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Background Temocillin is a narrow spectrum β-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Colistin is a drug of last resort to treat extreme drug-resistant Enterobacterales, but is limited by dose-dependent toxicity and the emergence of resistance. A recently developed antimicrobial pseudopeptide, Pep16, which acts on the cell membrane, may be synergistic with colistin and limit the emergence of resistance. We investigated Pep16 activity against Escherichia coli with varying susceptibility to colistin, in vitro and in a murine peritonitis model. Two isogenic derivatives of E. coli CFT073 (susceptible and resistant to colistin) and 2 clinical isolates (susceptible (B119) and resistant to colistin (Af31)) were used. Pep16 activity, alone and in combination with colistin, was determined in vitro (checkerboard experiments, time–kill curves, and flow cytometry to investigate membrane permeability). Toxicity and pharmacokinetic analyses of subcutaneous Pep16 were performed in mice, followed by the investigation of 10 mg/kg Pep16 + 10 mg/kg colistin (mimicking human concentrations) in a murine peritonitis model. Pep16 alone was inactive (MICs = 32–64 mg/L; no bactericidal effect). A concentration-dependent bactericidal synergy of Pep16 with colistin was evidenced on all strains, confirmed by flow cytometry. In vivo, Pep16 alone was ineffective. When Pep16 and colistin were combined, a significant decrease in bacterial counts in the spleen was evidenced, and the combination prevented the emergence of colistin-resistant mutants, compared to colistin alone. Pep16 synergizes with colistin in vitro, and the combination is more effective than colistin alone in a murine peritonitis by reducing bacterial counts and the emergence of resistance. Pep16 may optimize colistin use, by decreasing the doses needed, while limiting the emergence of colistin-resistant mutants. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To identify predictive factors of unfavourable outcome among patients hospitalized for COVID-19. We conducted a monocentric retrospective cohort study of COVID-19 patients hospitalized in Paris area. An unfavourable outcome was defined as the need for artificial ventilation and/or death. Characteristics at admission were analysed to identify factors predictive of unfavourable outcome using multivariable Cox proportional hazard models. Based on the results, a nomogram to predict 14-day probability of poor outcome was proposed. Between March 15th and April 14th, 2020, 279 COVID-19 patients were hospitalized after a median of 7 days after the first symptoms. Among them, 88 (31.5%) patients had an unfavourable outcome: 48 were admitted to the ICU for artificial ventilation, and 40 patients died without being admitted to ICU. Multivariable analyses retained age, overweight, polypnoea, fever, high C-reactive protein, elevated us troponin-I, and lymphopenia as risk factors of an unfavourable outcome. A nomogram was established with sufficient discriminatory power (C-index 0.75), and proper consistence between the prediction and the observation. We identified seven easily available prognostic factors and proposed a simple nomogram for early detection of patients at risk of aggravation, in order to optimize clinical care and initiate specific therapies. Since novel coronavirus disease 2019 pandemic, a minority of patients develops severe respiratory distress syndrome, leading to death despite intensive care. Tools to identify patients at risk in European populations are lacking. In our series, age, respiratory rate, overweight, temperature, C-reactive protein, troponin and lymphocyte counts were risk factors of an unfavourable outcome in hospitalized adult patients. We propose an easy-to-use nomogram to predict unfavourable outcome for hospitalized adult patients to optimize clinical care and initiate specific therapies. [ABSTRACT FROM AUTHOR]

Fosfomycin resistance in Escherichia coli results from chromosomal mutations or acquisition of plasmid-mediated genes. Because these mechanisms may be absent in some resistant isolates, we aimed at decipher the genetic basis of fosfomycin resistance in E. coli. Different groups of isolates were studied: fosfomycin-resistant mutants selected in vitro from E. coli CFT073 (MIC = 1 mg/L) and two groups (wildtype and non-wildtype) of E. coli clinical isolates. Single-nucleotide allelic replacement was performed to confirm the implication of novel mutations into resistance. Induction of uhpT expression by glucose-6-phosphate (G6P) was assessed by RT-qPCR. The genome of all clinical isolates was sequenced by MiSeq (Illumina). Two first-step mutants were obtained in vitro from CFT073 (MICs, 128 mg/L) with single mutations: G469R in uhpB (M3); F384L in uhpC (M4). Second-step mutants (MICs, 256 mg/L) presented additional mutations: R282V in galU (M7 from M3); Q558∗ in lon (M8 from M4). Introduction of uhpB or uhpC mutations by site-directed mutagenesis conferred a 128-fold increase in fosfomycin MICs, whereas single mutations in galU or lon were only responsible for a 2-fold increase. Also, these mutations abolished the induction of uhpT expression by G6P. All 14 fosfomycin-susceptible clinical isolates (MICs, 0.5–8 mg/L) were devoid of any mutation. At least one genetic change was detected in all but one fosfomycin-resistant clinical isolates (MICs, 32 – >256 mg/L) including 8, 17, 18, 5, and 8 in uhpA , uhpB , uhpC , uhpT , and glpT genes, respectively. In conclusion, novel mutations in uhpB and uhpC are associated with fosfomycin resistance in E. coli clinical isolates. [ABSTRACT FROM AUTHOR]

