Intra-hospital differences in antibiotic use correlate with antimicrobial resistance rate in Escherichia coli and Klebsiella pneumoniae: a retrospective observational study

Antibiotic resistance in gram-negative bacteria has increased worldwide [1]. Infections with resistant gram-negative bacteria are a particularly serious threat to public health because they are difficult to treat and are associated with high morbidity and mortality, and great healthcare costs [2].

Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) are among the most important gram-negative pathogens in the hospital setting, accounting for around one fifth of all pathogens causing healthcare-associated infections in the USA [3]. These two pathogens are frequent causes of catheter-associated urinary tract infections (CAUTI), surgical site infections (SSI) and ventilator-associated pneumonia (VAP) [3]. Risk factors for the emergence of infections with resistant gram-negative bacteria include existing comorbidities, presence of medical devices, previous invasive procedures and admission from a long-term care facility [4]. Despite the widespread belief that the most important driver in the selection of bacterial resistance is the use of antimicrobials, the relationship between antibiotic use and resistance rates across individual departments within a single hospital is not well studied. Willemsen et al. comprehensively investigated this relationship in a teaching hospital in the Netherlands and showed a correlation between ward-specific use and resistance rates for ciprofloxacin and amoxicillin-clavulanic acid in E. coli [5]. Compared to Willemsen et al. we have investigated resistance data for K. pneumoniae in addition to E. coli, included more antibiotics and used the annual antibiotic consumption per 100 bed-days per department over 9 years (2008–2016). Our objective was to identify antibiotics associated with a higher risk of resistance development in order to optimise the antibiotic prescribing practice particularly in those departments in our hospital with the highest antibiotic consumption.

Our analysis showed an association between use and resistance for amoxicillin-clavulanic acid, piperacillin-tazobactam, quinolones and trimethoprim-sulfamethoxazole in E. coli and for amoxicillin-clavulanic acid and trimethoprim-sulfamethoxazole in K. pneumoniae across different hospital departments.

It is intuitive that antibiotic resistance emerges predominantly in environments with high antibiotic consumption. This has been shown for individual countries [8] and individual hospitals [9‐11]. It is however conceivable that even antibiotic prescription within individual departments of the same hospital may affect bacterial resistance in the patients sharing the same environment, as bacteria can be transmitted from patient to patient and antibiotic resistance can spread between bacteria. In this regard, the results of our study confirmed the main findings reported by Willemsen et al. demonstrating that a higher use of amoxicillin-clavulanic acid and quinolones was associated with higher antimicrobial resistance in E. coli.

Interestingly, we only found associations between antibiotic use and resistance for some antibiotics and different associations between E. coli and K. pneumoniae.

A plausible explanation is the considerable difference in the quantitative use of the antibiotics studied across our hospital’s departments. Considering the substantial use of amoxicillin-clavulanic acid at our institution, it is not surprising that its use was associated with resistance in both microorganisms analysed. A wide quantitative range of antibiotic use across different departments may also facilitate the detection of an association, as observed for piperacillin/tazobactam, where the median consumption was low, but the range was very wide.

However, the resistance barrier of the individual antibiotics may also be relevant for the emergence of resistance. For cefepime, which is recommended in our internal antibiotic guidelines [12] as first-line antibiotic for several nosocomial infections (e.g. pneumonia and fever in neutropenia), we did not find an association between use and resistance, even though it was the second most frequently used antibiotic overall. Cefepime is a robust fourth generation cephalosporin, which is relatively stable against β-lactamases and maintains activity even against difficult organisms. In contrast, Enterobacteriaceae may acquire resistance to quinolones and trimethoprim-sulfamethoxazole more readily and we indeed observed significant associations between their use and resistance in E. coli.

Results for K. pneumoniae were less clear than for E. coli, mainly because the sample size was much smaller. In particular, for ceftriaxone, cefepime, piperacillin-tazobactam and gentamicin the number of susceptibility tests performed for K. pneumoniae (n = 369) was substantially lower than for E. coli (n = 1085).

Our first sensitivity analysis examined the potential temporal relationship between the consumption of antibiotics and the development of resistance a year later. However, the last year’s use did not have a stronger influence than the current use. Possible explanations are the relatively stable antibiotic use over time in our setting or a different timing of the emergence of resistance. Even a reverse causation is possible — the reduction in use due to the emergence of resistance.

