The effect of combining antibiotics on resistance: A systematic review and meta-analysis.

When and under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics. We searched CENTRAL, EMBASE and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to November 24th, 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. A patient was considered to have acquired resistance if, at the follow-up culture, a resistant bacterium was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials' risk of bias was assessed with the Cochrane tool. 42 trials were eligible and 29, including 5054 patients, were qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio (OR) for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68-2.25), with substantial between-study heterogeneity (I2 =77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions. The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall, is compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.

The impact of public health interventions on the future prevalence of ESBL-producing Klebsiella pneumoniae: a population based mathematical modelling study.

BACKGROUND: Future prevalence of colonization with extended-spectrum betalactamase (ESBL-) producing K. pneumoniae in humans and the potential of public health interventions against the spread of these resistant bacteria remain uncertain. METHODS: Based on antimicrobial consumption and susceptibility data recorded during > 13 years in a Swiss region, we developed a mathematical model to assess the comparative effect of different interventions on the prevalence of colonization. RESULTS: Simulated prevalence stabilized in the near future when rates of antimicrobial consumption and in-hospital transmission were assumed to remain stable (2025 prevalence: 6.8% (95CI%:5.4-8.8%) in hospitals, 3.5% (2.5-5.0%) in the community versus 6.1% (5.0-7.5%) and 3.2% (2.3-4.2%) in 2019, respectively). When overall antimicrobial consumption was set to decrease by 50%, 2025 prevalence declined by 75% in hospitals and by 64% in the community. A 50% decline in in-hospital transmission rate led to a reduction in 2025 prevalence of 31% in hospitals and no reduction in the community. The best model fit estimated that 49% (6-100%) of observed colonizations could be attributable to sources other than human-to-human transmission within the geographical setting. CONCLUSIONS: Projections suggests that overall antimicrobial consumption will be, by far, the most powerful driver of prevalence and that a large fraction of colonizations could be attributed to non-local transmissions.

Modifiable and nonmodifiable risk factors for non-ventilator-associated hospital-acquired pneumonia identified in a retrospective cohort study.

OBJECTIVES: Hospital-acquired pneumonia in nonventilated patients (nvHAP) belongs to the most common healthcare-associated infections. This study aimed to investigate risk factors for nvHAP in patients outside the intensive care unit, focusing on modifiable risk factors. METHODS: All inpatients admitted to an academic teaching hospital in Switzerland between 2017 and 2018 were included. nvHAP was defined according to European Centre for Disease Prevention and Control criteria. Patient days during and after ICU stay were excluded. Candidate risk factors-both constant and time varying-were included in uni- and multivariable Cox proportional hazards models. The decay ratio and the characteristic time of influence of hazard ratios (HRs) was estimated by adopting a linear decay in the Cox model. RESULTS: A total of 66 001 hospitalizations with 314 (0.48%) nvHAP and 471 401 patient days were included. Median age was 57 years (interquartile range: 38 to 71 years) and 32 253 (48.9%) patients were male. Among nonmodifiable risk factors, age (adjusted HR (aHR) 2.66 for age ≥60 years, 95% CI 1.59 to 4.45) and male sex (aHR 1.71, 95% CI 1.34 to 2.18) were independently associated with nvHAP. Time-varying exposures showing strongest independent association with nvHAP were tube feeding (aHR 3.24, 95% CI 2.17 to 4.83), impaired consciousness (aHR 2.32, 95% CI 1.63 to 3.31), and severely impaired activity and mobility (aHR 2.06, 95% CI 1.50 to 2.84). The association with nvHAP decayed within 7.1 to 13.2 days after these exposures ended. DISCUSSION: The risk for nvHAP varies with time, depending on the patient's medical condition and medical interventions. Several risk factors for nvHAP represent potential targets for specific prevention measures.

Decreasing Incidence and Determinants of Bacterial Pneumonia in People With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bacterial pneumonia is a leading reason for hospitalization among people with HIV (PWH); however, evidence regarding its drivers in the era of potent antiretroviral therapy is limited. METHODS: We assessed risk factors for bacterial pneumonia in the Swiss HIV Cohort Study using marginal models. We further assessed the relationship between risk factors and changes in bacterial pneumonia incidence using mediation analysis. RESULTS: We included 12927 PWH with follow-ups between 2008 and 2018. These patients had 985 bacterial pneumonia events during a follow-up of 100779 person-years. Bacterial pneumonia incidence significantly decreased from 13.2 cases/1000 person-years in 2008 to 6.8 cases/1000 person-years in 2018. Older age, lower education level, intravenous drug use, smoking, lower CD4-cell count, higher HIV load, and prior pneumonia were significantly associated with higher bacterial pneumonia incidence. Notably, CD4 cell counts 350-499 cells/µL were significantly associated with an increased risk compared to CD4 ≥ 500 cells/µL (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01-1.89). Decreasing incidence over the last decade can be explained by increased CD4-cell counts and viral suppression and decreased smoking frequency. CONCLUSIONS: Improvements in cascade of care of HIV and decrease in smoking may have mediated a substantial decrease in bacterial pneumonia incidence.