Background: Whether surgery modalities vary according to kinetics of pathological processes responsible for vertebral osteomyelitis (VO) is unclear. We therefore compared surgical modalities in patients with haematogenous pyogenic VO (HPVO) or tuberculous VO (TVO). Methods: Patients who had surgery for HPVO or TVO between January 1997 and June 2018 in a university hospital were included. Surgical indications, timing, and procedures and outcomes were evaluated at the end of treatment. Results: Seventy-eight patients (50 men) were included: 39 with HPVO and 39 with TVO; median age was 64 and 41 years, respectively. In patients with HPVO, surgery was performed early: 17 (44%) had surgery within 72 h of admission; main indication for surgery was neurological deficit in 29 patients that persisted in 12 patients (27%). In patients with TVO, surgery was performed later (p<.001), after two weeks in 20 patients (51%), and was indicated by a neurological deficit in 23 patients; among them, only one (4%) had residual deficit. Conclusions: Different kinetic profiles of the infectious processes explain the more rapid indication for surgery in patients with HPVO and the more favourable neurological recovery in patients with TVO. [ABSTRACT FROM AUTHOR]

Purpose: Cervical spine tuberculosis (CST) is a rare disease that may lead to severe neurological complications. The goal of the study was to compare the characteristics of patients with CST with those of patients with non-cervical spine tuberculosis (NCST). Methods: Between 1997 and 2016, we reviewed all cases of proven tuberculosis from a cohort of spine infections in a tertiary care hospital. Clinical, biological, and imaging data were collected at baseline and after treatment. Results: Fifty-one cases of spine tuberculosis were included: 14 with CST on imaging (27%) and 37 with no cervical localization. Median age was 39 y. Demographic characteristics, duration of symptoms and neurological findings of spine compression were similarly present at presentation in CST and NCST patients. On imaging, lesions were more often multifocal in CST than in NCST patients (9/14 [64%] versus 10/37 [27%], p =.014). Spinal surgery was required in 32/51 (63%) patients. At the end of follow-up (median: 20 months), cure rates were similar in CST and NCST patients but motor and/or sensitive functional sequel were more frequent in CST than NCST patients (6/14 [43%] versus 2/37 [5%], p =.003). Conclusions: Cervical involvement is present in more than a quarter of patients with spinal tuberculosis. Patients with CST had more frequent neurological sequelae than patients with NCST. This was mainly due to a more multifocal disease at presentation. Screening for cervical localization should be systematic in patients with spinal tuberculosis even in the absence of cervical symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The overall benefit of surgical management in the acute phase of hematogenous pyogenic vertebral osteomyelitis remains difficult to evaluate because of the balance between potential functional benefit versus complications of surgery. Methods: Between 2000 and 2013, in a tertiary care hospital, we analyzed a cohort of patients with hematogenous pyogenic vertebral osteomyelitis treated surgically and compared them to those treated medically. Neurologic deficit (using the ASIA impairment scale) and pain (using the analgesic level required) 4 months later, recurrences and infection-related deaths 12 months later were evaluated. A propensity score was developed to adjust for nonrandomized allocation to surgery. Results: Ninety patients were included (mean age 64 years, 63% male); 28 (31%) were treated surgically. After adjustment for the propensity score, the improvement in neurological deficit at 4 months did not differ between surgical and medical treatment (p =.82), but the reduction of pain tended to be greater in surgical versus medical treatment (p =.051). Recurrences of infection (5%) and infection-related deaths (12%) occurred at similar rates in both groups at 12 months (p = 1.00 for both). Conclusions: Patients with hematogenous pyogenic vertebral osteomyelitis requiring surgery improved equally as non-surgical patients in terms of neurological deficit and residual pain. This result was not hampered by increased complications related to surgery. When indicated, surgery is safe and effective in patients suffering from hematogenous pyogenic vertebral osteomyelitis. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

