Impact of the phenotypic expression of temocillin resistance in Escherichia coli on temocillin efficacy in a murine peritonitis model.

BACKGROUND: Temocillin is a narrow spectrum ß-lactam active against MDR Enterobacterales. Mechanisms of acquired resistance to temocillin are poorly understood. We analysed resistance mechanisms in clinical isolates of Escherichia coli and evaluated their impact on temocillin efficacy in vitro and in a murine peritonitis model. METHODS: Two sets of isogenic clinical E. coli strains were studied: a susceptible isolate (MLTEM16S) and its resistant derivative, MLTEM16R (mutation in nmpC porin gene); and temocillin-resistant derivatives of E. coli CFT073: CFT-ΔnmpC (nmpC deletion), CFTbaeS-TP and CFTbaeS-AP (two different mutations in the baeS efflux-pump gene).Fitness cost, time-kill curves and phenotypic expression of resistance were determined. Temocillin efficacy was assessed in a murine peritonitis model. RESULTS: MICs of temocillin were 16 and 64 mg/L for MLTEM16S and MLTEM16R, respectively, and 8, 128, 256 and 256 mg/L for E. coli-CFT073, CFT-ΔnmpC, CFTbaeS-TP and CFTbaeS-AP, respectively. No fitness cost of resistance was evidenced. All resistant strains showed heteroresistant profiles, except for CFTbaeS-AP, which displayed a homogeneous pattern. In vitro, temocillin was bactericidal against MLTEM16R, CFT-ΔnmpC, CFTbaeS-TP and CFTbaeS-AP at 128, 256, 512 and 512 mg/L, respectively. In vivo, temocillin was as effective as cefotaxime against MLTEM16R, CFT-ΔnmpC and CFTbaeS-TP, but inefficient against CFTbaeS-AP (100% mortality). CONCLUSIONS: Heteroresistant NmpC porin alteration and active efflux modification do not influence temocillin efficacy despite high MIC values, unfavourable pharmacokinetic/pharmacodynamic conditions and the absence of fitness cost, whereas homogeneously expressed BaeS efflux pump alteration yielding similar MICs leads to temocillin inefficacy. MIC as sole predictor of temocillin efficacy should be used with caution.

Inoculum effect of cefiderocol against NDM-1 producing Escherichia coli in vitro and in a murine model of peritonitis.

INTRODUCTION: Cefiderocol is a siderophore cephalosporin active in vitro against carbapenemase-producing Enterobacterales, including New Delhi metallo-ß-lactamases (NDM-1). A significant impact of the size of bacterial inoculum on its efficacy has been described in vitro, the clinical impact of which is unclear. Here, we analyse the inoculum effect of cefiderocol against E. coli-NDM-1 in vitro and in a murine peritonitis model. MATERIALS AND METHODS: Escherichia coli 62-pTOPO and its isogenic variant expressing NDM-1, 62-pTOPO-NDM, were constructed from a clinical strain. MICs and bactericidal kinetics were determined at standard (105 cfu/mL) and high inoculum (107 cfu/mL). The in vivo effect was assessed in a severe murine peritonitis model, comparing low (106 cfu/mL) and high (108 cfu/mL) inoculum. Survival rates, organ sterilization and bacterial counts in spleen and peritoneal fluid were compared. RESULTS: Cefiderocol MICs for 62-pTOPO and 62-pTOPO-NDM at standard and high inoculum were 0.008, 2, 2 and 1024 mg/L, respectively. Bactericidal activity was not achieved in vitro for 62-pTOPO-NDM at high inoculum with high cefiderocol concentrations (16 mg/L). In vivo, for 62-pTOPO-NDM, no difference was found in survival, organ sterilization or bacterial counts between low and high inoculum. For 62-pTOPO, no difference was observed in survival, despite less organ sterilization and higher bacterial counts in organs with the high inoculum. CONCLUSION: A significant inoculum effect of cefiderocol was observed in vitro for 62-pTOPO and 62-pTOPO-NDM. However, the effectiveness of cefiderocol was not reduced in vivo with a high bacterial inoculum. In vitro inoculum effect of cefiderocol may not be clinically significant.

