Consecutive Antibiotic Shortages Highlight Discrepancies between Microbiology and Prescribing Practices for Intra-abdominal Infections

Piperacillin-tazobactam (TZP) is frequently used for intra-abdominal infection (IAI). Our institution experienced consecutive shortages of TZP and cefepime, providing an opportunity to review prescribing patterns and microbiology for IAI.

institution noted an apparent surge in cefepime utilization during this period. This was followed almost immediately by a year-long shortage of cefepime. As TZP is commonly prescribed for the indication of intra-abdominal infection (IAI), we sought to characterize changes in antimicrobial prescribing and microbiology in patients with IAI during these shortages, with the hypothesis that Pseudomonas sp. is frequently covered empirically and infrequently isolated in IAI. We also assessed whether there were changes in rates of colonization with resistant organisms (methicillin-resistant Staphylococcus aureus [MRSA] and VRE) or C. difficile infection, as this has been noted by others in shortage scenarios (6,7). Finally, we also examined length of stay, intensive care unit (ICU) transfer, and in-hospital mortality as outcomes that could potentially be affected by disruption of prescribing patterns (and potentially suboptimal substitutions).

RESULTS
There were 7,668 episodes of antimicrobial prescribing for an indication of IAI across all four time periods (Table 1). During the TZP shortage, there was a 93% reduction in TZP usage for an indication of IAI (measured in days of therapy per 1,000 hospitalized patient-days), a 190% increase in cefepime usage, a 57% increase in ceftriaxone usage, a 13% increase in ciprofloxacin usage, and a 74% increase in metronidazole usage compared to the preshortage period ( Fig. 1). During the cefepime shortage, there was a 69% reduction in cefepime usage relative to the preceding (TZP shortage) period; however, there was only a 9% reduction compared to the preshortage period, and cefepime usage was lowest in the postshortage period. Meropenem was a restricted agent requiring antimicrobial stewardship approval throughout the time periods; usage was stable throughout the shortage periods. Vancomycin usage decreased across all four periods: there was a 40% reduction in the postshortage relative to the preshortage period. Rates of VRE colonization declined over time ( Review of selected cases. Among 416 (;5%) cases randomly selected for in-depth chart review, categorization of cases and positive C. difficile tests were similar across all time periods (Table 3), with the exception that there were fewer erroneous indication selections in the postshortage period. The proportion of cases with an infectious disease consult doubled in the TZP shortage period relative to the preshortage period and remained stable in subsequent periods, including the postshortage period.
Microbiology. Among the 416 cases, 92 (22.1%) had at least one organism isolated that was attributed to an intra-abdominal source. In the preshortage period, fewer cases (16/108; 15%) had an associated organism identified relative to subsequent time  (Table 3). The most commonly isolated organism was Escherichia coli, followed by Bacteroides fragilis. For community-acquired IAI (CA-IAI) cases, 27/91 (30%) had positive microbiologic data, none of which were Pseudomonas sp.; however, 39/91 (43%) reviewed cases of CA-IAI received initial empirical therapy that included antipseudomonal spectrum. For health care-associated IAI (HA-IAI) cases, 58/125 (46%) had positive microbiologic data, 3 of which were Pseudomonas aeruginosa; 82/125 (66%) received initial empirical therapy that included antipseudomonal spectrum. Among cases with positive culture data (n = 92), only 3 (3%) were due to P. aeruginosa and 6 organisms (7%) were ceftriaxone-nonsusceptible Enterobacterales, and all cases were HA-IAI ( Table 4). Cases of IAI due to P. aeruginosa included a patient with recurrent peritoneal dialysis catheter-associated peritonitis (with prior isolation of P. aeruginosa),  one with an indwelling biliary drain complicated by cholangitis, and one with inflammatory bowel disease complicated by C. difficile colitis who underwent fecal microbiota transplantation and subsequently developed polymicrobial bacteremia.