Temocillin, a 6-α-methoxy derivative of ticarcillin, is a forgotten antibiotic that has recently been rediscovered, and issues about clinical breakpoints and optimal therapeutic regimens are still ongoing. Temocillin spectrum is almost restricted to Enterobacteriaceae. The addition of the α-methoxy moiety on ticarcillin confers resistance to hydrolysis by Ambler classes A and C β-lactamases (extended spectrum β-lactamases, Klebsiella pneumoniae carbapenemase and AmpC hyperproduced enzymes). Temocillin is bactericidal, and the effect of inoculum size on its activity is relatively mild. The proportion of spontaneous resistant mutants in vitro to temocillin is low, as found in vivo. After intravenous infusion, temocillin showed a prolonged elimination half-life of approximately 5 h. The percentage of protein binding of temocillin is high (approximately 80%), and is concentration-dependent. Temocillin clearance is mainly renal, and urinary recovery is high, ranging from 72 to 82% after 24 h. Furthermore, the penetration of temocillin into bile and peritoneal fluid is high, but poor into cerebrospinal fluid. The cumulative percentage of a 24-h period during which the free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) at steady-state pharmacokinetic conditions seems to be the best pharmacokinetic/pharmacodynamic (PK/PD) index correlating with temocillin efficacy. An fT > MIC of 40-50% is associated with antibacterial effect and survival in vivo. Monte Carlo simulations performed in critically ill patients showed that the 2 g every 12 h and 2 g every 8 h regimens provide a 95% probability of target attainment of 40% fT > MIC up to an MIC of 8 mg/L. In less severely ill patients or in specific foci of infection, such as urinary tract infection, a 4 g daily regimen should be adequate for strains with temocillin MIC up to 16 mg/L. Data regarding actual wild-type MIC distribution, clinical efficacy, PK profiling in volunteers or patients, and PD targets are scarce, and further studies are required to support appropriate dosing recommendations and determination of clinical breakpoints. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Catheter-associated thrombosis (CAT) in patients with infected long-term central venous catheter (LTCVC) has been poorly studied.Methods: We prospectively included patients with infected LTCVC and collected clinical data. Doppler ultrasound was systematically performed to screen for CAT. Outcome (death or infection relapse) was evaluated 12 weeks after infection diagnosis.Results: 90 patients were included and CAT was diagnosed in 27 (30%). Local signs suggesting infection were more frequent in patients with CAT than without (11/27 versus 8/63, p = 0.03). Outcome was similar in patients with and without CAT. However, median duration of antimicrobials was longer (18 versus 14 days, p = 0.02), catheter removal tended to be more frequent (24/27 versus 46/63, p = 0.08), and anticoagulant therapy more often prescribed (17/27 versus 6/63, p < 0.01) in patients with CAT than without. Patients with occlusive thrombosis were more likely to haveStaphylococcus aureusinfections (4/7 versus 1/17, p = 0.02) and prolonged positivity of blood-cultures (3/7 versus 1/15, p = 0.02), than patients with non-occlusive thrombosis.Conclusion: CAT is associated with local signs suggesting infection. A more aggressive treatment in CAT cases allowed a similar outcome at 12 weeks between patients with and without CAT. Occlusive thrombosis represented a subgroup of patients at risk of delayed clearance of bacteremia.KEY MESSAGES30% of patients with infected long-term central venous catheter had catheter-associated thrombosis (CAT) and 89% of patients with CAT had no symptom specifically suggestive of thrombosis.More aggressive treatment (catheter removal, anticoagulant therapy and prolonged antimicrobial therapy) in patients with CAT allowed a similar outcome at 12 weeks than in patients without CAT.Occlusive thrombosis represented a subgroup of patients at risk of delayed bacteremia clearance. [ABSTRACT FROM PUBLISHER]

Objectives: To determine the genetic location and environment of the qnrA6 gene in Proteus mirabilis PS16 where it was first described and to characterize the quinolone resistance qnrA6 confers.Methods: Transformation experiments and Southern blotting were performed for plasmid and genomic DNA of P. mirabilis PS16 to determine the qnrA6 location. Combinatorial PCRs with primers in qnrA6 and genes usually surrounding qnrA genes were used to determine the genetic environment. The qnrA6 coding region, including or not the promoter region, was cloned into vectors pTOPO and pBR322 and the MICs of six quinolones were measured for transformants of Escherichia coli TOP10 and P. mirabilis ATCC 29906 Rif(R).Results: qnrA6 was shown to be chromosomally encoded in P. mirabilis PS16 and its genetic environment was 81%-87% similar to that of qnrA2 in the Shewanella algae chromosome. The 5138 bp region up- and downstream of qnrA6 contained an IS10 sequence surrounded by two ISCR1. This resulted in qnrA6 being displaced 1.9 kb from its native promoter but supplied a promoter present in ISCR1. qnrA6 cloned into pTOPO and pBR322 conferred a 4-32-fold increase in fluoroquinolone MICs when expressed in E. coli but only 2-3-fold in P. mirabilis. When including the promoter region, a further increase in resistance was observed in both species, reaching MIC values above clinical breakpoints for only P. mirabilis.Conclusions: qnrA6 is the first chromosomally located qnrA gene described in Enterobacteriaceae. The quinolone resistance conferred by qnrA6 depends on the proximity of an efficient promoter and the host strain where it is expressed. [ABSTRACT FROM AUTHOR]

Objective: To assess costs associated with implementation of a strict 'search and isolate' strategy for controlling highly drug-resistant organisms (HDRO). Design: Review of data from 2-year prospective surveillance (01/2012 to 12/2013) of HDRO. Setting: Three university hospitals located in northern Paris. Methods: Episodes were defined as single cases or outbreaks of glycopeptide-resistant enterococci (GRE) or carbapenemase-producing Enterobacteriacae (CPE) colonisation. Costs were related to staff reinforcement, costs of screening cultures, contact precautions and interruption of new admissions. Univariate analysis, along with simple and multiple linear regression analyses, was conducted to determine variables associated with cost of HDRO management. Results: Overall, 41 consecutive episodes were included, 28 single cases and 13 outbreaks. The cost (mean±SD) associated with management of a single case identified within and/or 48 h after admission was €4443±11 552 and €11 445±15 743, respectively (p<0.01). In an outbreak, the total cost varied from €14 864 ±17 734 for an episode with one secondary case (€7432±8867 per case) to €136 525 ±151 231 (€12 845±5129 per case) when more than one secondary case occurred. In episodes of single cases, contact precautions and microbiological analyses represented 51% and 30% of overall cost, respectively. In outbreaks, cost related to interruption of new admissions represented 77-94% of total costs, and had the greatest financial impact (R²=0.98, p<0.01). Conclusions: In HDRO episodes occurring at three university hospitals, interruption of new admissions constituted the most costly measure in an outbreak situation. [ABSTRACT FROM AUTHOR]