Advances in antibacterial treatment of adults with high-risk febrile neutropenia.

BACKGROUND: High-risk febrile neutropenia (HR-FN) is a life-threatening complication in patients with haematological malignancies or receiving myelosuppressive chemotherapy. Since the last international guidelines were published over 10 years ago, there have been major advances in the understanding and management of HR-FN, including on antibiotic pharmacokinetics and discontinuation/de-escalation strategies. OBJECTIVES: Summarizing major advances in the field of antibacterial therapy in patients with HR-FN: empirical therapy, pharmacokinetics of antibiotics and antibiotic stewardship. SOURCES: Narrative review based on literature review from PubMed. We focused on studies published between 2010 and 2023 about the pharmacokinetics of antimicrobials, management of antimicrobial administration, and discontinuation/de-escalation strategies. We did not address antimicrobial prophylaxis, viral or fungal infections. CONTENT: Several high-quality publications have highlighted important modifications of antibiotic pharmacokinetics in HR-FN, with standard dosages exposing patients to underdosing. These recent clinical and population pharmacokinetics studies help improve management protocols with optimized initial dosing and infusion rules for ß-lactams, vancomycin, daptomycin and amikacin; they highlight the potential benefits of therapeutic drug monitoring. A growing body of evidence also shows that antibiotic discontinuation/de-escalation strategies are beneficial for bacterial ecology and patients' outcome. We further discuss methods and limitations for implementation of such protocols in haematology. IMPLICATIONS: We highlight recent information about the management of antibacterial therapy in HR-FN that might be considered in updated guidelines for HR-FN management.

Enterococcal pyogenic liver abscesses: high risk of treatment failure and mortality.

Enterococci are the most frequent gram-positive bacteria recovered from pyogenic liver abscesses (PLA). This study aims to analyze the impact of the presence of Enterococcus spp. on PLA outcome. We retrospectively analyzed the characteristics and outcome of all PLA cases in which Enterococcus spp. was isolated between January 2010 and September 2019 in a French university hospital and compared them to PLA without Enterococcus spp. Enterococci were recovered from 68 of the 359 (19%) PLA cases. Among the 78 isolates, Enterococcus faecalis (n = 37, 47.7%) and Enterococcus faecium (n = 32, 41%) were the most frequent. Enterococcal PLA were more often of biliary origin (79.4% versus 54.6%, p < 0.001) or post-surgical (35.3% versus 18.6%, p = 0.004). Multivariate analysis showed an independent association between the isolation of Enterococcus spp. and 3-month mortality (HR 2.51, p = 0.011), primary failure (HR 2.15, p = 0.006), but not with relapses (HR 0.86, p = 0.739). In the subgroup of enterococcal PLA, portal vein thrombosis was the only factor significantly associated with 3-month mortality (univariate HR 3.45, p = 0.023) or primary treatment failure (multivariate, HR 4.02, p = 0.006). Enterococcus spp. identification in a PLA is associated with a higher mortality and primary treatment failure.

Analysis of 15 cases from a monocentric cohort of 307 liver abscesses.

