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

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

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

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

Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19.

Remdesivir has reported efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In intensive care unit (ICU) settings, in which multiple-organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir's metabolite (GS-441524) and sulfobutylether ß-cyclodextrin sodium (SEBCD). Additional studies may prove informative, particularly in the evaluations of therapeutic options for coronavirus disease 2019 (COVID-19).

Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study.

This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0-24h) divided by the MIC (AUC0-24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0-24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.).

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

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

Ceftriaxone and Cefotaxime Have Similar Effects on the Intestinal Microbiota in Human Volunteers Treated by Standard-Dose Regimens.

Ceftriaxone has a higher biliary elimination than cefotaxime (40% versus 10%), which may result in a more pronounced impact on the intestinal microbiota. We performed a monocenter, randomized open-label clinical trial in 22 healthy volunteers treated by intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for 3 days. We collected fecal samples for phenotypic analyses, 16S rRNA gene profiling, and measurement of the antibiotic concentration and compared the groups for the evolution of microbial counts and indices of bacterial diversity over time. Plasma samples were drawn at day 3 for pharmacokinetic analysis. The emergence of 3rd-generation-cephalosporin-resistant Gram-negative enteric bacilli (Enterobacterales), Enterococcus spp., or noncommensal microorganisms was not significantly different between the groups. Both antibiotics reduced the counts of total Gram-negative enteric bacilli and decreased the bacterial diversity, but the differences between the groups were not significant. All but one volunteer from each group exhibited undetectable levels of antibiotic in feces. Plasma pharmacokinetic endpoints were not correlated to alteration of the bacterial diversity of the gut. Both antibiotics markedly impacted the intestinal microbiota, but no significant differences were detected when standard clinical doses were administered for 3 days. This might be related to the similar daily amounts of antibiotics excreted through the bile using a clinical regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT02659033.).

Pneumocystis Cytochrome b Mutants Associated With Atovaquone Prophylaxis Failure as the Cause of Pneumocystis Infection Outbreak Among Heart Transplant Recipients.

Background: Although trimethoprim-sulfamethoxazole is the more efficient drug for prophylactic and curative treatment of pneumocystosis, atovaquone is considered a second-line prophylactic treatment in immunocompromised patients. Variations in atovaquone absorption and mutant fungi selection after atovaquone exposure have been associated with atovaquone prophylactic failure. We report here a Pneumocystis jirovecii cytochrome b (cyt b) mutation (A144V) associated with such prophylactic failure during a pneumocystosis outbreak among heart transplant recipients. Methods: Analyses of clinical data, serum drug dosage, and molecular modeling of the P. jirovecii Rieske-cyt b complex were performed to investigate these prophylactic failures. Results: The cyt b A144V mutation was detected in all infected, heart transplant recipient patients exposed to atovaquone prophylaxis but in none of 11 other immunocompromised, infected control patients not treated with atovaquone. Serum atovaquone concentrations associated with these prophylactic failures were similar than those found in noninfected exposed control patients under a similar prophylactic regimen. Computational modeling of the P. jirovecii Rieske-cyt b complex and in silico mutagenesis indicated that the cyt b A144V mutation might alter the volume of the atovaquone-binding pocket, which could decrease atovaquone binding. Conclusions: These data suggest that the cyt b A144V mutation confers diminished sensitivity to atovaquone, resulting in spread of Pneumocystis pneumonia among heart transplant recipients submitted to atovaquone prophylaxis. Potential selection and interhuman transmission of resistant P. jirovecii strain during atovaquone prophylactic treatment has to be considered and could limit its extended large-scale use in immucompromised patients.

In vivo daptomycin efficacy against experimental vancomycin-resistant Enterococcus faecium endocarditis.

Objectives: Daptomycin has become a first-line therapeutic option for vancomycin-resistant Enterococcus faecium infective endocarditis (IE). Although high doses (≥8 mg/kg) are often recommended, optimal doses, particularly for strains with MICs close to the susceptibility breakpoint (4 mg/L), are still debated. Methods: Daptomycin efficacy at doses equivalent to 8 mg/kg daptomycin (DAP8) and 12 mg/kg daptomycin (DAP12) in humans was evaluated in a rabbit model of aortic valve IE induced by 108 cfu of E. faecium reference strain Aus0004 (daptomycin MIC = 2 mg/L) or its in vitro mutant strain Mut4 (daptomycin MIC = 4 mg/L). Treatment began 48 h post-inoculation and lasted 5 days. Results: With Aus0004, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [6.05 (n = 12) and 2.15 (n = 10) versus 9.14 (n = 11), respectively; P < 0.001], with DAP12 being more effective than DAP8 concerning vegetation bacterial load (P < 0.001) and percentages of sterile vegetations (100% versus 0%, respectively; P < 0.001). Daptomycin-resistant Aus0004 mutants were detected in 8.3% of DAP8-treated vegetations. With Mut4, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [7.7 (n = 11) and 6.95 (n = 10) versus 9.59 (n = 11), respectively; P = 0.001 and P = 0.002], without any between-dose difference, but no vegetation was sterile. Moreover, 7 of 11 (63.6%) and 7 of 9 (77.8%) vegetations contained resistant mutants after DAP8 and DAP12, respectively. Conclusions: DAP12 was the most successful strategy against IE due to a WT E. faecium strain (daptomycin MIC = 2 mg/L). To treat IE strains with MIC = 4 mg/L, DAP8 or DAP12 monotherapy was poorly effective with the risk of resistant mutant emergence. Reassessment of the daptomycin susceptibility breakpoint for enterococci seems necessary.

