Investigating the association between antibiotic use and antibiotic resistance: impact of different methods of categorising prior antibiotic use

doi:10.1016/j.ijantimicag.2006.04.014

International Journal of Antimicrobial Agents

Volume 28, Issue 4, October 2006, Pages 325-332

https://doi.org/10.1016/j.ijantimicag.2006.04.014 Get rights and content

Abstract

Many studies have explored the association between antibiotic use and antibiotic resistance. However, methods employed in these studies to categorise prior antibiotic use (e.g. by class, by spectrum) have not been well described. The impact of using different categorisation methods on identifying risk factors for resistance is unknown. To explore these issues, we focused on extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella spp. (ESBL-EK) as a model. First, we conducted a systematic review of studies of risk factors for ESBL-EK to characterise past approaches to categorising antibiotic use. Second, we re-analysed data from a prior study of risk factors for ESBL-EK. Two separate multivariate models of risk factors for ESBL-EK were constructed: one with prior antibiotic use categorised by class and the other with prior antibiotic use categorised by spectrum of activity. Among the 20 articles that met the inclusion criteria for the systematic review, there was tremendous variability in how prior antibiotic use was categorised (e.g. by agent, class, spectrum and/or a combination of these). No study justified its choice of categorisation method. In the re-analysis of the existing data set, multivariate models of risk factors for ESBL-EK using ‘class’ and ‘spectrum’ categorisations differed substantially. In conclusion, there has been no consistent approach to categorising antibiotic use in studies of risk factors for ESBL-EK. Different categorisation schemes were shown to have a substantial impact on study results, particularly for the antibiotic exposures associated with resistance. Elucidating these issues is critical if effective strategies to curb resistance are to be designed.

Introduction

The continued emergence of antibiotic resistance is of great concern [1]. Many studies have focused on identifying risk factors for resistant infections to better inform effective strategies to counter their continued emergence [2], [3]. Prior antibiotic use has been identified as one of the most consistent and important modifiable risk factors associated with resistance [4], [5]. However, whilst numerous studies have explored the association between antibiotic use and resistance, the methods by which past studies have categorised prior antibiotic use have not been critically reviewed. For example, antibiotic use could be classified by agent (e.g. cefazolin), class (e.g. cephalosporins) or spectrum of activity (e.g. Gram-negative). Antibiotics are frequently grouped together in classes even though individual agents within the class may differ significantly [6] and such categorisations may mask important associations. It is unknown whether using different categorisation schemes results in different conclusions regarding the association between antibiotic use and resistance. To best identify possible targets for intervention, it is critical to distinguish whether a resistant pathogen is associated with use of a specific class of antibiotics versus use of agents with a common spectrum of activity.

Using the emergence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella spp. (ESBL-EK) as a model, this study had two primary aims: (1) to describe the variability in the medical literature with regard to categorising antibiotic use in studies of risk factors for resistance; and (2) to determine the impact of using different antibiotic categorisation schemes on identifying possible antimicrobial use targets for intervention.

Section snippets

Methods

To explore the variability and possible impact of antibiotic categorisation methods on the association between prior antibiotic use and ESBL-EK infections, we conducted two studies. First, we performed a systematic review of the existing literature investigating the association between prior antibiotic use and ESBL-EK. In this systematic review we focused specifically on elucidating published approaches for categorisation of prior antibiotic use. Second, using a previously published study

Systematic review

Twenty articles investigating risk factors for ESBL-EK fulfilled the inclusion criteria for the systematic review (Table 2) [7], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. Fifteen focused on adult populations, four included only children and one included patients of all ages. Of the 20 studies, 4 employed a cohort design whilst 16 were case–control studies.

