Unnecessary Use of Antimicrobials in Hospitalized Patients:  Current Patterns of Misuse With an Emphasis on the Antianaerobic Spectrum of Activity FREE

SEVERAL STUDIES^1- 4 performed in the 1970s demonstrated that antimicrobials were often used inappropriately in the hospital setting, and between 14% and 43% of all courses of antimicrobial therapy were deemed unnecessary because there was no evidence of infection. Since overuse of antimicrobials has contributed to the emergence and dissemination of antimicrobial-resistant nosocomial pathogens, many organizations and experts in infectious diseases have called for increased efforts to limit overuse of antimicrobials in the hospital setting.^5- 8 Recent studies^9- 10 examining overuse of antimicrobials in hospitals have focused on specific patient populations or specific indications for therapy. Current data regarding patterns of unnecessary antimicrobial use in adult hospitalized patients with a variety of medical and surgical conditions are needed to identify types of misuse that might be amenable to intervention.

One mechanism by which antimicrobials promote transmission of nosocomial pathogens is through elimination of competing normal bacterial flora, with subsequent overgrowth of pathogenic microorganisms.^8,11- 15 We have demonstrated that therapy with antibiotics that eliminate normal anaerobic intestinal flora results in overgrowth of vancomycin-resistant enterococci (VRE) in stool samples of colonized patients, whereas therapy with antibiotics with minimal activity against anaerobes does not.¹¹ Patients with high-density stool colonization were more likely to contaminate environmental surfaces with VRE than those with low-density colonization.¹¹ We have also demonstrated that antianaerobic antibiotics promote overgrowth of antimicrobial-resistant gram-negative bacilli in stool samples of mice and patients (Claudia K. Hoyen, MD, Nicole J. Pultz, BS, David L. Paterson, MD, D.C.A., C.J.D., unpublished data, 2002; Anita Bhalla, MD, Nicole J. Pultz, BS, Amy J. Ray, MD, Claudia K. Hoyen, MD, Elizabeth C. Eckstein, RN, C.J.D., unpublished data, 2002). Other investigators have demonstrated that antianaerobic antibiotics promote acquisition and overgrowth of Candida species in stool samples,^12- 13 with subsequent increased frequency of Candida species colonization at other sites.¹² These findings suggest that decreasing the use of antianaerobic antibiotics will limit the density of intestinal colonization with nosocomial pathogens and may reduce the spread of these organisms. We are unaware, however, of previous studies that have examined the utility of minimizing use of antianaerobic agents or that have determined how often such agents are used unnecessarily. Our objectives were to prospectively study unnecessary antimicrobial use in a tertiary care medical center and to test the hypothesis that agents with antianaerobic activity are often used when this spectrum of activity is not required.

MetroHealth Medical Center is a 650-bed tertiary care hospital in Cleveland, Ohio. The hospital has training programs for residents in internal medicine, family practice, obstetrics and gynecology, and several surgical subspecialties. The Department of Pharmacy provides a pharmacokinetics monitoring service for patients receiving vancomycin or aminoglycosides, and pharmacists are assigned to many of the hospital wards to make antimicrobial recommendations regarding appropriate dosing, potential medication interactions, and potential allergic reactions. A pocket-sized card containing information on antimicrobial dosing, antimicrobial costs, recommendations for empiric therapy, and the hospital's antibiogram is distributed annually to physicians.

We prospectively examined the necessity of oral and parenteral antimicrobial agents administered to adult inpatients for whom new antimicrobials were prescribed during a 2-week period in August 2001. Study patients were identified through daily review of pharmacy records. The patients were located in 6 medical wards, 3 surgical wards, 1 rehabilitation ward, 1 subacute skilled nursing ward, and 1 obstetric-gynecologic ward. Patients located in intensive care units at the time the new antimicrobials were prescribed were excluded from the study. Information regarding demographics, admitting service and ward, indication for antimicrobial therapy (prophylaxis vs treatment), clinical syndrome being treated, laboratory data, vital signs, radiologic tests, and complications of therapy was obtained through medical record review and recorded on a standardized data collection form. Patients' medical records were reviewed daily during antimicrobial therapy and once again 4 to 6 weeks after completion of therapy to assess whether additional complications associated with therapy had occurred. Patients who were transferred to hospital units other than those listed herein, including intensive care units, were followed up in their new units.