The aggregate of microorganisms residing on the surface of the skin, in the oropharynx and in the GI tract, known as the human microbiota, play a major role as natural reservoirs for bacterial resistance to antibiotics. Fluoroquinolones (FQ) are among the most prescribed antibiotics and a major increase in FQ resistance is occurring worldwide. High concentrations of FQ are found in microbial ecosystems explaining their profound effect on the clinically relevant bacteria that compose them. Yet, because of different local pharmacokinetics, distinct selective pressures occur in the different microbiota. Here we review the qualitative and quantitative impact of FQ on the three main human microbiota and their consequences, particularly in terms of emergence of antibiotic resistance. Finally, we review potential actions that could decrease the impact of FQs on microbiota. [ABSTRACT FROM AUTHOR]

Background Quinolone resistance is a major global clinical problem. It primarily emerges in microbiota under selective pressure. Studies evaluating the incidence and risk factors for carrying quinolone-resistant bacteria in hospitalized patients treated with fluoroquinolones (FQs) are lacking. Methods We prospectively included hospitalized patients treated with FQs. Nasal, throat and rectal swabs were performed before FQ treatment, at the end of FQ treatment and 30 days later. A ‘reference group’ of patients not receiving FQs was also included to determine the rates of quinolone resistance acquisition not linked to FQ treatment. Prevalence and incidence of quinolone-resistant strains of nasal coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, pharyngeal α-haemolytic streptococci and faecal Escherichia coli, and risk factors for emergence of quinolone resistance in FQ-treated patients were assessed. Results Four-hundred and fifty-one FQ-treated patients were included, as well as 119 subjects in the ‘reference group’. Emergence of quinolone resistance occurred in 110/213 (51.6%), 50/336 (14.9%), 53/290 (18.3%) and 46/336 (13.7%) of FQ-treated patients for CoNS, S. aureus, α-haemolytic streptococci and E. coli, respectively, significantly more than for reference patients for CoNS (23/65; P < 0.05), S. aureus (5/91; P < 0.02) and E. coli (4/84; P < 0.05), but not for α-haemolytic streptococci (15/70; P = 0.55). Emergence of resistance was not associated with the type of FQ received, the duration of therapy or the duration of hospital stay, but was associated with host factors such as immunosuppression and altered performance status. Conclusions FQs received during hospitalization account for high rates of emergence of resistance to FQs in clinically relevant bacteria from human microbiota, reflecting the important ecological impact of FQs. Host factors outweighed treatment or hospitalization characteristics as risk factors for carrying quinolone-resistant strains. [ABSTRACT FROM PUBLISHER]

Background/aims Behcet's disease (BD) is a well-known cause of Budd-Chiari syndrome (BCS). Data are lacking on the presentation and outcome of BCS related to BD. Methods We investigated the relationship between BD and BCS in 14 patients with both diseases and compared the results to 92 BCS patients without BD. Results Male gender (p = 0.003), North African origin (P = 0.007) and inferior vena cava obstruction (P <0.0001) were more frequent in patients with BD and BCS than in those with BCS alone and the plasma C-reactive protein level was higher (p = 0.003). Two of the patients with the combined diseases underwent recanalization of the vena cava and the hepatic veins, none received transjugular intrahepatic portosystemic shunts (TIPS), one received a surgical shunt and one underwent liver transplantation. TIPS were less frequent in patients with BD and BCS than in those with BCS alone (P = 0.019). Eighty six per cent of patients with BCS and BD received corticosteroids and immunosuppressive therapy. The 5-year transplantation-free survival rate was 63% in patients with BCS alone and 91% in those without BD (P = 0.11). In our series and in the literature, a high number of patients [12 (61.5%) and 11 (64.7%) respectively] treated with anticoagulation and corticosteroids and/or immunosuppressants did not require invasive treatment. Conclusion This study shows a higher frequency of IVC obstruction in patients with BCS and BD. Medical treatment with anticoagulation and immunosuppressive agents may improve the symptoms of BCS. Therefore early management with immunosuppressive and anticoagulation therapy appears to be the treatment of choice in patients with BCS and BD. [ABSTRACT FROM AUTHOR]