BACKGROUND: Out of the context of haematological patients, Candida sp. is rarely retrieved from pyogenic liver abscesses (PLA). OBJECTIVES: Our objective was to assess the risk factors for occurrence, and clinical, microbiological characteristics, management and outcome of Candida pyogenic liver abscesses (C-PLA). PATIENTS/METHODS: We retrospectively analysed C-PLA cases and compared them to pyogenic liver abscesses exclusively due to bacteria (B-PLA) included in our monocentric database on liver abscesses. Unfavourable course was defined as the occurrence of a primary treatment failure (PTF), recurrence after an initial cure, or death within 3 months after diagnosis. RESULTS: Between 2010 and 2018, 15 C-PLA and 292 B-PLA were included. All C-PLA had a biliary origin and were polymicrobial. All patients with C-PLA had at least one comorbidity at risk for Candida infection and 7 (53.3%) presented with sepsis requiring an admission in intensive care unit. Median duration of antifungal treatment was 42 days [24-55]. In multivariate analysis, compared with B-PLA, a medical history of malignancy (OR 4.16; 95%CI 1.15-18.72) or liver abscess (OR 7.39; 95%CI 2.10-26.62), and sepsis with severity criteria (OR 3.52; 95%CI 1.07-11.90) were independently associated with the occurrence of C-PLA. In multivariate analysis, C-PLA was associated with a higher risk of recurrence (HR 3.08; 95%CI 1.38-11.22). CONCLUSION: Candida liver abscesses in non-neutropenic is a rare and severe disease. The high rate of recurrence should lead to discuss a more intensive treatment.

Clinical and microbiological characteristics of reflux cholangitis following bilio-enteric anastomosis.

Twenty-five patients with reflux cholangitis (RC) defined as acute cholangitis (AC) with normal abdominal imaging occurring > 3 months after bilioenteric anastomosis were described and compared to 116 AC patients with biliary obstruction (tumoral, lithiasis). RC episodes occurred a median 4.5 months after surgery; 18 (72%) had recurrent RC (n ≥ 3). RC episodes were less severe than obstructive AC; the outcome was favorable with short antibiotic courses and no selection of antibiotic-resistance. However, multiple recurrent RC occurred in 20 patients (80%). Prophylactic or pre-emptive antibiotics were successful in 3 and 11 patients. Revision surgery for jejunal loop lengthening was successful in 2/4 patients.

Specificities of acute cholangitis in patients with cancer: a retrospective comparative study of 130 episodes.

Pancreatic and biliary duct cancers are increasing causes of acute cholangitis (AC). We retrospectively characterize 81 cancer-associated cholangitis (CAC) compared to 49 non-cancer-associated cholangitis (NCAC). Clinical and biological presentations were similar. However, in CAC, antibiotic resistance and inadequate empirical antibiotic therapy were more frequent; more patients required ≥ 2 biliary drainages; and mortality at day 28 was higher than in NCAC. Death was associated with initial severity and CAC in a multivariate analysis. Cholangitis associated with pancreatic or biliary duct cancers requires specific empirical antimicrobial therapy; early use of biliary drainage may improve outcomes.

Large retrospective study analysing predictive factors of primary treatment failure, recurrence and death in pyogenic liver abscesses.

PURPOSE: Pyogenic liver abscess (PLA) is a severe disease, which unfavourable evolution remains frequent. Our objective was to assess predictive factors of unfavourable outcome in patients with PLA. METHODS: We conducted a retrospective study in a French tertiary care centre. All patients admitted for PLA between 2010 and 2018 were included. Unfavourable course was defined as the occurrence of a primary treatment failure (PTF), recurrence of PLA after an initial cure, or death within 3 months after diagnosis. Hazard ratios (95% CI) were calculated with multivariable Cox proportional hazard models. RESULTS: 302 patients were included among which 91 (30.1%) patients had an unfavourable outcome because of PTF, recurrence or death in 55 (18.2%), 28 (9.2%) and 32 (10.6%) patients, respectively. Hepatic metastases (HR 2.08; 95% CI 1.04-4.15), a nosocomial infection (2.25; 1.14-4.42), portal thrombosis (2.12; 1.14-3.93), and the isolation of Enterococcus spp. (2.18; 1.22- 3.90) were independently associated with PTF. Ischemic cholangitis (6.30; 2.70-14.70) and the isolation of Streptococcus spp. (3.72; 1.36-10.16) were associated with the risk of recurrence. Charlson comorbidity index (HR 1.30 per one point; 95% CI 1.15-1.46; p < 0.001), portal thrombosis (3.53; 1.65-7.56) and the presence of multi-drug-resistant organisms (3.81; 1.73-8.40) were associated with mortality within 3 months following PLA diagnosis. PLA drainage was the only factor associated with a lower mortality (0.14; 0.06-0.34). CONCLUSION: Identification of specific risk factors may help to improve the management of PLA and to elaborate targeted recommendations according to patient's and disease's characteristics.