Enterococcus sp. was isolated in 13 cases, 11 of which were HA-IAI. One communityacquired case was a patient with metastatic gallbladder carcinoma admitted for cholangitis, and the other was a patient on peritoneal dialysis who presented with septic shock due to VRE bacteremia, potentially due to peritonitis versus endocarditis. Staphylococcus aureus was rarely identified as the causative organism (n = 4, 2 of which were MRSA) and was found exclusively in patients following procedures (3 patients had had abdominal surgery and 1 had had endoscopic retrograde cholangiopancreatography with common bile duct stent placement).

DISCUSSION
TZP is commonly prescribed for IAI in hospitalized patients and has antipseudomonal activity as well as providing coverage of increasingly resistant E. coli; however, the actual antimicrobial coverage intent may not be well understood by all prescribers (8). The microbiologic data from the subset of cases we reviewed demonstrate the relative rarity of Pseudomonas sp. as the causative organism, even for hospital-associated cases, in IAI. P. aeruginosa is infrequently carried in the gut of healthy humans and thus would not be generally expected to play a large role in IAI, especially from the community (9, 10). Even in ICU patients without specific perturbations in their gut flora, P. aeruginosa was infrequently identified compared to Enterobacterales (11). Here, ceftriaxone-nonsusceptible Enterobacterales were more common than Pseudomonas sp., and all had elevated MICs of cefepime, TZP, or both. Despite this, antipseudomonal antibiotics were commonly used for IAI, and the increased cefepime usage in the setting of a TZP shortage particularly highlights the discrepancy between prescribing practices and the microbiology of IAI.
The most recent Infectious Diseases Society of America (IDSA) guidelines for IAI recommend that empirical therapy for health care-associated IAI (HA-IAI) be driven by local microbiologic results, but they also state, "to achieve empirical coverage of likely pathogens, multidrug regimens that include agents with expanded spectra of activity against Gram-negative aerobic and facultative bacilli may be needed. These agents include meropenem, imipenem-cilastatin, doripenem, piperacillin-tazobactam, ceftazidime, or cefepime plus metronidazole. . ." (12). The empirical use of antimicrobial regimens with broad-spectrum Gram-negative organisms is also recommended for CA-IAI (12). Revised 2017 guidelines provided by the Surgical Infection Society highlight the need for individual risk assessment for various resistant pathogens; however, they also recommend the use of antimicrobials with broad-spectrum coverage of Gram-negative organisms for "high-risk" patients with CA-IAI and patients with HA-IAI (13). Other guidelines focus more on severity of illness as the indication for the empirical use of agents with broader spectra (14,15). However, our data suggest that considering all patients in these groups as being at high risk for IAI due to resistant Gram-negative organisms results in significant overutilization of agents with expanded spectra for Gram-negative organisms, and this recommendation may need to be revisited in the next edition. Furthermore, when resistant Gram-negative organisms were isolated from an abdominal source, extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales were more common than P. aeruginosa; thus, a carbapenem may be the superior agent over antipseudomonal beta-lactams, such as cefepime, when more broad-spectrum Gram-negative coverage is deemed appropriate (16,17). This highlights the importance of institutional guidelines and the need for better ways to identify the minority of patients with IAI due to resistant Gram-negative organisms. Existing guidelines additionally recommend considering empirical antimicrobial coverage directed against MRSA for patients with HA-IAI "who are known to be colonized with the organism or who are at risk of having an infection due to this organism because of prior treatment failure and significant antibiotic exposure" (12). Among the cases reviewed in our study, Staphylococcus aureus was rarely isolated and was exclusively found in patients with a history of recent surgery or procedure. Recommendations for empirical coverage of Enterococcus spp. generally include consideration based on individual patient risk given clinical characteristics and/or severity of illness, though risk factors are a Includes only organisms identified that were attributed to an intra-abdominal source (i.e., microbiology for erroneous selections was not included). More than 1 organism was isolated in 20 cases. Mixed flora was isolated in 26 cases.