Background Gaucher disease (GD) is a rare recessively inherited disorder caused by deficiency of a lysosomal enzyme, glucocerebrosidase. Accumulation of glucosylceramide or glucosylsphingosine in macrophages leads to increased production of ferritin and chitotriosidase and to decreases in hemoglobin concentration and platelet count, which are used as blood biomarkers. GD is treated by enzyme replacement therapy (ERT) or, sometimes by substrate reduction therapy. However, no physiological model for analysis of biomarkers change during ERT has been proposed. We aimed to develop a pathophysiological model to analyze biomarker's response to ERT and several covariates impact. Methods Changes in blood ferritin, chitotriosidase, hemoglobin and platelets were analyzed in French GD Registry patients receiving imiglucerase/alglucerase as ERT. We used simplified exponential pathophysiological model, with initial concentration, biomarkers amplitude of variation and rate constant of normalization during ERT. Changes in four biomarkers were analyzed separately and then all four together from initiation to discontinuation of ERT, or until the end of follow-up. Several covariates were tested, including age at ERT initiation, splenectomy, sex, genotype (N370S/N370S), and ERT dose. Results An exponential model gave a good data fit. The four biomarkers analysis showed that the rate of nomalization was the same for all biomarkers, with a half-life of 0.5 years. Predicted values of biomarkers at ERT's steady state were 40% and 10% of initial concentrations, for ferritin and chitotriosidase, respectively, and 120% and 200% for hemoglobin and platelets, respectively. We found that 3 covariates had an effect on initial concentration or on amplitude of variation in ferritin, hemoglobin and platelets: women and patients under 15 years of age had lower ferritin and hemoglobin concentrations, and patients under 15 years of age had higher platelet count. Splenectomized patients had higher ferritin concentrations and platelet count and lower amplitude of variation of hemoglobin. Conclusion We report the first dynamic model of biomarker changes in GD. It enabled us to estimate that 95% of biomarker response to ERT was achieved in 2 years, but with high inter-patient variability. We also found that with the current treatment, normalization of chitotriosidase and ferritin will occur in about 65% of patients. [ABSTRACT FROM AUTHOR]

Patients with cancer or hematologic diseases are particularly at risk of infection leading to high morbidity, mortality and costs. Extensive data show that optimization of the administration of antimicrobials according to their pharmacokinetic and pharmacodynamic parameters improves clinical outcome. Evidence is growing that when pharmacokinetic and pharmacodynamic parameters are used to target not only clinical cure but also eradication, the selection resistance is also contained. This is of particular importance in patients with neutropenia in whom increasing rates of drug-resistant Gram-negative bacteria have been reported, particularly Pseudomonas aeruginosa. Based on experimental and clinical studies, pharmacokinetic and pharmacodynamic parameters are discussed in this review for each antibiotic used in febrile neutropenia in order to help physicians improve dosing and optimization of antimicrobial agents. [ABSTRACT FROM AUTHOR]

In this prospective study, 50 patients with early-onset spinal implant infections received treatment consisting of debridement surgery with implant retention followed by combination antibiotic therapy for 3 months. Results were not inferior to those previously reported with longer treatments.Background. Optimal duration and modalities of antibiotic therapy for early-onset spinal implant infection (EOSII) remain controversial.Methods. Between November 2004 and November 2007, we conducted a prospective, monocentric study to assess the efficacy of a 3-month course of antibiotics for patients diagnosed with EOSII, as defined by a proven deep infection of the surgical site occurring within 30 days after spinal instrumented surgery. All patients with EOSII underwent surgical debridement with implant retention. Combination antibiotic therapy was administered intravenously for 2 weeks. Treatment was switched orally for the following 10 weeks.Results. 50 patients matched the inclusion criteria and were included in this study. The median age was 68 (interquartile range [IQR]: 51–75) years; the median ASA score was 2 (IQR: 2–2). Emergency spinal surgery had been performed in 18 patients. Staphylococcus aureus was the most frequently isolated pathogen (n = 27), followed by Enterobacteriaceae (n = 22) and coagulase-negative staphylococci (n = 6). Seventeen patients had polymicrobial infections, and 13 patients (26%) had bacteremia. The median time from the first symptoms of infection to debridement surgery was 3 days (IQR: 2–5 days). Three patients underwent 2 debridement surgeries. The median follow-up was 43 (IQR: 34–54) months. The 2-year survival rate for those who did not experience treatment failure was 88% (95% confidence interval [CI]: 75.7%–95.5%). Three patients experienced treatment failure (6%, 95% CI: 1.3%–16.5%), including 1 relapse due to methicillin-susceptible S. aureus and 2 reinfections with another pathogen.Conclusions. In this homogenous cohort of 50 patients with EOSII, treatment consisting of debridement surgery with implant retention followed by combination antibiotic therapy for 3 months appeared safe and effective. [ABSTRACT FROM AUTHOR]

Background. Emergence of quinolone-resistant Escherichia coli (QREC) is an increasing clinical challenge mostly originating in fecal microbiota. The dynamics of the emergence of QREC in feces from individuals exposed to ciprofloxacin is unknown.Methods. A total of 48 healthy volunteers received oral ciprofloxacin for 14 days. Fecal specimens were collected on days 0, 8, 14, and 42. Subpopulations of QREC were detected on selective agar, genetically characterized, and compared with quinolone-susceptible E. coli (QSEC) strains collected on different days.Results. On day 42, 34 subjects carried QSEC, and 14 carried QREC. Of the 14 who carried QREC, 9 carried quinolone-susceptible E. coli on day 0, 1 carried E. coli with a lower level of quinolone resistance on day 0, and 4 carried E. coli with similar levels of resistance and RAPD-genotypes on days 0 and 42. No plasmid acquisition and no selection of resistant mutants from the initial microbiota was evidenced in any case.Conclusions. In QREC emerging under ciprofloxacin pressure in the fecal microbiota, no proof of selection of quinolone-resistant mutants from the initial microbiota was evidenced, suggesting that QREC strains on day 42 were either present at undetectable levels in the initial microbiota or that exogenous acquisition of QREC strains occurred.Clinical Trials Registration. NCT00190151. [ABSTRACT FROM PUBLISHER]