The antibiotic use varied widely between the different departments and within the individual departments; there were significant variations in antibiotic use over time. Notably, the antibiotic use was high in predominantly surgical departments like urology, plastic and hand surgery, and otorhinolaryngology. Even though cefuroxime, which is recommended for perioperative prophylaxis, was not included in the analysis the high antibiotic use of these departments is probably due to the frequent use of amoxicillin-clavulanic acid and quinolones (urology) for perioperative prophylaxis that in some cases is given longer than suggested by international guidelines. During the study period, there were no specific antimicrobial stewardship interventions in any hospital department. Improving perioperative prophylaxis in the mentioned surgical departments will be a priority in the future.

To address the specificity of the association we compared nosocomial and community strains, given that the latter was not exposed to antibiotic use in the hospital. As expected, the association between antibiotic consumption and resistance tended to be systematically stronger for nosocomial strains than for community strains in E. coli even though we did not always find significant interactions. This result is consistent with another Swiss study showing that strains isolated ≥48 h after admission were less susceptible than those stemming from the community [13]. The same pattern was not found for K. pneumoniae, mainly because we did not observe many clear associations in the first place. Trimethoprim-sulfamethoxazole, for which the association persisted in community-acquired K. pneumoniae strains, is also frequently prescribed in the outpatient setting [14]. Furthermore, we could not distinguish patients with previous contacts with the healthcare system and some community-acquired infections could actually be healthcare-associated.

The accuracy of distinguishing community- from hospital-acquired pathogens plays an important role in our analyses. We chose a 2-day cut-off according to the Centers for Disease Control and Prevention (CDC) definition [15]. A stricter definition for hospital-acquired samples (i.e. a cut-off of five instead of 2 days after hospital admission) did not change any of the main findings, as the vast majority of samples (79% for E. coli and 81% for K. pneumoniae) was obtained after 5 days of hospital admission.

In recent years, several studies have analyzed the relationship between antibiotic use and development of resistance in Enterobacteriaceae. Consistent with our findings, several studies have described an association between in-hospital antibiotic use and resistance to quinolones in E. coli [16‐18]. This association may be particularly relevant for Switzerland with its comparatively higher quinolone consumption than other European countries [19].

Two other studies have reported associations in E. coli between amoxicillin-clavulanic acid [5, 20] and piperacillin-tazobactam [21, 22]. The main discrepancy between our results and those of other studies is the absence of an association between the use of ceftriaxone and the emergence of third-generation cephalosporin resistance in our study [20, 23, 24]. This may be due to a relatively low median use of ceftriaxone of 2.6 DDD/100 patient days compared to other studies.

Our study has several limitations. First, the number of AST available differed considerably among the antibiotics and the sample size was low for some. The majority of samples (65% of E. coli, and 51% of K. pneumoniae) originated from urine and a complete AST of these samples is only performed if routine testing shows several resistances. Therefore, the resistance data for cefepime, ceftriaxone, piperacillin-tazobactam and gentamicin was only available in one sixth of the urine samples. The low sample size reduces the power of the analysis, which was particularly problematic for K. pneumoniae where it severely hampered the conclusions. Moreover testing some antibiotics only in higher resistant isolates may lead to an overestimation of resistance in urinary samples against these antibiotics, due to sampling bias. Second, this was a single-centre study, therefore our results may not be generalizable to other contexts with potential differences in case-mix and epidemiologic characteristics. Third, we could not take into account individual risk factors for infections with resistant microorganisms (such as underlying diseases or previous antimicrobial therapy), because of the anonymization of the samples. Fourth, we did not analyse the association between the use of one particular antibiotic and the resistance to a second antibiotic. Fifth, the antibiotic consumption expressed in DDD per 100 bed-days does not reflect the adequacy of treatment in terms of proper dosage and duration. Sixth, we calculated antibiotic use based on deliveries to the hospital departments rather than administration to the patients. The departments of our hospital are advised to order only those antibiotics that are needed for daily use. Antibiotics that are delivered to the departments but are for some reason not administrated to the patients must be returned to the hospital pharmacy. We subtracted the returned antibiotics from the deliveries and are confident that our data reflect the real antibiotic administration to the patients.

However, to the best of our knowledge, our study is the first comprehensive analysis of the use of the most important antibiotics for the treatment of gram-negative bacteria and corresponding antimicrobial resistance across multiple departments within one institution. We included all clinical E. coli and K. pneumoniae samples isolated across 18 departments at our institution over the study period of 9 years and used the well-established, standardized ATC/DDD system. The study therefore has important relevance for clinical practice.

We have demonstrated that antibiotic use in different hospital departments is associated with resistance rates in E. coli and in K. pneumoniae for some but not all antibiotics and antibiotics differ in the strength of the association. Despite a high consumption of cefepime we could not demonstrate an association between its use and resistance rates. We will therefore continue to promote the use of cefepime over piperacillin/tazobactam as an empiric broad-spectrum antibiotic in our guidelines.