Activity of the combination of colistin and fosfomycin against NDM-1-producing Escherichia coli with variable levels of susceptibility to colistin and fosfomycin in a murine model of peritonitis.

BACKGROUND: Alternative treatments are needed against NDM-1-producing Escherichia coli. Colistin (COL) and fosfomycin (FOS) often remain active in vitro but selection of resistant mutants is frequent if used separately. We determined whether the combination of colistin and fosfomycin may be useful to treat infections with NDM-1-producing E. coli with varying levels of resistance. METHODS: Isogenic derivatives of E. coli CFT073 with blaNDM-1 and variable levels of resistance to colistin and fosfomycin (CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively) were used. The combination (colistin + fosfomycin) was tested in vitro and in a fatal peritonitis murine model. Mortality and bacterial loads were determined and resistant mutants detected. RESULTS: Colistin MICs were 0.5, 16 and 0.5 mg/L and fosfomycin MICs were 1, 1 and 32 mg/L against CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively. In time-kill curves, combining colistin with fosfomycin was synergistic and bactericidal against CFT073-NDM1 and CFT073-NDM1-FOS, with concentrations of 4× MIC (for both drugs), but not against CFT073-NDM1-COL (concentrations of colistin = 0.5× MIC), due to regrowth with fosfomycin-resistant mutants. Mice died less and bacterial counts were lower in spleen with the combination compared with monotherapy against all strains; the combination prevented selection of resistant mutants except for CFT073-NDM1-COL where fosfomycin-resistant mutants were found in all mice. CONCLUSIONS: Combining colistin and fosfomycin was beneficial in vitro and in vivo against NDM-1-producing E. coli, even with strains less susceptible to colistin and fosfomycin. However, the combination failed to prevent the emergence of fosfomycin-resistant mutants against colistin-resistant strains. Combining colistin and fosfomycin constitutes an alternative for treatment of NDM-1 E. coli, except against colistin-resistant strains.

Temocillin as an alternative treatment for acute bacterial cholangitis: a retrospective microbiology susceptibility-based study of 140 episodes.

With rising antibiotic resistance, alternatives to carbapenems are needed for acute cholangitis (AC). Temocillin reaches high biliary concentrations with limited impact on microbiota. We retrospectively included 140 AC episodes and assessed the efficacy of temocillin using microbiology susceptibility testing from blood cultures. Considering all bacteria collected by episode, resistance to temocillin, PIP/TAZ and 3GC occurred in 27/140 (26%), 32 (22.8%) and 31 (22%) episodes, respectively (p = 0.7). After documentation, temocillin could have spared PIP/TAZ or carbapenems in 14/26 and 4/11 episodes. Temocillin may constitute an alternative treatment after microbiological documentation by sparing carbapenems and/or PIP/TAZ, but not as an empirical therapeutic option.

Analysis of Paradoxical Efficacy of Carbapenems against Carbapenemase-Producing Escherichia coli in a Murine Model of Lethal Peritonitis.

