy for CAP being frequently prescribed for longer than recommended, the reproducibility of this finding across different facilities has not been assessed.[15, 16] The ASTF collaborated with the VHA Center for Medication Safety to assess total duration of antimicrobial therapy prescribed for veterans hospitalized with uncomplicated pneumonia.[17]

METHODS

This retrospective multicenter evaluation was conducted in 30 VHA facilities that volunteered to participate in this project. Inpatients discharged with a primary International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) diagnosis code for pneumonia (or pneumonia diagnosis secondary to primary sepsis diagnosis) during 2013 were evaluated.[18] Diagnoses, admissions, and patient demographics were identified using Veterans Affairs (VA) integrated databases through the Austin Integrated Technology Center. Up to 200 admissions per facility were randomly selected for review. Clinical pharmacists at each facility performed manual record reviews utilizing a standardized protocol and collection form. Completed cases were uploaded to a central database for analysis. Standardized chart abstraction was facilitated by detailed instructions, a data dictionary, and monthly conference calls.

Inclusion criteria required patient admission to any medical ward including intensive care unit (ICU) wards for 48 hours, receipt of >24 hours inpatient antimicrobial therapy (eg, at least 2 doses of a once‐daily antibiotic), documentation of pneumonia discharge diagnosis, and survival until discharge. Exclusion criteria were: complicated pneumonia (lung abscess, necrotizing pneumonia, thoracentesis performed), significant immunosuppression (cancer chemotherapy or absolute neutrophil count <1500 cell/mm³ within 28 days, organ transplantation, human immunodeficiency virus infection); or extrapulmonary infection (eg, meningitis, endocarditis).[3] Patients were also excluded if directly transferred from another inpatient facility, pneumonia occurred >48 hours after admission, index hospitalization was >14 days, previously hospitalized within 28 days prior to index admission, or discharged without documentation of completing a full course of therapy. In addition, patients who received initial therapy discordant with culture and susceptibility findings, were not clinically stable by discharge, or had gram‐negative nonfermentative bacilli cultured were excluded from analysis because according to the guidelines, either data are lacking to support a short duration of therapy such as initial discordant therapy, or a longer duration of therapy may be warranted such as gram‐negative nonfermentative bacilli and clinical instability at discharge.[4] Our intent for these exclusions was to minimize bias against clinician decision making for cases where a longer duration of therapy may have been appropriate.

Patients meeting all criteria had the following abstracted: demographics; prior healthcare exposures, admitting location (ICU or non‐ICU ward), parameters for calculation of Pneumonia Severity Index (PSI), culture results obtained 48 hours of admission, duration of antimicrobials administered during hospitalization and prescribed upon discharge (or recommendations for outpatient duration in the discharge summary for patients receiving medications from non‐VA sources), daily clinical stability assessment, Clostridium difficile infection (CDI) test results, and readmission or death within 28 days of discharge.[19]

Guideline‐similar CAP therapy duration was defined as a minimum of 5 days of antimicrobials, up to a maximum of 3 additional days beginning the first day the patient was afebrile and exhibited 1 sign of clinical instability (heart rate > 100 beats/minute, respiratory rate >24 breaths/minute, systolic blood pressure <90, oxygen saturation <90% or partial pressure of oxygen <60 mm Hg on room air or baseline O₂ requirements, or not returned to baseline mental status).[3] This definition was made by consensus decision of the investigators and was necessary to operationalize the relationship between clinical stability and appropriate duration of therapy. Guideline‐similar HCAP therapy duration was defined as 8 days.[4] CDI was defined in accordance with VA criteria for hospital onset and community‐onset healthcare‐facilityassociated CDI.[20] All‐cause hospital readmission and all‐cause death were defined as inpatient readmission or any death, respectively, within 28 days after discharge for the pneumonia admission.

Demographics, comorbidities, microbiology results, antimicrobial utilization, CDI, readmission, and death rates between guideline‐similar and guideline‐excessive duration of antimicrobial therapy groups were characterized with descriptive statistics, Mann‐Whitney U test, or ² test as indicated (significance defined as P < 0.05). Multivariable logistic regression (SAS version 9.3 [SAS Institute, Cary, NC]) was used to assess association between duration of therapy exceeding recommended guidelines with all‐cause readmission and all‐cause death after adjustment for pertinent covariates. Odds ratios (OR) with 95% confidence intervals ( 95% CI) were reported. This medication utilization evaluation (MUE) was reviewed by the Hines VHA Institutional Review Board for Human Subjects Protection. Based on VHA Policy Handbook 1058.05, which defines operations activities that may constitute research, the board determined that the evaluation constituted quality improvement rather than research, and thus was exempt from VHA Human Subjects Research requirements.