Assessing the drivers of syphilis among men who have sex with men in Switzerland reveals a key impact of screening frequency: A modelling study.

Over the last decade, syphilis diagnoses among men-who-have-sex-with-men (MSM) have strongly increased in Europe. Understanding the drivers of the ongoing epidemic may aid to curb transmissions. In order to identify the drivers of syphilis transmission in MSM in Switzerland between 2006 and 2017 as well as the effect of potential interventions, we set up an epidemiological model stratified by syphilis stage, HIV-diagnosis, and behavioral factors to account for syphilis infectiousness and risk for transmission. In the main model, we used 'reported non-steady partners' (nsP) as the main proxy for sexual risk. We parameterized the model using data from the Swiss HIV Cohort Study, Swiss Voluntary Counselling and Testing center, cross-sectional surveys among the Swiss MSM population, and published syphilis notifications from the Federal Office of Public Health. The main model reproduced the increase in syphilis diagnoses from 168 cases in 2006 to 418 cases in 2017. It estimated that between 2006 and 2017, MSM with HIV diagnosis had 45.9 times the median syphilis incidence of MSM without HIV diagnosis. Defining risk as condomless anal intercourse with nsP decreased model accuracy (sum of squared weighted residuals, 378.8 vs. 148.3). Counterfactual scenarios suggested that increasing screening of MSM without HIV diagnosis and with nsP from once every two years to twice per year may reduce syphilis incidence (at most 12.8% reduction by 2017). Whereas, increasing screening among MSM with HIV diagnosis and with nsP from once per year to twice per year may substantially reduce syphilis incidence over time (at least 63.5% reduction by 2017). The model suggests that reporting nsP regardless of condom use is suitable for risk stratification when modelling syphilis transmission. More frequent screening of MSM with HIV diagnosis, particularly those with nsP may aid to curb syphilis transmission.

Identifying the drivers of multidrug-resistant Klebsiella pneumoniae at a European level.

Beta-lactam- and in particular carbapenem-resistant Enterobacteriaceae represent a major public health threat. Despite strong variation of resistance across geographical settings, there is limited understanding of the underlying drivers. To assess these drivers, we developed a transmission model of cephalosporin- and carbapenem-resistant Klebsiella pneumoniae. The model is parameterized using antibiotic consumption and demographic data from eleven European countries and fitted to the resistance rates for Klebsiella pneumoniae for these settings. The impact of potential drivers of resistance is then assessed in counterfactual analyses. Based on reported consumption data, the model could simultaneously fit the prevalence of extended-spectrum beta-lactamase-producing and carbapenem-resistant Klebsiella pneumoniae (ESBL and CRK) across eleven European countries over eleven years. The fit could explain the large between-country variability of resistance in terms of consumption patterns and fitted differences in hospital transmission rates. Based on this fit, a counterfactual analysis found that reducing nosocomial transmission and antibiotic consumption in the hospital had the strongest impact on ESBL and CRK prevalence. Antibiotic consumption in the community also affected ESBL prevalence but its relative impact was weaker than inpatient consumption. Finally, we used the model to estimate a moderate fitness cost of CRK and ESBL at the population level. This work highlights the disproportionate role of antibiotic consumption in the hospital and of nosocomial transmission for resistance in gram-negative bacteria at a European level. This indicates that infection control and antibiotic stewardship measures should play a major role in limiting resistance even at the national or regional level.

Assessing the potential impact of transmission during prolonged viral shedding on the effect of lockdown relaxation on COVID-19.

A key parameter in epidemiological modeling which characterizes the spread of an infectious disease is the generation time, or more generally the distribution of infectiousness as a function of time since infection. There is increasing evidence supporting a prolonged viral shedding window for COVID-19, but the transmissibility in this phase is unclear. Based on this, we develop a generalized Susceptible-Exposed-Infected-Resistant (SEIR) model including an additional compartment of chronically infected individuals who can stay infectious for a longer duration than the reported generation time, but with infectivity reduced to varying degrees. Using the incidence and fatality data from different countries, we first show that such an assumption also yields a plausible model in explaining the data observed prior to the easing of the lockdown measures (relaxation). We then test the predictive power of this model for different durations and levels of prolonged infectiousness using the incidence data after the introduction of relaxation in Switzerland, and compare it with a model without the chronically infected population to represent the models conventionally used. We show that in case of a gradual easing on the lockdown measures, the predictions of the model including the chronically infected population vary considerably from those obtained under a model in which prolonged infectiousness is not taken into account. Although the existence of a chronically infected population still remains largely hypothetical, we believe that our results provide tentative evidence to consider a chronically infected population as an alternative modeling approach to better interpret the transmission dynamics of COVID-19.