The clinical benefit of carbapenems against carbapenemase-producing Enterobacteriaceae (CPE) remains in question. MICs of imipenem (IMP) and ertapenem (ERT) against isogenic derivatives of the wild-type strain Escherichia coli CFT073 producing KPC-3, OXA-48, or NDM-1 were 0.25, 2, 16, and 64 mg/liter for IMP and 0.008, 0.5, 8, and 64 mg/liter for ERT, respectively. Swiss ICR-strain mice with peritonitis were treated for 24 h with IMP or ERT. Despite a limited duration of time during which free antibiotic concentrations were above the MIC (down to 0% for the NDM-1-producing strain), IMP and ERT significantly reduced bacterial counts in spleen and peritoneal fluid at 24 h (P < 0.005) and prevented mortality. Several possible explanations were investigated. Addition of 4% albumin or 50% normal human serum did not modify IMP activity. Bacterial fitness of resistant strains was not altered and virulence did not decrease with resistance. In the presence of subinhibitory concentrations of ERT, growth rates of OXA-48, KPC-3, and NDM-1 strains were significantly decreased and filamentation of the NDM-1 strain was observed. The expression of blaNDM-1 was not decreased in vivo compared to in vitro No zinc depletion was observed in infected mice compared with Mueller-Hinton broth. In conclusion, a paradoxical in vivo efficacy of IMP and ERT against highly resistant carbapenemase-producing E. coli was confirmed. Alternative mechanisms of antibacterial effects of subinhibitory concentrations of carbapenems may be involved to explain in vivo activity. These results are in agreement with a potential clinical benefit of carbapenems to treat CPE infections, despite high carbapenem MICs.

Pyogenic liver abscess in liver transplant recipient: A warning signal for the risk of recurrence and retransplantation.

BACKGROUND: Pyogenic liver abscesses in liver transplant recipients (PLA-LTR) are a rare disease whose specificities compared with PLA in non-transplanted patients (PLA-C) are unknown. METHODS: A retrospective case-control study was conducted in a French academic hospital from January 1, 2010, to December 31, 2014. RESULTS: Among 176 patients diagnosed with PLA, 14 were LTR; each case was matched with 3 PLA-C controls by date of PLA diagnosis and pathophysiological mechanism of PLA. Median time from liver transplantation to PLA diagnosis was 34.5 months. Among 14 PLA-LTR, 8/14 (57.1%) had bacteremia and 10/14 (71.4%) had positive PLA cultures. Most commonly isolated bacteria were Enterobacteriaceae (9/14; 64.3%), Enterococcus spp. (4/14; 28.6%), and anaerobic bacteria (3/14; 21.4%). Clinical, radiological, and microbiological characteristics did not significantly differ between PLA-LTR and PLA-C but there was a tendency toward more diabetic patients and a less acute presentation. All but one PLA-LTR were associated with ischemic cholangitis, whereas this was a rare cause among PLA-C (13/14 vs 3/42, respectively, P < .001) among patients with PLA-LTR. In contrast, hepatobiliary neoplasia was rare in PLA-LTR but frequent in PLA-C (1/14 vs 24/42, P = .001). No significant difference was found between PLA-LTR and PLA-C in terms of duration of antibiotic therapy (6.5 and 6 weeks, respectively), PLA drainage rates (10/14 and 26/42, respectively), or mortality at 12 months after PLA diagnosis (2/14 and 5/42, respectively). Recurrence rates within the first year were observed in 6/14 patients (42.9%), and retransplantation was needed in 5/14 (35.7%). CONCLUSIONS: Occurrence of PLA in LTR is a severe event leading to high risk of recurrence and retransplantation.

Immunoglobulin Abnormalities in Gaucher Disease: an Analysis of 278 Patients Included in the French Gaucher Disease Registry.

Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase; polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study the risk factors, clinical significance, and evolution. Data for patients enrolled in the French GD Registry were studied retrospectively. The risk factors of PG and/or MG developing and their association with clinical bone events and severe thrombocytopenia, two markers of GD severity, were assessed with multivariable Cox models and the effect of GD treatment on gammaglobulin levels with linear/logarithmic mixed models. Regression of MG and the occurrence of hematological malignancies were described. The 278 patients included (132 males, 47.5%) were followed up during a mean (SD) of 19 (14) years after GD diagnosis. PG occurred in 112/235 (47.7%) patients at GD diagnosis or during follow-up and MG in 59/187 (31.6%). Multivariable analysis retained age at GD diagnosis as the only independent risk factor for MG (> 30 vs. ≤30 years, HR 4.71, 95%CI [2.40-9.27]; p < 0.001). Risk of bone events or severe thrombocytopenia was not significantly associated with PG or MG. During follow-up, non-Hodgkin lymphoma developed in five patients and multiple myeloma in one. MG was observed in almost one third of patients with GD. Immunoglobulin abnormalities were not associated with the disease severity. However, prolonged surveillance of patients with GD is needed because hematologic malignancies may occur.