The widespread presence of plasmid-mediated quinolone resistance determinants, particularly qnr genes, has become a current issue. By protecting DNA-gyrase from quinolones, Qnr proteins confer a low level quinolone resistance that is not sufficient to explain their emergence. Since Qnr proteins were hypothesized to act as DNA-binding protein regulators, qnr genes could have emerged by providing a selective advantage other than antibiotic resistance. We investigated host fitness of Escherichia coli isogenic strains after acquisition of the qnrA3 gene, inserted either alone onto a small plasmid (pBR322), or harbored on a large conjugative native plasmid, pHe96(qnrA3) found in a clinical isolate. The isogenic strains were derived from the susceptible E. coli CFT073, a virulent B2 group strain known to infect bladder and kidneys in a mouse model of pyelonephritis. In vitro experiments included growth analysis by automatic spectrophotometry and flow cytometry, and competitions with CFU enumeration. In vivo experiments included infection with each strain and pairwise competitions in absence of antimicrobial exposure. As controls for our experiments we used mutations known to reduce fitness (rpsL K42N mutation) or to enhance fitness (tetA deletion in pBR322). E. coli CFT073 transformed with pBRAM(PBR322-qnrA3) had significantly higher maximal OD than E. coli CFT073 transformed with pBR322 or pBR322DtetA, and in vivo competitions were more often won by the qnrA3 carrying strain (24 victories vs. 9 loss among 42 competitions, p = 0.001). In contrast, when pHe96(qnrA3) was introduced by conjugation in E. coli CFT073, it exerted a fitness cost shown by an impaired growth observed in vitro and in vivo and a majority of lost competitions (33/35, p,0.0001). In conclusion, qnrA3 acquisition enhanced bacterial fitness, which may explain qnr emergence and suggests a regulation role of qnr. However, fitness was reduced when qnrA3 was inserted onto multidrug-resistant plasmids and this can slow down its dissemination without antibiotic exposure. [ABSTRACT FROM AUTHOR]

Objectives To investigate knowledge and perceptions about antibiotic prescription in two university hospitals. Methods Physicians completed four case vignettes describing infections and a questionnaire. For each vignette, the physicians were asked to determine whether hospital admission and antibiotic treatment were needed; whether a treatment change was needed; and the duration of antibiotic treatment. The questionnaire collected data on beliefs and perceptions regarding antibiotic prescription. Results Of 412 eligible physicians, 206 agreed to participate. Factors associated with a vignette score above the median were anaesthesiologist/intensivist (adjusted odds ratio, 3.09; P = 0.02), perception of inappropriate antibiotic use as risky for the patient (adjusted odds ratio, 2.84; P = 0.03) and self-efficacy (adjusted odds ratio, 2.18; P = 0.02), whereas being a surgeon was associated with a vignette score lower than the median (adjusted odds ratio, 0.14; P < 0.0001). Conclusions The high participation rate suggested awareness of antibiotic use. Educational programmes specifically targeted at surgeons are needed. We identified cognitive factors that affect knowledge of antibiotic prescription, and may help in the design of education programmes and interventions aimed at improving antibiotic use. [ABSTRACT FROM PUBLISHER]

Background. Although optimization of the fluoroquinolone dosage increases the efficacy of this class of drugs against bacterial infections, its impact on the emergence of resistance in commensal bacteria is unknown. Methods. Six different 14-day dosages of oral ciprofloxacin were randomly assigned to 48 healthy volunteers. Individual pharmacokinetic and pharmacodynamic parameters combining antibiotic exposure in plasma, saliva, and stool specimens and ciprofloxacin minimum inhibitory concentrations (MICs) and mutant prevention concentrations against viridans group streptococci in the pharyngeal flora and Escherichia coli in the fecal flora were estimated. Their links with the emergence of resistance to nalidixic acid or ciprofloxacin in the fecal flora and to levofloxacin in the pharyngeal flora 7, 14, or 42 days after ciprofloxacin initiation were investigated. Results. Resistance emerged in the fecal and pharyngeal flora of 25% and 33% of the subjects, respectively, mainly when local concentrations of ciprofloxacin were less than the MIC. No variable that integrated pharmacokinetic data and pharmacodynamic parameters was found to differ significantly between the subjects in whom resistance emerged and those in whom it did not. Probabilities of the emergence of resistance were not significantly different across the different antibiotic dosages. Conclusions. Selection of resistant commensals during ciprofloxacin therapy is a frequent ecological side effect that is not preventable by dosage optimization. [ABSTRACT FROM AUTHOR]