There was tremendous variability across studies in the approach to

Discussion

In recent years, increased attention has been focused on methodological issues in epidemiological studies of antibiotic resistance [32], [33], [34]. The goal of such work is to promote increasingly rigorous investigations to elucidate more clearly the epidemiology of resistance. In particular, identifying modifiable risk factors is paramount in efforts to curb the further emergence of resistance. To this end, the current study is, to our knowledge, the first to investigate the impact of

Acknowledgments

This work was supported by the Public Health Service grant DK-02987-01 of the National Institutes of Health (Dr Lautenbach). This study was also supported in part by an Agency for Healthcare Research and Quality (AHRQ) Centers for Education and Research on Therapeutics co-operative agreement (U18-HS10399). The authors thank Brian L. Strom, MD, MPH, for his invaluable advice during the preparation of this manuscript. Dr Lautenbach had full access to all the data in the study and takes

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Use of evidence-based recommendations in an antibiotic care bundle for the intensive care unit
2018, International Journal of Antimicrobial Agents
Citation Excerpt :
Systematic reviews and meta-analyses have shown a significant association between previous antibiotic administration and isolation of methicillin-resistant Staphylococcus aureus [1], vancomycin-resistant enterococci [2,3] and multidrug-resistant Gram-negative bacteria [4].
To drive decisions on antibiotic therapy in the intensive care unit (ICU), we developed an antibiotic care bundle (ABC-Bundle) with evidence-based recommendations (EBRs) for antibiotic prescriptions.
We conducted a three-step prospective study. First, a systematic review was performed of the literature reporting EBRs for antibiotic usage in the ICU. Second, we developed an ABC-Bundle through a two-round, RAND-modified Delphi method with an international expert panel, including the most relevant EBRs on a 9-point Likert scale. Those EBRs that were considered mandatory by >50% of the experts were included in the bundle. Third, we assessed the adherence to and applicability of the bundle in two mixed university ICUs.
Out of 1190 potentially relevant articles, 14 (four guidelines, four randomised controlled trials and six systematic reviews) fulfilled the eligibility criteria. Six EBRs were classified as relevant: 1. Provide rationale for antibiotic start; 2. Perform appropriate microbiological sampling; 3. Prescribe empirical antibiotic therapy according to guidelines (Day 1); 4. Review diagnosis; 5. Evaluate de-escalation based on microbiological results (Days 2–5); and 6. Consider discontinuation of treatment (Days 3–5). Daily adherence to the ABC-Bundle, prospectively assessed in 861 days of therapy in 142 ICU patients, ranged from 2% to 37%.
The ABC-Bundle is a novel tool to improve delivery of appropriate antibiotic therapy to ICU patients. The low adherence in the prospective cohorts confirms the significant role that the ABC-Bundle could play in an antibiotic stewardship programme in the ICU setting.
Risk factors for bloodstream infections caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae
2011, Brazilian Journal of Infectious Diseases
The objective of this study was to identify risk factors for bacteremia by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae. Retrospective case-control study performed in a 450-bed acute care academic tertiary hospital in Barcelona, Spain. Cases included 53 patients with ESBL-producing E. coli or K. pneumoniae bacteremia, and 159 controls with non-ESBL-producing E. coli or K. pneumoniae bacteremia. Controls were matched in a 3:1 ratio to case patients according to species of infecting organism, age, and severity of illness in the 24-48h before blood sample collection for culture calculated by the Simplified Acute Physiology Score (SAPS II) system. Previous antimicrobials were more frequently administered to cases than to controls (56.5% vs 17%, p < 0.001). Binary logistic regression showed that the number (> 2) of different families of antimicrobials received within 90 days before bloodstream infection was the only predictor of ESBL-producing E. coli or K. pneumoniae in blood culture (OR = 2.29, 95% CI 1.35−3.88, p = 0.002).
Previous use of different families of antimicrobials (more than two) in patients with bloodstream infection caused by E. coli or K. pneumoniae increased the risk for ESBL-producing strains.
Risk factors for fluoroquinolone resistance in Gram-negative bacilli causing healthcare-acquired urinary tract infections
