Search

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 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]

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]

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 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]

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]

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]

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]

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]

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.

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]

Background Cancer-associated acute cholangitis (CAAC) are becoming more frequent and their characteristics may be changing with the evolution of cancer management. Our aim was to compare clinical, microbiological and outcome characteristics of CAAC to those of cancer-free acute cholangitis (CFAC). Methods All consecutive cases of acute cholangitis (AC) from November 2015 to March 2017 were collected retrospectively in a single tertiary care hospital in Clichy, France, specialized in gastroenterology. Hospital stays referred as AC by coding were screened. Patients fulfilling the 2018 Tokyo Guidelines diagnostic criteria for definite AC were included. Data were collected using a standardized form. CAAC were defined as AC that occurred in patients who had active cancer or history of cancer in the five previous years. CFAC were defined as AC in patient who no history of cancer, or in remission for more than 5 years. Comparison was made using Fisher or Student's t-test. P < 0.05 was considered as significant. Results 156 episodes of AC in 130 patients were analyzed. 101 had CAAC and 55 had CFAC. Age and sex did not differ (table 1), but CAAC had a higher Charlson's comorbidity index (4.4 vs. 1.7, P < 0.0001). Despite similar clinical presentation, CAAC had more pronounced cholestasis (Gamma GT 659 vs. 391UI/L; Alkaline phosphatases 526 vs. 309 UI/L; P < 0.0001 for both) and C-reactive protein level (133 vs. 97mg/L, P = 0.008, Table 2). E. coli was more common in CFAC (72.4% vs. 54% of positive blood cultures, P = 0.004). In bile cultures, Enterococci and multi-drug-resistant Gram negatives tended to be more frequent in CAAC than in CFAC (63 vs. 17%, P = 0.07 and 9.1% vs. 4.1%, P = 0.33, Table 2), respectively. CAAC more frequently required drainage (86.1% of cases vs. 43.6% in CFAC (P < 0.0001), including radiological drainage (42.5% vs. 12.5%; P = 0.008) and with multiple sessions (28.7% vs. 8.3%, P < 0.0001, Table 3). Antibiotherapy duration did not differ between the two groups. Despite similar initial severity, only 51.5% of patients with CAAC were alive, without febrile recurrence or other biliary drainage at day 28, vs. 85.5% of patients with CFAC (P < 0.0001, Table 3). Conclusion Despite comparable initial clinical presentation, management is more complex and outcome less favorable in CAAC vs. CFAC. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

In this article the author discusses the study about the use of reduced antibiotic pressure on the treatment of acute exacerbation of chronic obstructive pulmonary disease (COPD). He states that the study was not able to answer whether each treatment arm had sufficient antibacterial spectrum. He notes the impossibility of fluoroquinolone to treat COPD because there has been no research that revealed the increase of its clinical significance.

We investigated the evolution of lymphocyte subsets in blood samples from 94 consecutive patients with community-acquired pneumonia; these samples were obtained 72 hours after hospitalization and at follow-up, when the patients were considered to be cured. Acute-phase lymphocyte counts, as compared with follow-up counts, were decreased in the overall population (P < .0001); however, the percentage of CD4+ T cells remained unchanged during the course of pneumonia in each patient. These changes that were noted for the overall population were not significantly influenced by age, the presence (or not) of infection with human immunodeficiency virus (HIV), or etiologic microorganisms. Of the 68 HIV-seronegative patients, 12 had initial CD4+ T cell counts of <200/mm3; multivariate analysis revealed that this finding was significantly associated with the presence of an underlying disease or tuberculosis and an age of ⩾60 years. [ABSTRACT FROM PUBLISHER]