variably and vaguely defined (12)(13)(14)(15). Interestingly, the marked increase in cefepime use during the TZP shortage in this study was not accompanied by a concomitant surge in vancomycin use, suggesting that coverage of Enterococcus spp. may not play a large role in prescribers' antibiotic decision-making for IAI at our institution. The antimicrobial prescribing data from this study also highlight important points pertinent to antibiotic stewardship efforts in the setting of shortages. We observed a far more dramatic decrease in utilization of the shortage antibiotic during the TZP shortage. This may be due in part to the greater severity of the TZP shortage at our institution relative to the cefepime shortage; however, it is also likely that the restriction and preauthorization approach had a greater impact on prescribing practices than the prospective audit and feedback approach (18). Since the challenge in antibiotic shortage situations is helping prescribers to choose the most appropriate alternative antibiotic (not reducing utilization of a target antibiotic), strategies that maximize interaction with stewardship teams or otherwise provide more tailored guidance may be more advisable (19). At our institution, prescribers seemingly learned that there was a shortage of TZP and preferentially chose another antibiotic rather than calling the antibiotic stewardship team for prior authorization, which is known to be a potentially frustrating process for clinicians (20). This likely contributed to the large surge in cefepime utilization, whereas discussion with the antibiotic stewardship team might have led to more ceftriaxone use, consistent with the institutional guidance.
Our study was not designed to evaluate the reasons that prescribing practices were inconsistent with the provided guidance; however, possible explanations include low read rates for the email that was circulated or selective retention of information from the email (of note, recommendations for nosocomial infections were listed first, and the recommendations for CA-IAI were listed last). We also recognize that passive information has not been shown to frequently change practice (21). Other possible contributing factors include limited understanding of antimicrobial spectrum or misconceptions about the frequency of Pseudomonas sp. involvement in IAI (22,23) and the availability of different sets of guidelines that prescribers may reference (12)(13)(14)(15).
Our study was designed primarily to look at changes in antibiotic prescribing practices for IAI during specific b-lactam antibiotic shortages. Thus, our ability to detect overall changes in colonization rates of resistant organisms and rates of C. difficile, which have been previously associated with shortages (6, 7), was limited, and we cannot rule out contributions of temporal factors to the observed colonization rates. However, there was no increase in resistant-organism colonization or C. difficile infection among patients with IAI (as identified by selection of IAI as the indication for antibiotic orders). There also was no increase in in-hospital mortality during shortage periods. In fact, in-hospital mortality was highest in the preshortage period and declined over time. Based on the reviewed subset of cases, the frequency of infectious disease consultation and identification of pathogens was lowest in the preshortage period. However, the observational nature of this study precludes making conclusions about causality.
Another limitation of this study is the inclusion of patients based on a prescriber selecting IAI as the indication for an antibiotic order. Per our review of a subset of cases, approximately 12% of these indications were erroneous selections. However, the majority of erroneous selections were for patients receiving prophylaxis for spontaneous bacterial peritonitis in the setting of variceal bleeding (typically with ceftriaxone) or perioperative prophylaxis for patients undergoing abdominal surgery, both instances in which prescribers would be targeting similar organisms and which would be more likely to inflate ceftriaxone usage. Inclusion based on this parameter allowed the large number of patients, which is a strength, and allowed assessment at the point of prescribing for IAI, which is highly relevant for analysis of prescribing behavior from a stewardship standpoint. Furthermore, the erroneous selections did not impact the analysis of the microbiologic etiologies or rates of empirical use of antipseudomonal agents, as these were analyzed based on classification within the reviewed subset of cases. However, this method of identification for inclusion likely did miss some cases of IAI wherein IAI was not selected as the indication by prescribers at the time of the order.
Antibiotic shortages are a barrier to best antimicrobial stewardship practices (5,24). We found that the alternative selections prescribers made in the setting of TZP shortage were suboptimal, with cefepime being substituted at a rate that was not supported by the microbiologic epidemiology of IAI at our institution. Future research and guideline updates should seek to refine indications and recommendations for various resistant Gram-negative organisms (e.g., Pseudomonas sp. and ESBL-producing Enterobacterales). Institutional guidelines may be critical, particularly in the setting of antibiotic shortages; however, the best method for optimizing adherence to such guidance remains unclear.