2010, Journal of Hospital Infection
Citation Excerpt :
Data obtained included age, sex, race, hospital service (department), hospital location, number of hospital days both before and after the diagnosis of UTI, comorbid conditions, presence of a urinary catheter and use of inpatient antimicrobial therapy in the preceding 30 days. We categorised antimicrobial use by the individual agent and also by the class, as follows: (1) aminoglycosides; (2) β-lactam and β-lactamase inhibitors; (3) carbapenems; (4) cephalosporins; (5) fluoroquinolones; (6) penicillins; (7) macrolides; (8) others (clindamycin, doxycycline, metronidazole, nitrofurantoin, linezolid, cotrimoxazole and vancomycin).20,21 Categorical variables were expressed as proportions whereas continuous variables were expressed in terms of mean (±SD) or median (range) depending on the sample distribution.
The prevalence of urinary tract infections caused by fluoroquinolone-resistant Gram-negative bacilli (FQ-resistant GNB-UTIs) has been increasing. Previous studies that explored risk factors for FQ resistance have focused only on UTIs caused by Escherichia coli and/or failed to distinguish colonisation from infection. We conducted a case–control study at two medical centres within the University of Pennsylvania Health System to identify risk factors for FQ resistance among healthcare-acquired GNB-UTIs. Subjects with positive urine cultures for GNB and who met Centers for Disease Control and Prevention criteria for healthcare-acquired UTI were eligible. Cases were subjects with FQ-resistant GNB-UTI and controls were subjects with FQ-susceptible GNB-UTI matched to cases by month of isolation and species of infecting organism. In total, 251 cases and 263 controls were included from 1 January 2003 to 31 March 2005. Independent risk factors (adjusted odds ratio; 95% confidence interval) for FQ resistance included male sex (2.03; 1.21–3.39; P = 0.007), African-American race (1.80; 1.10–2.94; P = 0.020), chronic respiratory disease (2.58; 1.18–5.62; P = 0.017), residence in a long term care facility (4.41; 1.79–10.88; P = 0.001), hospitalisation within the past two weeks (2.19; 1.31–3.64; P = 0.003), hospitalisation under a medical service (2.72; 1.63–4.54; P < 0.001), recent FQ exposure (15.73; 6.15–40.26; P < 0.001), recent cotrimoxazole exposure (2.49; 1.07–5.79; P = 0.033), and recent metronidazole exposure (2.89; 1.48–5.65; P = 0.002).
Clinical and economic outcomes of decreased fluconazole susceptibility in patients with Candida glabrata bloodstream infections
2010, American Journal of Infection Control
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Data were primarily collected from the Pennsylvania Integrated Clinical and Administrative Research Database (PICARD). PICARD integrates administrative and clinical information (eg, demographics, diagnoses, pharmacy information, hospital charges) for both inpatient and outpatient activity occurring within the University of Pennsylvania Health System and has been used successfully in prior studies focusing on antimicrobial resistance.15,16 The primary outcomes were 30-day inpatient mortality and postculture hospital charges accrued from the date of the first positive blood culture until patient discharge or death.
The impact of reduced fluconazole susceptibility on clinical and economic outcomes in patients with Candida glabrata bloodstream infections (BSI) is unknown.
A retrospective cohort study was conducted to evaluate 30-day inpatient mortality and postculture hospital charges in patients with C glabrata BSI with decreased fluconazole susceptibility (minimum inhibitory concentration [MIC] ≥ 16 μg/mL) versus fluconazole-susceptible C glabrata BSI (MIC ≤ 8 μg/mL). These analyses were adjusted for demographics, comorbidities, and time at risk. Secondary analyses limited the C glabrata group with decreased fluconazole susceptibility to MIC ≥ 64 μg/mL.
There were 45 (31%) deaths among 144 enrolled patients: 19 deaths (25%) among 76 patients with C glabrata BSI with decreased fluconazole susceptibility and 26 deaths (38%) among 68 patients with fluconazole-susceptible C glabrata BSI. Decreased fluconazole susceptibility was not independently associated with increased 30-day inpatient mortality (adjusted odds ratio, .60; 95% confidence interval (CI): .26-1.35; P = 0.22) or hospital charges (multiplicative change in hospital charges, .93; 95% CI: .60-1.43; P = 0.73). Older age was associated with increased mortality and increased time at risk was associated with increased hospital charges.
Crude mortality rates remain high in patients with C glabrata BSI. However, decreased fluconazole susceptibility was not associated with increased mortality or hospital charges.