RESULTS

There were 3881 admissions eligible for chart review. After manual chart review of inclusion and exclusion criteria, 1739 (44.8%) patients were available for duration of therapy analysis. (Figure 1). Only 1 admission for each patient was analyzed.

Figure 1

The cohort was comprised primarily of elderly male patients (96.6%) of whom more than two‐thirds were hospitalized for CAP (Table 1). Most patients had significant disease severity as indicated by PSI score; however, only 12% were directly admitted to the ICU. Blood cultures were collected in >95% of cases; lower respiratory cultures were obtained in 39.9% of cases.

Commonly administered antimicrobials during hospitalization and at discharge are summarized in Table 2. Anti‐pseudomonal ‐lactams and antimethicillin‐resistant Staphylococcus aureus antimicrobials were more frequently administered to patients with HCAP, whereas third‐generation cephalosporins and macrolides were more likely to be administered to patients with CAP. Fluoroquinolones were prescribed to 55.3% of patients upon discharge.

Overall, 13.9% of patients with uncomplicated pneumonia received guideline‐similar duration of therapy (Table 3). A greater proportion of HCAP patients (29.0%) received guideline‐similar therapy duration as compared to CAP patients (6.9%) (P < 0.01 (Table 3). Median duration of therapy was 7 days (interquartile range [IQR] = 78 days) for guideline‐similar therapy compared to 10 days (913 days) for therapy duration in excess of guideline recommendations. Overall, 97.1 % of patients met clinical stability criteria before day 4 of therapy, yet 50% received 4 days of intravenous (IV) therapy (median was 4 days, IQR = 36 days). Antimicrobial therapy was generally completed after discharge, as only 17.3% received their entire treatment course during hospitalization. Median duration of outpatient oral (PO) antimicrobial therapy was twice as long for guideline‐excessive therapy compared to guideline‐similar therapy (6 vs 3 days), whereas duration of inpatient IV and PO antimicrobial therapy was similar. Patients discharged on a fluoroquinolone were more likely to receive guideline‐similar duration of therapy. The VHA classifies facilities into 3 levels of complexity, with lower scores indicating more complex facilities.[21] Guideline‐similar therapy duration occurred in 10.4% of cases in lower complexity facilities (levels 2 and 3),and 15.1% in more complex facilities (level 1) (P = 0.01). The median duration of therapy was similar for more and less complex facilities, respectively (10 days, IQR = 812 days vs 10 days, IQR = 813 days).

The 28‐day postdischarge all‐cause readmission rate for patients who received guideline‐similar therapy duration was higher (17.4%) than for patients who received therapy duration in excess of guideline recommendations (12.2%) (P = 0.03). After adjustment for covariates associated with readmission (HCAP, age, prior skilled nursing facility residence, PSI score comorbidity elements), we found no evidence that patients who received guideline‐similar therapy duration were more likely to be readmitted than were patients who received guideline‐excessive duration (OR: 1.1 [95% CI: 0.8, 1.7]) (Table 3). Likewise, no difference in 28‐day all‐cause postdischarge mortality was identified between guideline‐similar and guideline‐excessive duration after adjustment for the same covariates (adjusted OR: 0.5 [95% CI: 0.2, 1.2]) (Table 4).

CDI cases (n = 15) were too sparse to adequately perform multivariable logistic regression analysis; however, a higher percentage of patients who received guideline‐similar duration of therapy developed CDI compared to patients who received guideline‐excessive duration of therapy (40.0% vs 13.6%, P < 0.01). The median duration of therapy for patients who did and did not develop CDI was similar (8 days, IQR = 714 days vs 10 days, IQR = 812 days, P = 0.85, respectively). Patients who developed CDI had a higher rate of HCAP diagnosis (1.5% vs 0.6%; P = 0.06), were more likely to have concomitant non‐pneumonia infection (40.0% vs 9.5%, P < 0.01), have chronic comorbidity (86.7% vs 59.1%, P = 0.03), and to have been admitted to the ICU (26.7% vs 12.1%, P = 0.09).