Unexpected Activity of Oral Fosfomycin against Resistant Strains of Escherichia coli in Murine Pyelonephritis.

Fosfomycin tromethamine activity is well established for oral treatment of uncomplicated lower urinary tract infections, but little is known about its potential efficacy in pyelonephritis. Ascending pyelonephritis was induced in mice infected with 6 strains of Escherichia coli (fosfomycin MICs, 1 µg/ml to 256 µg/ml). The urine pH was 4.5 before infection and 5.5 to 6.0 during infection. Animals were treated for 24 h with fosfomycin (100 mg/kg of body weight subcutaneously every 4 h), and the CFU were enumerated in kidneys 24 h after the last fosfomycin injection. Peak (20.5 µg/ml at 1 h) and trough (3.5 µg/ml at 4 h) levels in plasma were comparable to those obtained in humans after an oral dose of 3 g. Fosfomycin treatment significantly reduced the bacterial loads in kidneys (3.65 log10 CFU/g [range, 1.83 to 7.03 log10 CFU/g] and 1.88 log10 CFU/g [range, 1.78 to 5.74 log10 CFU/g] in start-of-treatment control mice and treated mice, respectively; P < 10-6). However, this effect was not found to differ across the 6 study strains (P = 0.71) or between the 3 susceptible and the 3 resistant strains (P = 0.09). Three phenomena may contribute to explain this unexpected in vivo activity: (i) in mice, the fosfomycin kidney/plasma concentration ratio increased from 1 to 7.8 (95% confidence interval, 5.2, 10.4) within 24 h in vitro when the pH decreased to 5, (ii) the fosfomycin MICs for the 3 resistant strains (64 to 256 µg/ml) decreased into the susceptible range (16 to 32 µg/ml), and (iii) maximal growth rates significantly decreased for all strains and were the lowest in urine. These results suggest that local fosfomycin concentrations and physiological conditions may favor fosfomycin activity in pyelonephritis, even against resistant strains.

Temocillin breakpoints in pyelonephritis: evaluation in a murine model due to ESBL-producing Escherichia coli clinical isolates.

BACKGROUND: Due to a spectrum restricted to Enterobacteriaceae and stability against ESBL and AmpC enzymes, temocillin is of major interest for the treatment of pyelonephritis. But there are still uncertainties about the optimal regimen and clinical breakpoints. OBJECTIVES: To study in a murine model of pyelonephritis the activity of temocillin against Escherichia coli isolates with different MICs in order to evaluate clinical breakpoints. METHODS: Four clinical uropathogenic E. coli isolates with temocillin MICs of 8 mg/L (Ec8), 16 mg/L (Ec16), 32 mg/L (Ec32) and 64 mg/L (Ec64) were evaluated. Antibiotic 24 h T>MIC achieved in humans was reproduced in mice with either intravenous temocillin (2 g q12h or 2 g q8h) or intravenous imipenem (1 g q8h). Efficacy was assessed by bacterial count in kidneys. RESULTS: Compared with controls, temocillin at 2 g q12h was highly efficient against Ec8 (-3.32 log10 cfu/g and negative cultures in 93% of mice; P < 0.001); imipenem gave similar results. Temocillin at 2 g q12h also induced high reduction of bacterial count against Ec16 (-2.92 log10 cfu/g; P < 0.001), albeit cultures were negative in only 48% of mice. In contrast, no significant effect was observed in mice infected by Ec32 (-0.01 log10 cfu/g; P = 0.981) or Ec64 (-0.55 log10 cfu/g; P = 0.523). Even temocillin at 2 g q8h failed to control Ec32 infection (-1.55 log10 cfu/g; P = 0.197). CONCLUSIONS: This model suggests a clinical breakpoint up to 16 mg/L for non-severe pyelonephritis treated with temocillin at 2 g q12h, a value consistent with the few previous available data.