Background Dalbavancins' (DAL) long half-life and favorable susceptibility profile makes it an attractive option for salvage therapy for endocarditis caused by Staphylococcus aureus (SA), including those with elevated vancomycin (VAN) MIC. The aim of our study was to establish the PKPD of DAL based on a rabbit model of infection and extrapolate those results to the design of human treatment regimens. Methods Data from a rabbit endocarditis model of SA with VAN MICs of 2 and 8 mg/L were fitted using an inoculum-size dependent model and the Pmetrics software. Then, the results were linked to a human PK model to simulate regimens with or without a loading dose. Probability of target attainment (PTAs) for achieving bacterial density of <2 log CFU per gram of vegetation was compared with outcomes based on standard antibiotic therapy (SAT) at 3, 10, 21, 31, and 42 days. Results Mean (SD) PTAs of 34.3% (10.5%), 61.3% (7.0%), 73.5% (5.4%), 79.5% (4.3%), and 83.1% (3.4%) were estimated for all regimens combined with maximum PTAs of 41.8%, 63.6%, 77.8%, 86.6%, and 88.9% for the highest weekly dose at 3, 10, 21, 31 and 42 days of therapy, respectively. While all approaches should achieve an adequate probability of clearing of the colonies by day 21, only doses near 2,000 mg/week are likely to approximate sterilization rates similar to that expected by the SAT at day 42. We observed no meaningful differences in PTAs for weekly vs. daily dosing given with a load. Also, increasing the total weekly dose over 2,000 mg seems to offer minimal additional benefit (Figure 1A–D). Trough-level accumulation is expected as total weekly doses increase, showing a median (IQR) of 62.6 (73.1,85.2) [101.8 (89.9,117.4)] mg/L and 106.5 (91.63,123.6) [135.3 (118.3,156.0)] mg/L at 42 days for the 1,000 mg and 1,500 mg weekly [in equal daily fractions] doses, respectively. Conclusion Our design suggests that these DAL dosing regimens in humans are likely to provide reasonable rates of sterilization when treating endocarditis caused by SA isolates, and administration of near 2,000 mg weekly doses may be considered to improve upon sterilizing effect, but at the cost of accumulating DAL levels. Efficacy and safety of new regimens should be confirmed in well-controlled clinical trials. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background A strategy used by bacterial strains to resist β-lactam antibiotics is the expression of metallo-β-lactamases (MBL) requiring zinc for activity. The use of a zinc chelator may restore carbapenem activity against MBL-producing Enterobacteriaceae. DMSA is a heavy metal chelator approved in humans with a satisfactory safety record. Our objective was to evaluate the activity of DMSA in combination with carbapenems, in vitro and in a fatal murine peritonitis model, against MBL-producing Escherichia coli. Methods Isogenic derivatives of wild-type E. coli CFT073 producing the MBL NDM-1, VIM-2, IMP-1, and the serine carbapenemases OXA-48 and KPC-3 were constructed. Minimum inhibitory concentrations (MICs) of imipenem, meropenem, and ertapenem were determined against each strain alone or in combination with DMSA. Mice were infected with E. coli CFT073 or NDM-1 and treated intraperitoneally for 24 hours with imipenem 100 mg/kg every 4 hours, DMSA 200 mg/kg every 4 hours, or both. Mice survival rates and bacterial counts in peritoneal fluid (PF) and spleen were assessed at 24 hours. Results In vitro , DMSA in combination with each carbapenem permitted a significant decrease of the MICs against all MBL-producing strains, in a concentration-dependent manner. The maximum effect was found for the NDM-1 strain with a 6- to 8-fold MIC reduction, depending on the carbapenem used. NDM-1 strain became susceptible to carbapenems with concentrations of DMSA ≥6 mM. Increasing zinc concentrations above 1 mg/L (average human plasma concentration) did not alter this effect. No benefit of DMSA was observed against non-MBL strains. In vivo , when used alone, the DMSA regimen was not toxic in uninfected mice and ineffective against NDM-1-infected mice (100% mortality). Combination of imipenem and DMSA significantly reduced bacterial counts in PF and spleen as compared with imipenem alone (P < 0.001), and reduced mortality, although not significantly (11% vs. 37%, respectively, P = 0.12). No benefit of the combination was observed against CFT073. Conclusion DMSA is highly effective in vitro in reducing carbapenems MICs against MBL-producing E. coli and appears as a promising strategy in combination with carbapenems for the treatment of NDM-1-related infections. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]