How to optimize administration of cefoxitin for the treatment of extended spectrum producing Enterobacteriaceae-related infection?

Pharmacological and clinical data regarding cefoxitin for the treatment of ESBL-producing Enterobacteriaceae-related infections are limited. We performed a multicentric prospective cohort study to evaluate continuous/prolonged, or intermittent infusion of cefoxitin. We assessed the plasma concentration as a function of the duration of infusion and then performed a simulation of the percentage of patients who would reach the PK/PD targets, set at 100% ƒT> MIC or 100% ƒT>4 MIC. Eighty-one patients were included. All patients were treated with 6 gr./day. MICs to cefoxitin ranged from 0.5 to 64 mg/L. Sixteen (19.7%) patients were infected with strains with cefoxitin MICs ≥ 8 mg/L. In all patients infected with strains with MICs ≤ 6 mg/L, PK/PD objectives (100% ƒT> MIC) were achieved with prolonged or continuous infusion. In contrast, when MICs were 8 mg/L only, continuous infusion was sufficient to achieve the PK/PD objectives (100% ƒT> MIC). Extended infusion of cefoxitin is necessary for the treatment of non-UTI ESBL-related infections.

No significant difference between ceftriaxone and cefotaxime in the emergence of antibiotic resistance in the gut microbiota of hospitalized patients: A pilot study.

BACKGROUND: Ceftriaxone and cefotaxime share a similar antibacterial spectrum and similar indications but have different pharmacokinetic characteristics. Ceftriaxone is administered once daily and 40% of its clearance is by biliary elimination, whereas cefotaxime requires three administrations per day and shows less than 10% biliary elimination. The high biliary elimination of ceftriaxone suggests a greater impact of this antibiotic on the gut microbiota than cefotaxime. The objective of this study was to compare the impact of ceftriaxone and cefotaxime on the gut microbiota. METHODS: A prospective clinical trial was performed that included 55 patients treated with intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for at least 3 days. Three fresh stool samples were collected from each patient (days 0, 3, and 7 or at the end of intravenous treatment) to assess the emergence of third-generation cephalosporin (3GC)-resistant Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, toxigenic Clostridioides difficile, and vancomycin-resistant enterococci. RESULTS: The emergence of 3GC-resistant gram-negative enteric bacilli (Enterobacteriaceae) (5.9% vs 4.7%, p > 0.99), Enterococcus spp, and non-commensal microorganisms did not differ significantly between the groups. Both antibiotics reduced the counts of total gram-negative enteric bacilli and decreased the cultivable diversity of the microbiota, but the differences between the groups were not significant. CONCLUSION: No significant difference was observed between ceftriaxone and cefotaxime in terms of the emergence of resistance.

A rapid, automatic and accurate assay for quantifying temocillin in human serum and CSF using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry. Clinical application.

Temocillin is a ß-lactamase-resistant penicillin used for the treatment of multiple drug-resistant Gram-negative bacteria. To maximize efficacy and avoid adverse effects, the dose regimen has to be quickly adjusted to the clinical situations. This necessitates the development of a rapid, reliable and accurate analytical method. Temocillin and the stable isotopically labeled internal standard ([13 C6 ]-amoxicillin) were extracted from either serum or cerebrospinal fluid by a turbulent flow liquid chromatographic method and eluted onto an octadecyl-silica phase with polar endcapping. Mass spectrometry was conducted using an exact mass determination method by electrospray positive ionization high-resolution mass spectrometry. The LLOQ and ULOQ of the present method were determined to be 0.4 and 200 µg/ml for serum and cerebrospinal fluid samples, respectively. The total analysis time was <7 min. The recovery ranged from 87.7 to 120.8%. Intra- and inter-day precision and trueness were tested at four concentration levels: 0.4, 8, 40 and 160 µg/ml. Values were 6.33 ± 1.53, 8.8 ± 1.3, 8.8 ± 0.36 and 2.1 ± 0.76%, and 5.0 ± 0.54, 9.9 ± 1.0, 5.8 ± 1.6 and 0.1 ± 1.1%, for inter- and intra-day analysis, respectively. Temocillin was found to be stable under all relevant laboratory conditions. The method was cross-validated with a microbiological assay. This method is suitable for accurate measurement of temocillin concentration in small volumes of serum or cerebrospinal fluid. Thanks to the online extraction procedure, the overall analytical time is compatible with high-throughput analysis for clinical application.