Enterobacteriaceae are now the predominant pathogens isolated in bloodstream infections complicating orthotopic liver transplantation (OLT). We conducted a retrospective cohort study of patients who underwent OLT in a University hospital between 01/01/1997 and 31/03/2003 to investigate the risk factors of Enterobacteriaceae bacteremia (EB) after OLT. EB was defined as the isolation of an Enterobacteriaceae species from at least one blood culture within 3 months following OLT. Pre-, per- and postoperative variables were collected from the medical records and analyzed in relation to EB. Forty (12.5%) of the 320 patients developed EB. The origin of EB was abdominal in 32% of the patients, urinary in 18%, pulmonary in 10%, and primary in the remaining 40% of the patients. Two-thirds of EB occurred within 1 month following OLT. The main pathogens were Escherichia coli (42%), Enterobacter cloacae (17%) and Klebsiella pneumoniae (17%). Susceptibility rates varied from 82.5% for ciprofloxacin to 95% for amikacin. Fourteen patients (35%) with EB died. Variables significantly associated with EB after multivariate analysis were a MELD score >20 (OR: 2.79 [1.24–6.30], P = 0.013), transplantation for posthepatitic B (OR: 4.47 [1.67–11.98], P = 0.03) or posthepatitic C (OR: 3.79 [1.59–9.01], P = 0.03) cirrhosis, a positive bile culture (OR: 3.47 [1.19–10.13], P = 0.023) and return to surgery (including retransplantation) (OR: 2.72 [1.32–5.58], P = 0.006). EB is a frequent and severe complication following OLT. Patients grafted for a posthepatitic cirrhosis, with a severe pretransplantation status, with a positive bile culture and those undergoing reoperation have a high risk of developing EB. [ABSTRACT FROM AUTHOR]

This study was designed to investigate the role of hypermutability of Staphylococcus aureus on bacterial fitness and antibiotic resistance in a model of chronic bone infection. An isogenic pair of strains, S. aureus RN4220 and its mutator counterpart inactivated in the mutL gene were used in a rat model of osteomyelitis of the tibia. The effect of the mutator phenotype in the emergence of antibiotic resistance was assessed in rats infected by each strain separately and treated with rifampicin for 5 days. No difference between the two strains was found in bacterial growth in vitro and in bacterial survival in the animal model, indicating no fitness defect in the mutator strain. In competition studies performed in rats coinfected with the two strains at a same ratio and sacrificed at different times from day 3 to day 42 postinoculation, the mutator strain was clearly disadvantaged because it was found in all rats and at all study times at lower counts ( P<0.05 from day 14 to day 42). Two of the 16 rats infected by the mutator strain and none of the 14 rats infected by the wild-type strain had acquired rifampicin-resistant mutants ( P=0.4). Data suggest that the S. aureus mutator phenotype was associated with a decreased bacterial fitness in vivo and did not confer significant advantage in the acquisition of antibiotic resistance in a model of chronic bone infection. [ABSTRACT FROM AUTHOR]

Background. A consensus conference recommended empirical antibiotic therapy for all patients with postoperative meningitis and treatment withdrawal after 48 or 72 h if cerebrospinal fluid culture results are negative. However, this approach is not universally accepted and has not been assessed in clinical trials. Methods. We performed a cohort study of all patients who received a diagnosis of postoperative meningitis from January 1998 through May 2005 in a teaching hospital. From January 1998 through September 2003 (control period), guidelines were lacking or were not implemented. From October 2003 through May 2005 (interventional period), all patients received a predefined intravenous antibiotic therapy that was discontinued on the third day if the meningitis was considered aseptic. Clinical outcome and duration of antibiotic therapy were analyzed for each patient. Results. Seventy-five episodes of postoperative meningitis (21 cases of bacterial meningitis and 54 cases of aseptic meningitis) were investigated. Patients with aseptic meningitis received antibiotic treatment for a mean ± standard deviation duration of 11 ± 5days during the control period and 3.5± 2 days during the intervention period (P = .001). The duration of antibiotic treatment for bacterial meningitis was not significantly different between the 2 periods. All episodes of bacterial and aseptic meningitis were cured, and complications were rare during both periods. Conclusions. Stopping antibiotic treatment after 3 days is effective and safe for patients with postoperative meningitis whose cerebrospinal fluid culture results are negative. [ABSTRACT FROM AUTHOR]

Abstract: It has been suggested that mutator phenotype could be associated with an increase in virulence, but to date experimental evidences are lacking. Epidemiological studies have revealed that urinary tract infection isolates encompass the highest proportion of mutator strains within the Escherichia coli species. Using the uropathogenic strain CFT073 and its mutS− mutator mutant, we show that the mutator strain is selected in vitro in urine and in the late stages of infection in a mouse model having urinary tract infection. Thus, we report that, under specific conditions, i.e., urinary tract infection, the mutator phenotype may confer an advantage in pathogenesis. [Copyright &y& Elsevier]

Studies the expression of glycopeptide-resistance gene in response to vancomycin and teicoplanin in the cardiac vegetations of rabbits infected with VanB-type Enterococci faecalis. Resistance to vancomycin; Constitutive or teicoplanin-inducible expression of the resistance genes; Detection of rounded heaps containing fluorescent bacteria in vegetation slides from rabbits treated with vancomycin; Detection of teicoplanin-resistant mutants as fluorescent bacteria in rabbits.