Within 24 hours of the initiation of therapy, one of the study investigators (M.T.H. or C.J.D.) determined whether the antimicrobial regimen was necessary or unnecessary. An antimicrobial regimen was defined as unnecessary if no antimicrobial therapy was indicated for the clinical condition being treated. If an antimicrobial regimen was necessary, additional assessments were made regarding whether all of the components of the regimen were necessary. Components of a regimen were classified as unnecessary if redundant antimicrobials (2 agents with the same spectrum of activity in the absence of an indication for combination therapy) were prescribed, one antimicrobial in a regimen supplied a spectrum of activity that was not indicated, a component of a regimen was continued after culture results demonstrated that it was unnecessary (adjustment of therapy not made in a timely manner), and if the duration of therapy was longer than necessary. Therapy was defined as longer than necessary if the length of therapy exceeded standard recommendations for treatment duration or if the use of empiric antibiotics was continued despite negative evaluations for infectious syndromes and/or a noninfectious condition was demonstrated to be responsible for the clinical syndrome.

The determination of the necessity of a prescribed antimicrobial was based on standard guidelines or principles for diagnosis and treatment of infectious diseases.^16- 30 Standard recommendations for antimicrobial prophylaxis for surgical procedures were used.¹⁶ Hospital-acquired infections were defined by the Centers for Disease Control and Prevention criteria.¹⁷ Treatment guidelines for hospital-acquired infections were based on Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) practice guidelines when available.^18- 20 Diagnostic criteria and treatment guidelines for community-acquired infections were based on IDSA practice guidelines when available.^21- 25 If IDSA or ATS guidelines were not available, diagnostic and treatment recommendations from current textbooks of infectious diseases, other subspecialty textbooks, or published articles were used.^26- 33

We defined antianaerobic antibiotics as agents with potent in vitro activity against anaerobes present in the intestinal tract and/or that have been demonstrated to markedly inhibit intestinal anaerobes in humans.¹¹ Such agents available on the hospital formulary included metronidazole, clindamycin, piperacillin-tazobactam, ceftriaxone, cefotetan, cefoxitin, ampicillin-sulbactam, amoxicillin–clavulanic acid, meropenem, imipenem-cilastatin, and gatifloxacin.

Data were analyzed using SPSS statistical software version 10.0 (SPSS Inc, Chicago, Ill). Bivariate analyses were performed to compare necessary and unnecessary treatment regimens. Continuous data were analyzed using unpaired t tests. Categorical data were assessed using the Pearson χ² test. The costs of the unnecessary antimicrobial therapies were based on average wholesale prices. The antimicrobial costs of the entire course of therapy were calculated, including agents administered during hospitalization and after discharge. The hospital's institutional review board approved the study protocol.

One hundred twenty-nine patients received 153 antimicrobial regimens during the study period (range, 1-3 regimens per patient). Figure 1 summarizes our findings regarding the necessity of antimicrobial therapy. Of 1941 total antimicrobial days of therapy, 576 (30%) were deemed unnecessary. A total of 255 (44%) of the 576 unnecessary days of therapy were attributable to 36 unnecessary antimicrobial regimens. Analysis of the 117 regimens that were necessary revealed that an additional 321 days of therapy were unnecessary. Antianaerobic agents accounted for 203 (35%) of the 576 unnecessary antimicrobial days of therapy. Overall, 75 (58%) of the 129 study patients received at least 1 day of unnecessary antimicrobial therapy, and 44 (34%) received 1 or more days of unnecessary antianaerobic therapy.

Table 1 provides a comparison of the characteristics of patients receiving necessary vs unnecessary regimens. Treatment regimens were unnecessary more frequently than prophylaxis regimens (27% vs 14%), but the difference was not statistically significant (P = .10). Overall, regimens prescribed by internal medicine or family practice physicians were significantly more likely to be unnecessary than those prescribed by surgery or obstetrics-gynecology physicians (30 [32%] of 95 vs 6 [10%] of 58, P = .003). When prophylaxis regimens were excluded from the analysis, the difference between these groups remained significant (P = .047).

Table 2 summarizes the reasons for the unnecessary days of therapy for all antimicrobials and for the subset of agents with antianaerobic activity. The most common reasons for unnecessary therapy included administration of antimicrobials for longer than recommended durations (192 days of therapy), administration of antimicrobials for noninfectious or nonbacterial syndromes (187 days of therapy), and treatment of colonizing or contaminating microorganisms (94 days of therapy). The reasons for unnecessary antianaerobic therapy were similar to the reasons for all unnecessary therapy.

In addition to the 203 days of unnecessary antianaerobic therapy given in Table 2, 98 days of necessary antimicrobial therapy contained antianaerobic activity when an equally efficacious alternative regimen with minimal antianaerobic activity was available. The most common syndromes for which antianaerobic antibiotics were prescribed when the antianaerobic spectrum of activity was not necessary included uncomplicated skin or soft tissue infections (6 patients), urinary tract infections (3 patients), and uncomplicated acute upper or lower respiratory tract infections (5 patients).