Hypervirulent Klebsiella pneumoniae in Cryptogenic Liver Abscesses, Paris, France.

Liver abscesses containing hypervirulent Klebsiella pneumoniae have emerged during the past 2 decades, originally in Southeast Asia and then worldwide. We hypothesized that hypervirulent K. pneumoniae might also be emerging in France. In a retrospective, monocentric, cohort study, we analyzed characteristics and outcomes for 199 consecutive patients in Paris, France, with liver abscesses during 2010-2015. We focused on 31 patients with abscesses containing K. pneumoniae. This bacterium was present in most (14/27, 52%) cryptogenic liver abscesses. Cryptogenic K. pneumoniae abscesses were more frequently community-acquired (p<0.00001) and monomicrobial (p = 0.008), less likely to involve cancer patients (p<0.01), and relapsed less often (p<0.01) than did noncryptogenic K. pneumoniae liver abscesses. K. pneumoniae isolates from cryptogenic abscesses belonged to either the K1 or K2 serotypes and had more virulence factors than noncryptogenic K. pneumoniae isolates. Hypervirulent K. pneumoniae are emerging as the main pathogen isolated from cryptogenic liver abscesses in the study area.

Ceftriaxone promotes the emergence of AmpC-overproducing Enterobacteriaceae in gut microbiota from hospitalized patients.

Epidemiological data suggest that ceftriaxone may promote the emergence of commensal AmpC-overproducing Enterobacteriaceae because of a high biliary excretion. We tested this hypothesis in hospitalized patients either treated by ceftriaxone alone or receiving no antibiotics. Hospitalized patients with no previous antibiotics or hospitalization in the last 3 months, treated only with ceftriaxone, were prospectively included. For each ceftriaxone-treated patient, a control patient receiving no antibiotics was included. Clinical data and stools were collected at T0 (before antibiotics) and T1 (at the end of ceftriaxone treatment or at discharge) and T2 (3-6 months after T1) for the ceftriaxone-treated patients and at T0 and T1 for control patients. Third-generation cephalosporin-resistant Enterobacteriaceae were detected, identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), and characterized genetically. Clonal relatedness was evaluated by random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR). Fifteen ceftriaxone and 22 control patients were included. Patients' characteristics did not differ. At T0, 2/15 ceftriaxone-treated versus 1/22 control patients carried third-generation cephalosporin-resistant Enterobacteriaceae (p = 0.6). At T1, 4/15 (27%) ceftriaxone-treated patients carried AmpC producers versus 0/22 control patients (p = 0.02). Additionally, two and three subjects carried extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae in the ceftriaxone and control groups, respectively (p = 1). At T2, three ceftriaxone-treated patients still carried AmpC-producing Enterobacteriaceae with the same RAPD profile as at T1. In hospitalized subjects with no other selective pressure, treatment by ceftriaxone alone promotes the gut colonization by AmpC-overproducing Enterobacteriaceae in over a quarter of patients, with a persistent carriage after the end of antibiotic exposure. The ecological impact of ceftriaxone should not be underestimated.

An outbreak of Pneumocytis jirovecii pneumonia among liver transplant recipients.