DISCUSSION

IDSA/ATS guidelines for pneumonia duration of therapy generally agree with other professional society guidelines including the British Thoracic Society and National Institute for Health and Care Excellence.[22, 23] In contrast to existing evidence and guideline recommendations, this multi‐centered evaluation identified prolonged durations of antimicrobial therapy prescribed in 93% and 71% of patients with uncomplicated CAP and HCAP (Table 3), respectively.[3, 4, 5, 6, 7, 8, 9, 10, 11, 12] Almost all (97.1%) uncomplicated CAP and HCAP patients met clinical stability criteria before day 4 of hospitalization, yet the median duration of IV therapy was 4 days. Because criteria for IV to PO conversion and the clinical stability definition utilized in this analysis were similar, many patients may have been eligible for PO therapy earlier, favorably impacting length of stay, cost, and adverse effects.[3, 12, 24, 25, 26] Although median days of inpatient PO therapy administered was 1 day (IQR = 03 days), inpatient observation after PO conversion may not be necessary. The duration of PO therapy was based on calendar days, where if a patient received 1 dose of a once daily antibiotic (ie, levofloxacin), they were considered to have received 1 day of inpatient PO antibiotics even if discharged the same day.

Approximately half of all days of therapy occurred after discharge. Although the median therapy duration for inpatients was similar, the median duration of antimicrobials administered upon hospital discharge was twice as long for patients receiving guideline‐excessive compared to guideline‐similar duration of therapy. The median excess in antibiotic duration is almost entirely accounted for by excess outpatient days of therapy. This is an important consideration for antimicrobial stewardship programs that tend to focus on inpatient antimicrobial use.

Noteworthy observations include the low rate of respiratory tract culture collection (41%) and frequent use of fluoroquinolones upon discharge. Collection of respiratory tract cultures is recommended for all patients with HCAP and patients with CAP who have risk factors for resistant pathogens, characteristics that were common in this cohort.[3, 4] Recently, we identified that respiratory culture collection is associated with increased de‐escalation rates in HCAP, and that culture‐negative patients frequently receive fluoroquinolones.[27] IDSA/ATS CAP guidelines discourage empirically switching to PO fluoroquinolone therapy based on bioavailability considerations alone.[3] Further, fluoroquinolones are considered to be associated with high risk of CDI.[28, 29] Prescription of fluoroquinolone upon discharge was associated with guideline‐similar duration of therapy and was not shown to be associated with CDI; however, power to detect differences between exposures to specific antimicrobials and CDI was low.

CDI was more common in patients with CAP (1.2% vs 0.5%) and HCAP (3.2% vs 0.8%) who received duration of therapy similar with guideline recommendations. This observation is confounded, as patients with CDI had significantly greater comorbidity as well as secondary infections and tended to more frequently receive ICU care. There were no differences in adjusted rates of readmission or death between patients receiving guideline‐similar and guideline‐excessive duration of therapy.

Evaluation strengths included exclusion of patients with complicating conditions possibly requiring prolonged antimicrobial treatment courses, which allowed the evaluation to focus on patients most likely to benefit from shorter course therapy. The definition of appropriate therapy duration was based upon daily assessment of clinical stability criteria that paralleled the CAP guidelines. The definition utilized objective parameters while accounting for patient variability in achieving clinical stability criteria. Finally, the analyses of clinical end points suggest that shorter duration of therapy may be as safe and effective as longer duration of therapy in uncomplicated pneumonia.

Limitations include those common to other analyses conducted within the VHA, including a predominantly elderly male cohort.[30] Only ICD‐9‐CM codes consistent with a discharge diagnosis of pneumonia were used to identify the cohort, and clinical impressions not documented in the medical record may have impacted the clinician's treatment duration decisions. The upper limit of appropriate duration of therapy for CAP was arbitrarily set at up to 3 days beyond meeting clinical stability criteria to provide a reasonable duration of appropriate therapy beyond clinical stability to operationalize the duration of therapy recommendations within the context of the IDSA/ATS guidelines. Additionally, CIs for the ORs of readmission and mortality were broad, and thus too imprecise to determine whether guideline‐similar durations increased or decreased readmission or mortality in comparison with therapy that exceeded guideline recommendations. We could not fully assess the potential for association between guideline‐excessive therapy duration and risk for CDI due to sparse cases. Finally, non‐VA prescription data were not available for all patients, and we relied on intended duration of therapy as recommended by the discharging provider in 4.1% of cases.

