Incidence of infection with multidrug-resistant Gram-negative bacteria and vancomycin-resistant enterococci in carriers: a systematic review and meta-regression analysis.

BACKGROUND: Carriers of multidrug-resistant bacteria are at risk of infections with these bacteria; the precise size of this risk is unclear. We aimed to quantify the effect of gut colonisation on subsequent risk of infection with multidrug-resistant bacteria. METHODS: We performed a systematic review and meta-regression analysis. We searched PubMed, Embase, Web of Science Core Collection, and Google Scholar for follow-up studies published from Jan 1, 1995, to March 17, 2022, that measured the incidence of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and from Jan 1, 1995, to March 15, 2022, that measured the incidence of infections with vancomycin-resistant enterococci (VRE). We included original cohort studies and case-control studies that used incidence-density sampling, included 50 or more patients with enteric colonisation or positive urinary samples as a surrogate marker of colonisation, or both, and analysed infections clearly preceded by colonisation. We did not use any language restrictions. We excluded studies not reporting length of follow-up. Summary data were extracted and independently cross-verified by two authors. Carriage was defined as MDR-GNB or VRE, detected in faecal or urinary cultures. Our primary outcomes were cumulative incidence and incidence density of infection in patients colonised by multidrug-resistant bacteria. To estimate pooled incidences, general linearised mixed-effects meta-regressions were used, adjusting for varying follow-up durations. This study is registered with PROSPERO, CRD42020222415. FINDINGS: Of the 301 studies identified, 44 studies (26 on MDR-GNB, 14 on VRE, and four on both MDR-GNB and VRE) from 14 countries were retained for qualitative synthesis, 40 of which were analysed with meta-regression, comprising data for 14 049 patients colonised with multidrug-resistant bacteria. The pooled cumulative incidence of infection was 14% (95% CI 10-18; p<0·0001) at a median follow-up time of 30 days for MDR-GNB (845 cases of infection in 9034 patients colonised) and 8% (5-13; p<0·0001) at 30 days for VRE (229 cases of infection in 4747 patients colonised). Infection incidence density (4·26 infections per 1000 patient-days; 95% CI 1·69-6·82) and cumulative incidence of infection (19%, 95% CI 15-25; p<0·0001; 602 cases of infection in 4547 patients colonised) were highest for carbapenem-resistant Gram-negative bacteria at 30 days. Risk of bias was rated low to moderate. INTERPRETATION: The risk of infection was substantial, with the highest risk for patients colonised with carbapenem-resistant Gram-negative bacteria and the lowest in patients with VRE. These data might help to guide prophylactic and treatment decisions and form a valuable resource for planning clinical trials on targeted prevention. FUNDING: The Netherlands Organization for Health Research and Development.

Association of Proton Pump Inhibitor Use With Risk of Acquiring Drug-Resistant Enterobacterales.

Importance: Proton-pump inhibitors (PPIs) have been associated with the risk of colonization with drug-resistant bacteria; however, possible confounding by lifestyle-associated factors and disease severity casts doubt on this association, and whether the risk is dose dependent is not known. Objectives: To assess the association between PPI use and the risk of acquiring drug-resistant Enterobacterales and to examine interactions with possible microbiome-altering agents. Design, Setting, and Participants: This nested case-control study involved 2239 hospitalized adult (aged ≥18 years) patients identified from the microbiology laboratory database of Amsterdam University Medical Centers between December 31, 2018, and January 6, 2021. Patients in the case group had newly detected extended-spectrum ß-lactamase (ESBL)- or carbapenemase-producing Enterobacterales (identified by clinical specimens). Risk-set sampling was used to assign patients with negative results for ESBL- and carbapenemase-producing Enterobacterales to the control group, who were then matched on a 5:1 ratio with patients in the case group by age and culture date. A second validation case-control study included matched pairs (1:1 ratio; 94 in each group) of patients who were prospectively enrolled. Exposures: Proton pump inhibitor use and clinical data at 30 days (primary exposure) and 90 days (secondary exposure) before the date of culture. Main Outcomes and Measures: Adjusted incidence rate ratios (aIRRs) of ESBL- or carbapenemase-producing Enterobacterales acquisition by PPI dose and time risk windows (30 days for the primary outcome and 90 days for the secondary outcome) were estimated using conditional logistic regression models. Results: Among 2239 hospitalized patients (51.1% male; mean [SD] age, 60.9 [16.7] years), 374 were in the case group (51.6% male; mean [SD] age, 61.1 [16.5] years) and 1865 were in the matched control group (51.0% male; mean [SD] age, 60.9 [16.7] years). The aIRR for PPI use overall was 1.48 (95% CI, 1.15-1.91) at 30 days. Sensitivity analyses and the analysis of the pair-matched study with prospectively enrolled patients (aIRR, 2.96, 95% CI, 1.14-7.74) yielded similar results; findings were consistent in subgroups and corroborated by a negative-control exposure analysis. No association with microbiome-disturbing agents was found; laxatives and antibiotics were independently associated with a more than 2-fold increase in the risk of acquisition (antibiotics: aIRR, 2.78 [95% CI, 2.14-3.59]; laxatives: aIRR, 2.26 [95% CI. 1.73-2.94]). Conclusions and Relevance: In this study, after careful control for confounding and sensitivity analyses, PPI use was associated with increases in the risk of acquiring ESBL- or carbapenemase-producing Enterobacterales among adult hospitalized patients. These findings emphasize the need for judicious use of PPIs.