BACKGROUND: An outbreak of Pneumocystis pneumonia (PCP) in liver transplant recipients occurred between 2009 and 2011 at the Beaujon University Hospital just after immediate-release tacrolimus was replaced by extended-release tacrolimus. We conducted a retrospective study to analyze the transmission mode of Pneumocystis, the role of the change in the immunosuppressive regimen, and the factors associated with PCP. PATIENTS AND METHODS: To analyze transmission, we built a transmission map. Two control groups were built. First, to assess the role of the change from tacIR to tacER, cases were matched to controls transplanted before 2009 (tacIR control group). Tacrolimus trough concentrations were compared between the 2 groups. Then, to assess factors associated with PCP, each PCP case was matched to 2 control patients: the one transplanted just before and the one just after (PCPAsFact control group). No PCP prophylaxis was given to any patient. RESULTS: Fifteen cases of PCP were recorded. A contact between a case and a patient who developed PCP afterward was identified in 4 occasions. The comparison of tacrolimus trough concentrations did not conclude to a difference in the exposure to the drug. Lymphopenia was the only factor independently associated with the occurrence of PCP (odds ratio 0.78, 95% confidence interval 0.61-0.99, P = .04). CONCLUSION: Our results suggest that patient-to-patient transmission was not the main mode of transmission of PCP. We found no evidence that the switch from tacIR to tacER led to an overexposure to tacrolimus. Our results suggest the possibility of targeted prophylaxis in immunosuppressed liver transplant recipients.

Autochthonous Case of Eosinophilic Meningitis Caused by Angiostrongylus cantonensis, France, 2016.

We report a case of a 54-year-old Moroccan woman living in France diagnosed with eosinophilic meningitis caused by Angiostrongylus cantonensis. Diagnosis was based on clinical symptoms and confirmed by testing of serum and cerebrospinal fluid samples. Physicians should consider the risk for A. cantonensis infection outside of endemic areas.

Ecological impact of ciprofloxacin on commensal enterococci in healthy volunteers.

Background: The ecological impact of ciprofloxacin on commensal enterococci is unknown. Methods: Forty-eight healthy volunteers received ciprofloxacin from day (D) 0 to D14; stools were collected on D7, D14 and D42. Fluoroquinolone-susceptible and -resistant enterococci (FQ-SE and FQ-RE) were detected and quantified by culture, and identified by MALDI-TOF MS. The relative abundance of FQ-RE over FQ-SE was determined. The genetic basis of fluoroquinolone resistance was deciphered by partial sequencing of gyrA and parC genes. Clonal relatedness was determined by random amplification of polymorphic DNA PCR. Clinical trial no.: NCT00190151. Results: Enterococci were carried by 47/48 (98%) subjects. Total counts were reduced during ciprofloxacin therapy (4.0 and 3.9 log cfu/g on D7 and D14 versus 5.9 log cfu/g before and 6.9 log cfu/g after treatment; P < 0.05). Twenty-one out of 48 (44%) carried FQ-RE; among them, 21/21 carried Enterococcus faecium , 19 carried Enterococcus faecalis and 11 carried other species. Five out of 48 (10%) harboured FQ-RE (ciprofloxacin MIC >4 mg/L) before treatment (all E. faecium ), 6 on D7 (3 E. faecium and 3 E. faecalis ), 8 on D14 (4 E. faecium and 4 E. faecalis ) and 10 (21%) on D42 (9 E. faecium and 1 E. faecalis ). The relative abundance of FQ-RE increased from 44% on D0 to 73% and 75% on D7 and D14, respectively. No acquisition of fluoroquinolone resistance among endogenous D0 strains was evidenced. All (14/14) distinct Fluoroquinolone-resistant E. faecalis clones were gyrA / parC double mutants with high-level resistance (ciprofloxacin MIC >64 mg/L). In contrast, 34/35 E. faecium exhibited low-level resistance (ciprofloxacin MIC 4-32 mg/L) with no gyrA / parC mutation, but overexpressed the chromosomal Efm qnr gene. As compared with Fluoroquinolone-susceptible strains, Fluoroquinolone-resistant E. faecium were more frequently ampicillin resistant and Fluoroquinolone-resistant E. faecalis were more highly resistant to gentamicin. Conclusions: Although intrinsically poorly susceptible to fluoroquinolones, gut populations of enterococci are highly impacted both quantitatively and qualitatively by ciprofloxacin.