Most quality assessments of pneumonia treatment have focused on antimicrobial selection and timely administration or conversion from IV to PO therapy.[31, 32] This evaluation identified potential opportunities for expansion of antimicrobial stewardship activities during the transition of care setting. The efficacy of short‐course ‐lactam, macrolide, or fluoroquinolone therapy for CAP appears equivalent to longer treatment regimens with no difference in adverse event rates, suggesting that optimal duration of therapy may be a rational target for quality improvement.[5, 6, 7, 8, 9, 10, 11, 12, 15, 31] Recommendations for HCAP duration of therapy are extrapolated from a prospective multicentered study, which randomized patients with hospital‐acquired pneumonia to receive 8 versus 15 days of therapy, that identified similar outcomes to ours.[4, 12]

Single‐center studies have identified that antimicrobial therapy for pneumonia is frequently prescribed for longer than recommended by guidelines, which found a similar median duration of therapy as our evaluation.[15, 16] Similar to Jenkins et al., we observed a high rate of fluoroquinolone prescriptions upon discharge.[16]

There are few published examples of interventions designed to limit excessive duration of therapy, particularly for antimicrobials prescribed upon hospital discharge.[15, 33, 34] Serial procalcitonin measurements have been used to guide duration of therapy for pneumonia; however, the costbenefit ratio of procalcitonin measurement is unclear.[35, 36] Procalcitonin use was uncommon, and none of the participating facilities in our evaluation utilized a specific algorithm to guide therapy duration. Limited data suggest that patient‐level prospective audit with feedback may be effective. Advic et al. evaluated management of presumed CAP before and after education and prospective feedback to medical teams concerning antimicrobial selection and duration of therapy.[15] The intervention led to a decrease in median duration of therapy from 10 days (IQR = 813 days) to 7 days (IQR = 78 days) without increasing clinical failure or readmission rates. We recently reported a single‐center evaluation in which pharmacists utilizing a decision support tool while performing discharge medication reconciliation were able to reduce excessive mean duration of therapy from 9.5 days ( 2.4 days) to 8.3 days ( 2.9 days) in patients without complicated pneumonia, with a 19.2% reduction in duration of therapy prescribed at discharge.[37] A similar approach utilizing pharmacists performing discharge review has recently been reported in a community hospital.[38]

Future work should recognize that few patients complete their entire course of therapy as inpatients, and the majority of treatment is prescribed upon discharge. Pivotal time points for antimicrobial stewardship intervention include day 2 to 3 of hospitalization when conveying suggestions for antimicrobial de‐escalation and/or IV to PO conversion, and toward the end of hospitalization during discharge planning. Although it may not be feasible for antimicrobial stewards to review all uncomplicated cases of pneumonia during hospitalization, most facilities have a systematic process for reviewing medications during transitions of care. We believe that interventions intended to assess and recommend shortened courses of therapy are appropriate. These interventions should include a mechanism for support by stewardship personnel or other infectious diseases specialists. Based on our evaluation, the ASTF produced and disseminated clinical guidance documents and tools to triage pneumonia case severity and assess response to therapy. Qualified personnel are encouraged to use this information to make recommendations to providers regarding excessive duration of therapy for uncomplicated cases where appropriate. Other work should include an in‐depth assessment of clinical outcomes related to treatment duration, investigation of provider rationale for prolonged treatment, and duration of antimicrobial therapy prescribed upon discharge for other common disease states. Finally, manual chart review to classify uncomplicated cases and related outcomes was laborious, and automated case identification is technologically plausible and should be explored.[39]

In conclusion, this national VHA MUE found that patients with uncomplicated pneumonia were commonly prescribed antimicrobials for the duration of therapy in excess of guideline recommendations. Patients with uncomplicated pneumonia who received therapy duration consistent with guideline recommendations did not have significantly different all‐cause readmission and death rates compared to patients receiving prolonged treatment. Approximately half of all therapy was prescribed upon hospital discharge, and clinicians as well as antimicrobial stewardship programs should consider these findings to address excessive duration of antimicrobial therapy upon hospital discharge.

Disclosures: Karl Madaras‐Kelly is employed full time by Idaho State University and has a without compensation appointment as a clinical pharmacist at the Boise VA Medical Center. He receives grant support unrelated to this work through the Department of Veterans Affairs subcontracted to Idaho State University. Muriel Burk is employed full time through the Department of Veterans Affairs as clinical pharmacy specialist in outcomes and medication safety evaluation. Christina Caplinger was employed by the Department of Veterans Affairs as an infectious diseases fellow at the time this work was completed. She is currently employed by Micromedex. Jefferson Bohan is employed full time by the Department of Veterans Affairs as an infectious diseases fellow. Melinda Neuhauser is employed full time through the Department of Veterans Affairs as a clinical pharmacy specialistinfectious diseases. Matthew Goetz is employed full time through the Department of Veterans Affairs as an infectious diseases physician. Rhongping Zhang is employed full time through the Department of Veterans Affairs as a data analyst. Francesca Cunningham is employed full time through the Department of Veterans Affairs as the director of the VA Center for Medication Safety. This work was supported with resources and use of the Department of Veterans Affairs healthcare system. The views expressed in this article are solely those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The authors report no conflicts of interest.

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.