Study objectives: To evaluate the management of community-acquired pneumonia (CAP) by general practitioners (GPs) in terms of clinical efficiency and adherence to official recommendations. Design: Prospective cohort study. Setting: Community-based study from 11 French counties. Patients: Adult patients clinically suspected of having CAP who were seen by GPs were included after confirmation of the presence of an infiltrate on chest radiographs. Intervention: The management of the patients was left to the discretion of the GP. Measurements and results: One hundred thirty patients were included in the study, and 13 patients (10%) were immediately hospitalized because of the severity of the pneumonia. The remaining 117 patients were treated as outpatients: 108 of 117 patients (92%) were cured, and 9 patients were subsequently hospitalized because of the failure of ambulatory treatment. Diagnostic error (n = 6) rather than antibiotic failure (n = 3) was the most frequent cause of the failure of ambulatory treatment. Only 40% of the patients received an initial antibiotic treatment that was in agreement with French recommendations. However, the rate of antibiotic failure leading to hospitalization was low (3 of 117 patients; 2.6%) and similar for patients treated or not according to recommendations (p > 0.5). Overall, five patients (4%) died; all deaths occurred during hospitalization and were related to the severity of the underlying disease but not to the choice of antibiotic treatment. Conclusions: The management of CAP by GPs was clinically effective despite a poor adherence to official recommendations. Our results suggest that adequate assessment of severity rather than adherence to recommendations for antibiotic treatment had an impact on clinical outcome of CAP managed by GPs. [ABSTRACT FROM AUTHOR]

Presents a study on the relationship between nasal carriage of Staphylococcus aureus (SA) and the risk of infection in liver transplant recipients. Risk factors associated with liver transplant; Comparison of the characteristics of methicillin-resistant SA carriers and methicillin-susceptible SA carriers; Association between the preoperative carrier status and the occurrence of infection after surgery.

The conditions for the emergence of resistance to cefpirome and ceftazidime were studied in rabbits with experimental aortic endocarditis due to . The MIC of cefpirome was 16 mg/L and that of ceftazidime was 4 mg/L. Resistant mutants with MICs of ≥ 64 mg/L were obtained to cefpirome after a single passage and to ceftazidime after five passages. A single dose of 50 mg/kg intramuscularly gave mean peak serum concentrations of 110·0 ±31·7 mg/L for cefpirome compared with 67·7 ±21·4 mg/L for ceftazidime and the half-lives were 1·2 ±0·1 h and 2·1 ±0·4 h, respectively. After treating infected rabbits for 4 days with various dosing regimens, resistant strains were only detected in those animals in which the time that the serum concentration exceeded the MIC was less than half of the dosing interval. There was no evidence of emergent resistance when the serum concentrations exceeded the MIC for a longer period nor when amikican was combined with the cephalosporins on the first day of therapy. Moreover, once differences in MICs and pharmacokinetics were taken into account, both antibiotics had a similar propensity to induce resistance. [ABSTRACT FROM PUBLISHER]

Enterococcus faecalis BM4281 is resistant to vancomycin, susceptible to teicoplanin (VanB phenotype), and intrinsically resistant to low levels of gentamicin. The efficacy of glycopeptides against BM4281 was investigated in a rabbit model of experimental endocarditis for reduction of bacterial counts in cardiac vegetations and selection of mutants with increased resistance to glycopeptides. Teicoplanin led to a 100-fold reduction of bacteria in the vegetations, whereas vancomycin had no effect. Monotherapy with either antibiotic selected mutants with homogeneous or heterogeneous resistance to high levels of both glycopeptides. Vancomycin also selected mutants that required the antibiotic for growth. The combination of gentamicin plus teicoplanin was bactericidal, prevented the emergence of mutants, and allowed sterilization of the vegetations in 25% of the rabbits, indicating that the combination may be an alternative if penicillin cannot be used against VanB-type enterococci. [ABSTRACT FROM PUBLISHER]

The case of a human immunodeficiency viruspositive patient with rectal stenosis caused by a tumor that completely regressed in response to gancyclovir is presented.Several biopsies from the tumoral mass failed to show any stigmata of non-Hodgkin's lymphoma, adenocarcinoma, or Kaposi sarcoma. No parasites could be detected in rectal biopsies. Viral inclusions showing both Epstein-Barr virus and cytomegalovirus on immunostained sections suggested an unusual form of viral infection.Antiviral therapy (gancyclovir 10 mg/kg/day) had a dramatic effect on pain and discharge of blood, and suppressed rectal difficulties within three days of therapy. The antiviral treatment was stopped at Day 10 because of leukopenia. Endoscopic and histologic examinations revealed normal rectal mucosa after 3, 6, 9, 12, and 18 months of follow-up.This is the first case of complete and long-term regression of a rectal stenosis secondary to a tumoral mass in response to antiviral therapy in patients with human immunodeficiency virus. [ABSTRACT FROM AUTHOR]