Gut colonisation by extended-spectrum ß-lactamase-producing Escherichia coli and its association with the gut microbiome and metabolome in Dutch adults: a matched case-control study.

BACKGROUND: Gut colonisation by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli is a risk factor for developing overt infection. The gut microbiome can provide colonisation resistance against enteropathogens, but it remains unclear whether it confers resistance against ESBL-producing E coli. We aimed to identify a potential role of the microbiome in controlling colonisation by this antibiotic-resistant bacterium. METHODS: For this matched case-control study, we used faeces from 2751 individuals in a Dutch cross-sectional population study (PIENTER-3) to culture ESBL-producing bacteria. Of these, we selected 49 samples that were positive for an ESBL-producing E coli (ESBL-positive) and negative for several variables known to affect microbiome composition. These samples were matched 1:1 to ESBL-negative samples on the basis of individuals' age, sex, having been abroad or not in the past 6 months, and ethnicity. Shotgun metagenomic sequencing was done and taxonomic species composition and functional annotations (ie, microbial metabolism and carbohydrate-active enzymes) were determined. Targeted quantitative metabolic profiling (proton nuclear magnetic resonance spectroscopy) was done to investigate metabolomic profiles and combinations of univariate (t test and Wilcoxon test), multivariate (principal coordinates analysis, permutational multivariate analysis of variance, and partial least-squares discriminant analysis) and machine-learning approaches (least absolute shrinkage and selection operator and random forests) were used to analyse all the molecular data. FINDINGS: No differences in diversity parameters or in relative abundance were observed between ESBL-positive and ESBL-negative groups based on bacterial species-level composition. Machine-learning approaches using microbiota composition did not accurately predict ESBL status (area under the receiver operating characteristic curve [AUROC]=0·41) when using either microbiota composition or any of the functional profiles. The metabolome also did not differ between ESBL groups, as assessed by various methods including random forest (AUROC=0·61). INTERPRETATION: By combining multiomics and machine-learning approaches, we conclude that asymptomatic gut carriage of ESBL-producing E coli is not associated with an altered microbiome composition or function. This finding might suggest that microbiome-mediated colonisation resistance against ESBL-producing E coli is not as relevant as it is against other enteropathogens and antibiotic-resistant bacteria. FUNDING: None.

Gastric acid suppression, lifestyle factors and intestinal carriage of ESBL and carbapenemase-producing Enterobacterales: a nationwide population-based study.

BACKGROUND: Gastric acid-suppressive therapy has been suggested to increase the risk for intestinal carriage of MDR Enterobacterales, but there is scarce community-based evidence substantiating this risk. OBJECTIVES: To investigate if acid-suppressant use is associated with a risk of intestinal carriage of ESBL and carbapenemase-producing Enterobacterales (ESBL-E) in the open population, and to assess possible modifying factors. METHODS: Within the framework of a nationwide seroprevalence study, we identified a population-based cross-sectional cohort comprising 2746 adults (≥18 years), who provided stool specimens between February 2016 and June 2017. Specimens were tested by phenotypic assays and confirmatory genotype analysis to detect carriage of ESBL-E. Covariate data were extracted from self-administered questionnaires. ORs and 95% CIs were estimated using multivariable multilevel logistic regression, controlling for confounders informed by directed acyclic graphs. RESULTS: Among 2746 participants, 316 (11.5%) used acid suppressants; the prevalence of ESBL-E carriage was 7.4% (95% CI, 6.1%-8.6%). Current use of acid suppressants was not associated with ESBL-E carriage (adjusted OR [aOR], 1.05; 95% CI, 0.64-1.74); lifestyle and comorbidity did not modify this association. A higher BMI (≥25 kg/m2) (aOR, 1.42 [95% CI, 1.02-1.98]), non-Western ethnic origin (aOR, 1.96 [95% CI, 1.34-2.87]), travel to Eastern-Mediterranean, Western-Pacific or South-East Asia regions (aOR, 3.16 [95% CI, 1.71-5.83]) were associated with ESBL-E carriage. Sensitivity analyses confirmed these results; spline analysis supported a BMI-associated risk. CONCLUSIONS: In this open population study, current use of acid suppressants was not associated with ESBL-E carriage. Travel to high-endemic regions and non-Western ethnicity were confirmed as risk factors, while a higher BMI emerged as a potential new risk for ESBL-E carriage.