Table 3 lists clinical scenarios associated with all of the unnecessary antimicrobial regimens and some of the regimens in which only part of the regimen was unnecessary. Specific examples are provided to illustrate both cases in which standard guidelines were applied and cases in which determinations were based on standard principles of infectious diseases. The most common scenario treated with unnecessary antimicrobials was asymptomatic bacteriuria, 01brenda funguria, or pyuria.

The total average wholesale price of all unnecessary antimicrobials prescribed for the study patients was $14 599.98, corresponding to an estimated yearly average wholesale price of $350 399.52. Table 4 lists the total and unnecessary antimicrobial days of therapy by agent and the costs of the unnecessary doses administered. Ciprofloxacin was the agent that was most often prescribed unnecessarily. An additional $3828 in excess antimicrobial costs were estimated for 23 courses of necessary therapy in which a less expensive but equally effective agent was available or a change from intravenous to oral formulation was not made in a timely manner.

Of the 36 unnecessary antimicrobial treatment regimens, 9 (25%) were associated with complications or adverse effects that were possibly attributable to the therapy. Six patients experienced minor gastrointestinal adverse effects, such as nausea or diarrhea. One patient was noted to have urinary tract colonization with Candida species after completing antimicrobial therapy. One patient developed bacteremia with a multi–drug-resistant strain of Pseudomonas aeruginosa after receiving ciprofloxacin therapy for asymptomatic bacteriuria. One patient was readmitted to the hospital for 2 days when he developed Clostridium difficile colitis after receiving an unnecessary course of piperacillin-tazobactam.

Considerable efforts have been made in recent years to educate physicians and the public about the importance of minimizing the unnecessary use of antimicrobials.^5- 8 Despite these efforts, nearly one third of antimicrobial days of therapy prescribed for hospitalized patients in our institution were not necessary. This proportion of unnecessary use is similar to the findings of other investigators in the 1970s.^1- 4 Thirty-five percent of the unnecessary antimicrobial days of therapy consisted of agents with potent activity against anaerobes, and these agents were also frequently prescribed when equally efficacious alternatives with minimal antianaerobic activity were available.

The normal anaerobic intestinal flora provide an important host defense by inhibiting growth of potentially pathogenic microorganisms.^11,14 As noted previously, antibiotics that eliminate anaerobes have been shown to promote intestinal overgrowth of nosocomial pathogens.^11- 15 Antianaerobic antibiotics have also been associated with VRE bacteremia.³⁴ Studies are needed to determine whether limiting the use of such agents will be an effective means to decrease rates of transmission and infection with nosocomial pathogens that colonize the intestinal tract. Our data suggest that a control program in our institution that minimized all types of unnecessary antimicrobial use would eliminate approximately 60% of the unnecessary use of the antianaerobic spectrum of activity. Substitution of antianaerobic antibiotics with equally efficacious alternatives with minimal antianaerobic activity would further reduce the unnecessary use of this spectrum of activity.

In addition to promoting transmission and infection with nosocomial pathogens, the overuse of antimicrobials in hospitals may have several other adverse implications for patients and health care systems. The unnecessary antimicrobials prescribed in this study added significantly to the direct costs of medical care (Table 4). Indirect costs related to management of adverse effects or complications associated with unnecessary antimicrobial use were not calculated in this study but may also be significant. For example, we did not calculate the costs of C difficile testing in patients who developed antibiotic-associated diarrhea nor did we calculate hospitalization costs for the patient readmitted with C difficile colitis after an unnecessary antimicrobial regimen. Ancillary costs of administering antimicrobials, such as intravenous catheter placements, intravenous tubing, and nursing time, were also not calculated. Finally, acceptance of high rates of unnecessary antimicrobial use in teaching hospitals will contribute to continued unnecessary antimicrobial use among future generations of physicians.

Forty-four percent of the unnecessary days of therapy were due to treatment regimens that were entirely unnecessary. Several common clinical scenarios accounted for most of these unnecessary treatment regimens (Table 3). For example, asymptomatic bacteriuria in elderly patients or individuals with indwelling bladder catheters was often treated with antimicrobials. Asymptomatic bacteriuria occurs frequently in such patients, and randomized trials have demonstrated that antimicrobial therapy provides no benefit.^25,32,35 Several patients with noninfectious or nonbacterial upper and lower respiratory tract syndromes received antibacterial therapy. It is likely that even more patients may have received such unnecessary therapy if our study had been performed during the winter respiratory virus season. Interventions targeting the elimination of antimicrobial therapy for the most common scenarios listed in Table 3 would result in significant reductions in unnecessary antimicrobial use. We agree with the recommendation that all hospitals should review antimicrobial use in their institutions to identify their own local patterns of misuse.⁸