MATERIALS AND METHODS
Data. Antimicrobial usage, infection rate and culture data, and patient demographics were extracted from the University of Virginia Clinical Data Repository and Infection Prevention and Control Database. Adult patients admitted to the University of Virginia Health System in Charlottesville, VA, between March 2014 and February 2018 who received an antimicrobial with "intra-abdominal infection" as the indication in the electronic medical record (Epic, Verona, WI) during their admission were included. Indication selection was required to sign intravenous antibiotic orders throughout the study period; prescribers could select one of 20 provided indications or enter a free-text indication. These patients were Patients less than 18 years of age and duplicate patients readmitted within 30 days of the initial admission were excluded. Antimicrobial utilization was assessed using days of therapy (DOT) per 1,000 patient-days. Antimicrobials on the inpatient hospital formulary that are commonly prescribed for IAI at our institution were specifically measured, including TZP, cefepime, ceftriaxone, ciprofloxacin, metronidazole, meropenem, and vancomycin. Usage of other antimicrobials for IAI was also measured in one composite category. Positivity for VRE or MRSA on surveillance screening and positive C. difficile PCR (GeneXpert; Cepheid, Sunnyvale, CA) were also assessed during these four periods, as well as length of admission, admission to an ICU, and in-hospital mortality. There were no significant changes to infection control practice regarding contact precautions or surveillance screening criteria for MRSA or VRE during the study period. In 2017, a previously described diagnostic stewardship initiative including a computerized clinical decision support tool for C. difficile testing was introduced (25), which was associated with reductions in overall testing but not a change in the percentage of positive tests across all hospitalized patients. Institutional antimicrobial stewardship practices. During the TZP shortage, a 24/7 formulary restriction and preauthorization strategy was used, with a physician leader primarily holding the pager during that time, while during the cefepime shortage, a prospective audit with feedback approach was used and was largely led by an infectious diseases-trained pharmacist. Guidance regarding preferred substitutions for various indications, including community-acquired and nosocomial IAI, was distributed via email during the TZP shortage. Cefepime plus metronidazole was recommended for nosocomial sepsis of abdominal origin, and ceftriaxone plus metronidazole was recommended for community-acquired IAI (CA-IAI) (Fig. 2). Guidance was not provided during the cefepime shortage for IAI, as cefepime was not considered a typical first-line choice for this infection. Meropenem was a restricted agent requiring prior authorization by the antimicrobial stewardship team throughout all time periods.
In-depth review of cases. A subset of cases (approximately 5%) were electronically randomly selected for in-depth chart review. Each case was categorized as CA-IAI, HA-IAI, possible IAI, or erroneous indication selection. HA-IAI was defined using the Surgical Infection Society Guidelines on IAI (13), with the exception that use of broad-spectrum antimicrobial therapy during the preceding 90 days was defined as intravenous antimicrobial exposure. Possible IAI included cases in which IAI was one of multiple possible diagnoses and in which there was potential for IAI (e.g., antibiotics were administered in the setting of esophageal perforation; however, a clinically evident infection did not subsequently develop). Cases in which the prescriber inappropriately chose IAI as the indication were categorized as erroneous (e.g., for peri-operative prophylaxis after abdominal surgery or prophylaxis for spontaneous bacterial peritonitis in patients with cirrhosis and variceal bleeding). Additional information extracted from the chart during in-depth review included the initial antibiotic chosen, culture data, C. difficile testing data, infectious diseases consult presence, and narrative summary of the hospital course. Culture results considered attributable to IAI included blood cultures in the setting of clinically diagnosed IAI (excluding those consistent with blood culture contamination) or culture specimens obtained via surgical or percutaneous drainage (e.g., drained abscesses).
Analysis. Data analysis was performed with R using the Stats package (R, version 3.5.1). The Kruskal-Wallis test was used for continuous variables, and a chi-square test was performed for categorical variables. Antimicrobial usage data were reported as DOT per 1,000 hospitalized patient-days for each period. For binary outcomes, logistic regression was performed to compare rates across time periods when the chi-square test indicated a significant difference between time periods. Descriptive statistics were used for analysis of data from the in-depth review of a subset of cases.
Ethics statement. Database and chart review were approved by the University of Virginia Institutional Review Board (IRB no. 18393 and 20562) with a waiver of consent.