Evaluation of the Association Between Gastric Acid Suppression and Risk of Intestinal Colonization With Multidrug-Resistant Microorganisms: A Systematic Review and Meta-analysis.

Importance: Acid suppressants inhibit gastric acid secretion and disrupt the intestinal microbiome. Whether acid suppression increases the risk of colonization with multidrug-resistant microorganisms (MDROs) is unclear. Objectives: To systematically examine the association of use of acid suppressants with the risk of colonization with MDROs and to perform a meta-analysis of current evidence. Data Sources: PubMed, Embase, the Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials were searched from database inception through July 8, 2019. Study Selection: Study selection was performed independently by 2 authors (R.P.J.W. and C.M.J.E.V.-G.) on the basis of predefined selection criteria; conflicts were resolved by consensus or by an adjudicator (K.v.D.). Human observational studies (case control, cohort, and cross-sectional) and clinical trial designs were selected if they quantified the risk of MDRO colonization in users of acid suppressants in comparison with nonusers. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) recommendations were followed. Data were extracted independently by the same 2 authors, and adjudication was conducted when necessary. Risk of bias was assessed according to a modified Newcastle-Ottawa Scale. Pooled odds ratios (ORs) were estimated using random-effects models; heterogeneity was evaluated using the I2 method. Main Outcomes and Measures: The primary outcome measure was intestinal colonization with MDROs of the Enterobacterales order (producing extended-spectrum ß-lactamases, carbapenemases, or plasmid-mediated AmpC ß-lactamases), vancomycin-resistant enterococci, methicillin-resistant or vancomycin-resistant Staphylococcus aureus, or multidrug-resistant Pseudomonas or Acinetobacter species. Results: A total of 26 observational studies including 29 382 patients (11 439 [38.9%] acid suppressant users) met the selection criteria. Primary meta-analysis of 12 studies including 22 305 patients that provided adjusted ORs showed that acid suppression increased the odds of intestinal carriage of MDROs of the Enterobacterales order and of vancomycin-resistant enterococci by roughly 75% (OR = 1.74; 95% CI, 1.40-2.16; I2 = 68%). The odds were concordant with the secondary pooled analysis of all 26 studies (OR = 1.70; 95% CI, 1.44-1.99; I2 = 54%). Heterogeneity was partially explained by variations in study setting and the type of acid suppression. Conclusions and Relevance: Acid suppression is associated with increased odds of MDRO colonization. Notwithstanding the limitations of observational studies, the association is plausible and is strengthened by controlling for confounders. In view of the global increase in antimicrobial resistance, stewardship to reduce unnecessary use of acid suppressants may help to prevent MDRO colonization.

Interaction between tramadol and selective serotonin reuptake inhibitors: are doctors aware of potential risks in their prescription practice?

OBJECTIVES: The combination of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) with tramadol can result in serotonin syndrome, characterised by neuromuscular and autonomic nervous system excitation and altered mental state. The incidence of serotonin syndrome with this combination of drugs is low, and the serotonin syndrome is generally mild or moderate in form, but can be life threatening and is more easily prevented than treated. We aimed to investigate whether prescribers in a general hospital were aware of this risk and if it influenced their prescriptions. METHODS: A questionnaire was sent to 194 physicians in a general teaching hospital with over 650 beds in The Netherlands. The questionnaire presented four cases, two of whom used an SSRI or SNRI among other medications, and asked the respondents to prescribe an opioid in each case. The respondents were not aware of the focus of our research. Actual prescription rates of tramadol in admitted patients who did or did not use an SSRI or SNRI were assessed using the hospital pharmacy database. RESULTS: Based on the questionnaire, respondents prescribed tramadol equally in patients with or without concomitant use of SSRIs/SNRIs. About one-third of respondents who prescribed tramadol indicated they were aware of the potential interaction with SSRIs/SNRIs. About one-fifth deliberately avoided tramadol because a potential interaction with SSRIs/SNRIs was identified. However, there was no difference in actual tramadol prescriptions, as recorded in the hospital pharmacy database: 23.8% of SSRI/SNRI users received tramadol versus 24.6% of non-SSRI/SNRI-users (calculated OR 0.96; 95% CI 0.78 to 1.17). CONCLUSIONS: In total, 20-30% of prescribers in a general hospital were aware of the potential interaction between tramadol and SSRIs or SNRIs, yet this did not translate to a difference in tramadol prescriptions between SSRI/SNRI users and non-users, as documented in the hospital pharmacy database. A physician's decision to prescribe tramadol to SSRI/SNRI users may be guided by a comprehensive individual benefit-risk assessment; expected benefits of tramadol may outweigh the small risk of serotonin syndrome. In order to increase awareness of the potential risk of a serotonin syndrome, hospital pharmacies may play an important role in signalling the potential interaction and providing information on the benefits and risks of tramadol and alternative analgesics in the presence of SSRIs or SNRIs.