Continuous infusion of ceftolozane/tazobactam is associated with a higher probability of target attainment in patients infected with Pseudomonas aeruginosa.

Ceftolozane/tazobactam (CTZ/TZ) exhibits time-dependent antimicrobial activity, and prolonged infusion can better achieve the pharmacodynamic target than an intermittent bolus. We aimed to compare the use of prolonged or continuous infusion with intermittent administration of CTZ/TZ for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. We performed a multicentric prospective cohort study to evaluate continuous, prolonged, or intermittent infusion of CTZ/TZ. We assessed the plasma concentration as a function of the duration of infusion and then performed a simulation of the percentage of patients who would reach the PK/PD targets, set at 100% ƒT> MIC or 100% ƒT>4 MIC. Seventy-two patients were enrolled with a median [IQR] age of 48.5 [32.4-63.2] years. Fifty-seven (79%) were hospitalized in an intensive care unit. Thirty-seven (51.4%) were immunosuppressed, and the in-hospital mortality rate was 15.2%. The major site of infection was the respiratory tract (66.7%). The PK/PD objectives (100% ƒT>4 MIC) were achieved for all patients infected with strains with CTZ/TZ MICs < 4 mg/L, regardless of the mode of administration. In contrast, intermittent bolus administration and prolonged infusion did not achieve the PK/PD objectives when the CTZ/TZ MICs were ≥ 4 mg/L. However, the PK/PD objectives (100% ƒT>4 MIC) were achieved for strains with MICs up to 8 mg/L in patients receiving continuous infusion of CTZ/TZ. A dosing regimen of 2 g/1 g CTZ/TZ administered every 8 h as a 1-h intravenous infusion, as currently recommended, did not provided adequate coverage to achieve a sufficient probability of target attainment for P. aeruginosa strains with MICs ≥ 4 mg/L.

Encapsulation of Cwp84 into pectin beads for oral vaccination against Clostridium difficile.

We have designed an oral vaccine against Clostridium difficile infection. The virulent factor Cwp84, that is a cystein protease highly immunogenic in patients with C. difficile-associated disease, was entrapped within pectin beads. Beads encapsulating Cwp84 were shown to be stable in the simulated intestinal medium and to release the cystein protease once in the simulated colonic medium. Three groups of hamsters were immunized, the first receiving pectin beads encapsulating Cwp84, the second unloaded beads and the third one free Cwp84. After three immunizations by the intragastric route, all groups received clindamycine. Post-challenge survival with a strain of C. difficile showed that 2 days after infection, all hamsters treated with unloaded beads and all hamsters treated with free Cwp84 have deceased after 7 days, whereas about 40% of hamsters administered with Cwp84-loaded beads survived 10 days after challenge, proving that oral vaccination provides partial protection. These first data obtained with an oral vaccine against C. difficile appear promising for preventing this infection.

Rapid eradication of Listeria monocytogenes by moxifloxacin in a murine model of central nervous system listeriosis.

Listeriosis is a rare but life-threatening infection. A favorable outcome is greatly aided by early administration of antibiotics with rapid bactericidal activity against Listeria monocytogenes. Moxifloxacin, a new-generation fluoroquinolone with extended activity against gram-positive bacteria, has proved its effectiveness in vitro against intracellular reservoirs of bacteria. The efficacies of moxifloxacin and amoxicillin were compared in vivo by survival curve assays and by studying the kinetics of bacterial growth in blood and organs in a murine model of central nervous system (CNS) listeriosis. We combined pharmacokinetic and pharmacodynamic approaches to correlate the observed efficacy in vivo with plasma and tissue moxifloxacin concentrations. Death was significantly delayed for animals treated with a single dose of moxifloxacin compared to a single dose of amoxicillin. We observed rapid bacterial clearance from blood and organs of animals treated with moxifloxacin. The decrease in the bacterial counts in blood and brain correlated with plasma and cerebral concentrations of antibiotic. Moxifloxacin peaked in the brain at 1.92 +/- 0.32 microg/g 1 hour after intraperitoneal injection. This suggests that moxifloxacin rapidly crosses the blood-brain barrier and diffuses into the cerebral parenchyma. Moreover, no resistant strains were selected during in vivo experiments. Our results indicate that moxifloxacin combines useful pharmacokinetic properties and rapid bactericidal activity and that it may be a valuable alternative for the treatment of CNS listeriosis.