Risk factors for fluconazole resistance in patients with Candida glabrata bloodstream infection: Potential impact of control group selection on characterizing the association between previous fluconazole use and fluconazole resistance
2010, American Journal of Infection Control
Citation Excerpt :
The following patient information was collected: demographic information (ie, age, sex, and race), hospitalization characteristics (ie, hospital and time at risk [time from hospital admission to the first positive blood culture]), comorbidities (ie, human immunodeficiency virus infection, malignancy, diabetes, neutropenia, solid organ transplantation, hematopoietic stem cell transplantation, cirrhosis, and end-stage renal disease requiring dialysis), and events occurring 30 days before the positive C glabrata blood culture, including receipt of total parenteral nutrition, chemotherapy, immunosuppression, and/or antimicrobial agents, and intensive care unit stay (collected as binomial variables). Antimicrobial agents evaluated included fluconazole, voriconazole, caspofungin, amphotericin, penicillin, amoxicillin, ampicillin, amoxicillin/clavulanate, ampicillin/sulbactam, nafcillin, piperacillin, piperacillin/tazobactam, cefazolin, cephalexin, ceftriaxone, ceftazidime, cefepime, imipenem, meropenem, aztreonam, gentamicin, tobramycin, amikacin, kanamycin, levofloxacin, ciprofloxacin, ofloxacin, doxycycline, azithromycin, clarithromycin, erythromycin, chloramphenicol, clindamycin, linezolid, metronidazole, quinupristin/dalfopristin, trimethoprim/sulfamethoxazole, and vancomycin.14 Demographic and patient health information of cases and controls were compared in bivariate analyses using the χ2 or Fisher's exact test for categorical variables and the Student t test or Wilcoxon's rank-sum test for continuous variables.
Although Candida glabrata is an emerging infection, risk factors for fluconazole resistance in patients with C glabrata bloodstram infection (BSI) have not been well elucidated.
A case-control study was conducted to evaluate the primary risk factor of interest, previous fluconazole use, adjusting for demographics, comorbidities, time at risk, and antimicrobial exposure and assessing for effect modification. Secondary analyses were performed limiting the case group to C glabrata BSIs with a minimum inhibitory concentration (MIC) ≥64 μg/mL.
Previous fluconazole use was not a significant risk factor for fluconazole-resistant C glabrata BSI in primary analysis (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 0.7-3.2) but was borderline significant in secondary analysis (aOR, 3.2; 95% CI, 0.9-11.3). Increased time at risk was an independent risk factor in primary (aOR, 1.02; 95% CI, 1.002-1.04) and secondary analyses (aOR, 1.03; 95% CI, 1.004-1.06).
Increased time at risk was the only significant risk factor for fluconazole resistance. Future studies are needed to further evaluate the relationship between previous fluconazole use and fluconazole-resistant C glabrata BSI isolates with MIC ≥64 μg/mL.
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Investigating the association between antibiotic use and antibiotic resistance: impact of different methods of categorising prior antibiotic use

Abstract

Introduction

Section snippets

Methods

Systematic review

Discussion

Acknowledgments

Chest

J Clin Epidemiol

J Hosp Infect

J Hosp Infect

J Hosp Infect

J Hosp Infect

J Hosp Infect

Microbial threats to health: emergence, detection, and response

Can better prescribing turn the tide of resistance?

Nat Rev Microbiol

Antimicrobial resistance determinants and future control

Emerg Infect Dis

The commonality of risk factors for nosocomial colonization and infection with antimicrobial-resistant Staphylococcus aureus, enterococcus, gram-negative bacilli, Clostridium difficile, and Candida

Ann Intern Med

The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens

Clin Infect Dis

Extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes

Clin Infect Dis

The Sanford guide to antimicrobial therapy

The use of antibiotics: a clinical review of antibacterial, antifungal and antiviral drugs

Principles and practice of infectious diseases

The impact of confounder selection criteria on effect estimation

Am J Epidemiol

Risk factors for and outcomes of bloodstream infection caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species in children

Pediatrics

International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial infections

Ann Intern Med

Risk factors for the development of extended-spectrum beta-lactamase-producing bacteria in nonhospitalized patients

Eur J Clin Microbiol Infect Dis