Spare and repair the gut microbiota from antibiotic-induced dysbiosis: state-of-the-art.

Homeostasis of the intestinal microbiota is currently recognized as a major contributor to human health. Furthermore, intestinal dysbiosis is associated with a multitude of consequences, including intestinal colonization by antibiotic-resistant or pathogenic bacteria, such as Clostridioides difficile, and reduced efficacy of promising anticancer immunotherapies. By far, the most immediate and drastic exposure leading to dysbiosis is antibiotic treatment. Many attempts have been made to prevent or repair antibiotic-associated dysbiosis. Here, we review these innovations and the difficulties associated with their development.

NSCLC Immunotherapy Efficacy and Antibiotic Use: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan-Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I2 of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval [CI]: 1.13-1.90) for PFS and 1.69 (95% CI: 1.25-2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1-8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [-60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.

Burden of Clostridium difficile Infections in French Hospitals in 2014 From the National Health Insurance Perspective.

OBJECTIVE To describe the hospital stays of patients with Clostridium difficile infection (CDI) and to measure the hospitalization costs of CDI (as primary and secondary diagnoses) from the French national health insurance perspective DESIGN Burden of illness study SETTING All acute-care hospitals in France METHODS Data were extracted from the French national hospitalization database (PMSI) for patients covered by the national health insurance scheme in 2014. Hospitalizations were selected using the International Classification of Diseases, 10 th revision (ICD-10) code for CDI. Hospital stays with CDI as the primary diagnosis or the secondary diagnosis (comorbidity) were studied for the following parameters: patient sociodemographic characteristics, mortality, length of stay (LOS), and related costs. A retrospective case-control analysis was performed on stays with CDI as the secondary diagnosis to assess the impact of CDI on the LOS and costs. RESULTS Overall, 5,834 hospital stays with CDI as the primary diagnosis were included in this study. The total national insurance costs were €30.7 million (US $33,677,439), and the mean cost per hospital stay was €5,267±€3,645 (US $5,777±$3,998). In total, 10,265 stays were reported with CDI as the secondary diagnosis. The total national insurance additional costs attributable to CDI were estimated to be €85 million (US $93,243,725), and the mean additional cost attributable to CDI per hospital stay was €8,295±€17,163, median, €4,797 (US $9,099±$8,827; median, $5,262). CONCLUSION CDI has a high clinical and economic burden in the hospital, and it represents a major cost for national health insurance. When detected as a comorbidity, CDI was significantly associated with increased LOS and economic burden. Preventive approaches should be implemented to avoid CDIs. Infect Control Hosp Epidemiol 2017;38:906-911.

Diversity of extended-spectrum ß-lactamase-producing Enterobacteriaceae on hospital admission.

Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae have become prevalent in both the hospital and the community. We describe the epidemiology of ESBL-producing isolates and patient characteristics at hospital admission. Data on clinical properties, medical history, previous hospitalizations, and previous antibiotic treatments were collected. ESBL genes (bla(CTX-M), bla(TEM), and bla(SHV)) were identified by polymerase chain reaction. One hundred and sixteen patients carried 122 ESBL-producing Enterobacteriaceae: 79 Escherichia coli, 26 Klebsiella pneumoniae, 16 Enterobacter spp., and 1 Citrobacter koseri. ESBL-producing E. coli were associated with admission from home (odds ratio (OR) 3.04, p = 0.02) and a history of recent urinary tract infection (OR 3.38, p = 0.04), and exhibited a lower rate of antimicrobial resistance to aminoglycosides (p ≤ 0.005) and co-trimoxazole (p = 0.003), whereas other ESBL-producing Enterobacteriaceae tended to be associated with a recent surgery (OR 0.42, p = 0.057). Although the CTX-M enzymes were more frequently found in E. coli (76%), they were also identified in other Enterobacteriaceae (45%), suggesting penetration of CTX-M-type enzymes into both community- and hospital-acquired enterobacterial species.

Carriage of methicillin-resistant Staphylococcus aureus in home care settings: prevalence, duration, and transmission to household members.

BACKGROUND: Several studies have documented prolonged colonization with hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) after hospital discharge. However, information is lacking about factors associated with prolonged MRSA colonization and MRSA transmission to household contacts. METHODS: From February 2003 to March 2004, adult inpatients (except obstetric patients) were screened for MRSA carriage before discharge to home health care. Bivariate and multivariate analyses were performed to evaluate rates and risk factors of MRSA carriage at discharge, MRSA clearance within 1 year, and MRSA transmission to household contacts. RESULTS: We identified MRSA in 191 of the 1501 patients screened before discharge to home health care (12.7%). Of the 148 patients with MRSA who were observed, 75 cleared the organism within 1 year, with an estimated median time to clearance of 282 days (95% confidence interval [CI], 233-313 days). Clearance of MRSA was associated with self-sufficiency in daily activities (hazard ratio, 0.63; 95% CI, 0.40-1.00) (P = .049). Of the 188 included household contacts, 36 acquired MRSA (19.1%). Factors associated with household MRSA acquisition were older age (adjusted odds ratio, 1.71 per life decade; 95% CI, 1.32-2.21) (P = .001) and participation in the health care of the index patient (adjusted odds ratio, 3.58; 95% CI, 1.33-9.62) (P = .01). CONCLUSIONS: Hospital-acquired MRSA carriage was common at discharge to home health care and was frequently prolonged. Transmission occurred in nearly 20% of household contacts and was associated with older age and participation in health care of the index patient. Household contacts should apply infection control measures similar to those recommended in the hospital setting.