Twenty-seven percent of the unnecessary days of therapy were due to continuation of initially necessary therapy for a longer than required duration. Eighty percent of these unnecessary days of therapy were due to continuation of necessary regimens beyond the durations recommended by standard guidelines. Improving adherence to guidelines for treatment duration would therefore be the most effective means to reduce this type of misuse. The remaining 20% of these unnecessary days of therapy occurred when regimens initiated for suspected infections were continued despite identification of a noninfectious origin or failure to identify any source of infection. Reassessment of the need for antimicrobial therapy after a few days of therapy would be required to reduce this type of misuse. Such reassessments of the necessity and appropriateness of antimicrobial therapy have been effective in reducing antimicrobial costs^36- 37 and antimicrobial resistance and superinfections in an intensive care unit setting.³⁶

For several reasons, our results probably represent an underestimation of the unnecessary days of therapy and the associated costs and complications. First, unnecessary antimicrobial use is common in intensive care units.³⁶ We did not include patients located in intensive care units at the time antimicrobials were initially prescribed. Second, in some situations experts have differing opinions regarding whether antimicrobial therapy is indicated. In such cases, we classified therapy as necessary. Third, standard guidelines for therapy often provide a range of appropriate durations (eg, 4-6 weeks for treatment of osteomyelitis or endocarditis), and we considered antimicrobials to be necessary as long as they fell within these ranges. Clinicians often choose the longer duration of therapy when given such an option (M.T.H., D.C.A., N.P.P., M.K.L., C.J.D., unpublished data, 2002). Fourth, the potential cost savings that might have been realized if less expensive, equally efficacious agents were chosen or if more timely conversions from parenteral to oral formulations had occurred are not shown in Table 4; we estimated additional excess costs of $3828 that were attributable to such factors. Finally, we included only complications that were associated with unnecessary regimens, not those that might have been related to longer than necessary or redundant therapy. Studies that include interventions to limit unnecessary use of antibiotics are needed to provide a more accurate assessment of the effect of unnecessary antimicrobials on clinical and economic outcomes.

Further studies are needed to determine the reasons why physicians prescribe unnecessary antimicrobials for hospitalized patients. Patients' demands for antimicrobials are often cited as a reason for unnecessary prescriptions in the outpatient setting,²¹ but such demands were unlikely to motivate much of the unnecessary use that we observed (eg, asymptomatic bacteriuria). Possible reasons suggested for excessive antimicrobial use in hospitals include the acutely ill and complex status of patients, diagnostic uncertainty, pressure to keep lengths of stay short, and prescribing by clinically inexperienced physicians, as in teaching hospitals.³⁸ Most of the unnecessary antimicrobials administered during this study did not seem to involve complex decision making for severely ill patients, as might have been seen if we had included patients located in intensive care units at the time antimicrobials were prescribed. Another possible reason for excessive antimicrobial use is that physicians may lack a full appreciation of the frequency with which antimicrobial therapy is associated with adverse effects, not only for the individual patient but also for the broader microbiologic environment. They may, therefore, have a low threshold to give antimicrobials, because they believe that these agents are unlikely to cause harm.

Our study has several limitations. We studied only one teaching hospital during a 2-week period. Although our findings may not be applicable to institutions with intensive antimicrobial control programs, many hospitals lack such programs. Antimicrobial use in teaching hospitals may differ from nonteaching hospitals; however, previous studies have also documented high rates of inappropriate antimicrobial use in nonteaching hospitals.⁴ Because the categorization of therapy as necessary or unnecessary was based solely on information available in the medical records, some necessary regimens may have been misclassified as unnecessary due to inadequate documentation of the reasons for therapy. However, it is also possible that a greater number of unnecessary regimens might have been identified if we had interviewed and examined patients.

In summary, antimicrobials and their antianaerobic spectrum of activity were frequently used unnecessarily in a tertiary care medical center. We identified several common clinical scenarios associated with unnecessary antimicrobial use that may be amenable to intervention. Further studies are needed to determine if limiting the unnecessary use of antianaerobic antimicrobials will be effective as a control measure for nosocomial pathogens that colonize the intestinal tract.

Corresponding author and reprints: Curtis J. Donskey, MD, Infectious Diseases Section, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd, Cleveland, OH 44106 (e-mail: curtisd123@yahoo.com).

Accepted for publication July 29, 2002.

This study was supported by a Career Development Award grant to Dr Donskey from the Department of Veterans Affairs, Washington, DC.