Rapid adaptation of antibiotic therapy for community-acquired peritonitis using direct cultures on antibiotic agar plates: pilot study.

BACKGROUND: Treatment of peritonitis requires prompt surgery and antibiotic therapy. It usually takes two or three days to obtain definitive results of peritoneal cultures and to adapt empirical antibiotic therapy. We assessed the potential time gain associated with direct culture of peritoneal samples on antibiotic agar (AA). METHODS: Peritoneal samples from 31 consecutive patients undergoing surgery for suspected community-acquired peritonitis were cultured according to the standard method and on AA containing one of the following five regimens: amoxicillin/clavulanic acid + gentamicin, ticarcillin/clavulanic acid + gentamicin, cefotaxime +metronidazole, piperacillin/tazobactam, or ertapenem. We compared the treatment modifications made by physicians aware only of the results of the standard method with the modifications the AA method would have indicated. RESULTS: Fewer isolates were identified by direct culture on AA than by the standard method (17 vs. 45; p = 0.0001), but definitive results were obtained much more rapidly (median 1 [range 1-3] days vs. 3 [range 2-7] days; p < 0.0001). Antibiotic regimens were changed for 14 patients on the basis of the results of the standard method (broader antibiotic spectrum and narrower spectrum in seven patients each). With the AA method, these changes could have been indicated after a median of 1 (range 1-2) days instead of 4 (range 1-11) days (p = 0.0006). The AA method missed only one resistant bacterial strain and isolated nine strains not detected by the standard method, including an extended-spectrum beta-lactamase-producing Escherichia coli. A complicated outcome was more frequent in patients having isolates found with the AA but not the standard method (86% vs. 21%; p = 0.003). CONCLUSION: Use of the AA method for culture of peritoneal samples from patients with community-acquired peritonitis speeds appropriate adaptation of antibiotic therapy and warrants further investigation.

Epidemiology of multidrug-resistant bacteria in patients with long hospital stays.

OBJECTIVE: To determine rates of colonization with multidrug-resistant (MDR) bacteria (ie, methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant Enterococcus [VRE], extended-spectrum beta -lactamase [ESBL]-producing Enterobacteriaceae, and Acinetobacter baumannii) after prolonged hospitalization and to assess the yield of surveillance cultures and variables associated with colonization with MDR bacteria. DESIGN: Prospective observational cohort study conducted from February 6 to May 26, 2006. METHODS: All patients who spent more than 30 days in our university hospital (Paris, France) were included. Rectal and nasal swab samples obtained during day 30 screening were examined for MRSA, VRE, ESBL-producing Enterobacteriaceae, and A. baumannii. RESULTS: Of 470 eligible patients, 439 had surveillance culture samples available for analysis, including 51 patients (11.6%) with a history of colonization or infection due to 1 or more types of MDR bacteria (MRSA, recovered from 35 patients; ESBL-producing Enterobacteriaceae, from 16 patients; A. baumannii, from 6 patients; and VRE, from 0 patients) and 37 patients (9.5% of the 388 patients not known to have any of the 4 MDR bacteria before day 30 screening) newly identified as colonized by 1 or more MDR bacteria (MRSA, recovered from 20 patients; ESBL-producing Enterobacteriaceae, from 16 patients; A. baumannii, from 1 patient; and VRE, from 0 patients). A total of 87 (19.8%) of 439 patients were identified as colonized or infected with MDR bacteria at day 30. Factors that differed between patients with and without MRSA colonization included age, McCabe score, comorbidity score, receipt of surgery, and receipt of fluoroquinolone treatment. Patients with ESBL-producing Enterobacteriaceae colonization were younger than patients with MRSA colonization. CONCLUSIONS: Differences in the variables associated with MRSA colonization and ESBL-producing Enterobacteriaceae colonization suggest differences in the epidemiology of these 2 organisms. Day 30 screening resulted in a 72.5% increase in the number of patients identified as colonized with at least 1 type of MDR bacteria.

CD16 promotes Escherichia coli sepsis through an FcR gamma inhibitory pathway that prevents phagocytosis and facilitates inflammation.

Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion.

Acquired gentamicin resistance by permeability impairment in Enterococcus faecalis.

Enterococci are intrinsically resistant to low levels of aminoglycosides. We previously selected in vitro and in vivo Enterococcus faecalis with intermediate-level resistance to gentamicin that did not abolish synergism with a cell-wall-active agent (E. Aslangul et al., Antimicrob. Agents Chemother. 49:4144-4148, 2005). The aim of this study was to investigate the mechanism of resistance to gentamicin in the 1688-G3 third-step mutant (MIC, 512 microg/ml) of E. faecalis JH2-2. No mutations were found in the genes for L6 ribosomal protein and the four copies of 16S rRNA. Production of a known aminoglycoside-modifying enzyme was unlikely due to the distinct resistance phenotype and absence of the corresponding genes. Efflux was also unlikely since ethidium bromide MICs were similar for JH2-2 and 1688-G3 and since the pump inhibitors reserpine and verapamil had no effect on gentamicin resistance in both strains. To study gentamicin accumulation, we developed a nonisotopic method based on a fluorescent polarization immunoassay. Impaired gentamicin accumulation was observed in 1688-G3 compared to JH2-2 and was only partially reversible by the N,N'-dicyclohexylcarbodiimide (DCCD) uncoupler agent. The lower sensitivity of 1688-G3 to DCCD suggested alteration of the FoF1-ATPase. However, no mutations were detected in the structural genes (atp) for the Fo channel and no difference in transcript levels of atpB and atpE was found between 1688-G3 and JH2-2. Our data are compatible with acquisition of intermediate-level gentamicin resistance by uptake impairment in E. faecalis.

Secular trends in mortality associated with bloodstream infections in 4268 patients hospitalized in a cancer referral center between 1975 and 1989.

OBJECTIVE: To study the trends in mortality over 15 years in hospitalized cancer patients with bloodstream infection. METHODS: The yearly incidence rates and risk of death, by type of microorganism, were calculated for 4268 cancer patients hospitalized between 1975 and 1989 in a French cancer referral center. The relative risk of death (RR) associated with each type of microorganism was estimated using the proportional hazards model, taking into account age, hospital ward, underlying disease, geographical origin and year of the first positive blood culture. RESULTS: The incidence of these infections was five-fold higher in 1989 than in 1975. The largest increases were for coagulase-negative staphylococci (CNS), yeasts and Staphylococcus aureus. For the 3756 patients who had a single-microorganism bloodstream infection, the risk of death compared with that of patients with CNS infection was significantly increased in those with Pseudomonadaceae (RR=5.0), yeasts (RR=3.4), Enterobacteriaceae (RR=3.2), S. aureus (RR=2.8) and streptococci (RR=2.1). The risk of death was not significantly different between patients with a single or several positive blood cultures nor between those with nosocomial or non-nosocomial infections. When the study period was divided in two time periods (1975 to 1982 vs 1983 to 1989), a significant variation (p=0.001) in risk of death associated with the different microorganisms was observed. Most risks were lower from 1983 to 1986 than before 1982. This decrease reached 60% for both S. aureus and Pseudomonadaceae. CONCLUSIONS: These data support of continuing use of aggressive empirical antimicrobial therapy for cancer patients with fever.

Surveillance of intestinal colonization and of infection by vancomycin-resistant enterococci in hospitalized cancer patients.

OBJECTIVE: To study epidemiologic features of and risk factors for intestinal colonization and infection by vancomycin-resistant enterococci (VRE) in cancer patients. METHODS: During a 41-month period, over 7600 fecal samples and all samples from sterile sites from hospitalized cancer patients were screened for VRE. Species were identified and isolates analyzed by pulsed-field gel electrophoresis (PFGE) of SmaI DNA restriction fragments. Antibiotic resistance was characterized by MIC determinations, and polymerase chain reaction for vanA, vanB, and vanC1 genes. Plasmid contents were analyzed before and after PstI and HindIII restriction, and by Southern hybridization with a vanA probe. Two case-control studies were performed to identify risk factors for colonization or infection by VRE, respectively. RESULTS: Eighty-two isolates were recovered from 81 patients. Most (72%) isolates were Enterococcus faecium VanA/vanA, with 37 different PFGE types, each of which was found in only one to four patients, except for type P1, which was found in 20 patients hospitalized over a 3-month period in the pediatric wards. Plasmid analysis suggested that only two types of plasmid were carrying gene vanA, as part of a transposon related to transposon Tn 1546 from reference strain E. faecium BM4147. Seventy-seven patients were colonized during the study period. Six of them became infected. Four patients were infected but not colonized. Only one patient died during the course of infection, but intestinal colonization persisted for months in the survivors. Case-control analysis revealed that cephalosporin treatment was a significant risk factor for colonization. No significant risk factor for infection was found in colonized patients. CONCLUSION: Colonization by VRE was mostly endemic and the colonized patients were not often infected. However, when clustered cases of colonization occurred, they were then associated with an increased rate of infection.