Oropharyngeal Bacterial Colonization after Chlorhexidine Mouthwash in Mechanically Ventilated Critically Ill Patients.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Oropharyngeal care with chlorhexidine to prevent ventilator-associated pneumonia is currently questioned, and exhaustive microbiologic data assessing its efficacy are lacking. The authors therefore aimed to study the effect of chlorhexidine mouthwash on oropharyngeal bacterial growth, to determine chlorhexidine susceptibility of these bacteria, and to measure chlorhexidine salivary concentration after an oropharyngeal care. METHODS: This observational, prospective, single-center study enrolled 30 critically ill patients under mechanical ventilation for over 48 h. Oropharyngeal contamination was assessed by swabbing the gingivobuccal sulcus immediately before applying 0.12% chlorhexidine with soaked swabs, and subsequently at 15, 60, 120, 240, and 360 min after. Bacterial growth and identification were performed, and chlorhexidine minimal inhibitory concentration of recovered pathogens was determined. Saliva was collected in 10 patients, at every timepoint, with an additional timepoint after 30 min, to measure chlorhexidine concentration. RESULTS: Two hundred fifty bacterial samples were analyzed and identified 48 pathogens including Streptococci (27.1%) and Enterobacteriaceae (20.8%). Oropharyngeal contamination before chlorhexidine mouthwash ranged from 10 to 10 colony-forming units (CFU)/ml in the 30 patients (median contamination level: 2.5·10 CFU/ml), and remained between 8·10 (lowest) and 3·10 CFU/ml (highest count) after chlorhexidine exposure. These bacterial counts did not decrease overtime after chlorhexidine mouthwash (each minute increase in time resulted in a multiplication of bacterial count by a coefficient of 1.001, P = 0.83). Viridans group streptococci isolates had the lowest chlorhexidine minimal inhibitory concentration (4 [4 to 8] mg/l); Enterobacteriaceae isolates had the highest ones (32 [16 to 32] mg/l). Chlorhexidine salivary concentration rapidly decreased, reaching 7.6 [1.8 to 31] mg/l as early as 60 min after mouthwash. CONCLUSIONS: Chlorhexidine oropharyngeal care does not seem to reduce bacterial oropharyngeal colonization in critically ill ventilated patients. Variable chlorhexidine minimal inhibitory concentrations along with low chlorhexidine salivary concentrations after mouthwash could explain this ineffectiveness, and thus question the use of chlorhexidine for ventilator-associated pneumonia prevention.

Outbreak of Pneumocystis jirovecii Infection Among Heart Transplant Recipients: Molecular Investigation and Management of an Interhuman Transmission.

Background: An outbreak of Pneumocystis jirovecii pneumonia (PCP) occurred among heart transplant recipients (HTR) at the outpatient clinic of a university hospital, from March to September 2015. Clinical, therapeutic, biological, and molecular data were analyzed to determine its origin and control the outbreak. Methods: Clinical and biological data regarding all HTR followed in the outpatient clinic were collected. PCP diagnosis was based on microscopy and real-time polymerase chain reaction (PCR). Investigations were performed by building a transmission map, completed by genotyping Pneumocystis isolates and by a control of chemoprophylaxis observance. Asymptomatic exposed patients were screened for colonization using real-time PCR. Results: Among 124 HTR, 7 PCP cases were confirmed. Screening identified 3 additional patients colonized by P. jirovecii. All patients were cured, and no further cases were identified after trimethoprim-sulfamethoxazole prophylaxis was introduced in the entire cohort. Genotyping demonstrated the same strain in all PCP cases and colonized patients. All cases were linked with possible transmission chains from 2 possible index patients. Interhuman transmission was significantly associated with more frequent visits in the outpatient clinic. Six cases were receiving atovaquone as a prophylaxis. The occurrence of PCP was significantly associated with atovaquone prophylaxis. Conclusions: This is the first outbreak with detailed molecular analysis in HTR so far. Genotyping and transmission chain confirmed interhuman transmission in all colonized/infected PCP cases. Outpatient clinic layout and high encounters probably caused this PCP cluster, which was controlled after systematic trimethoprim-sulfamethoxazole prophylaxis in exposed patients.

Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis jirovecii.

Objectives: Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients. In volunteers, there was wide inter-individual variability in atovaquone bioavailability. The aim of this study was to assess the plasma concentrations of atovaquone in immunocompromised patients under PCP prophylaxis. Methods: Adult haematology or HIV-positive patients receiving atovaquone (750 mg oral suspension twice a day) for PCP prophylaxis were included. Plasma concentrations were assessed using UV-HPLC, around 12 h after the evening dose (Cmin) and 1-5 h after the morning dose (Cmax). Results: A total of 82 measurements were performed in 33 patients. This included 19 HSCT recipients, 7 haematology non-transplant patients and 7 HIV-positive patients. The median Cmin (IQR) was 11.3 µg/mL (6.2-27.8) and the median Cmax was 13.4 µg/mL (6.0-28.3). The Cmin and Cmax of atovaquone were not different between HIV-negative and HIV-positive patients, or between HSCT and non-HSCT patients. Atovaquone concentrations were not influenced by the co-administration of valaciclovir (n = 20) or ciclosporin (n = 11), by gut graft-versus-host disease (n = 7) or by the intake of atovaquone with food. Nineteen of the 33 (58%) patients had Cmin <15 µg/mL, a threshold associated with a low rate of clinical response in PCP treatment. Conclusions: Atovaquone is poorly absorbed in more than half of immunocompromised patients and its bioavailability varies between individuals. These unpredictable variations raise the question of therapeutic drug monitoring, in order to identify patients with low concentrations and those who could benefit from regimen adaptation or from alternatives.

Staphylococcus aureus osteo-articular infection: usefulness of the determination of daptomycin serum concentration to explain a treatment failure.

We report two cases of treatment failure in patients with osteoarticular infection associated with Staphylococcus aureus bacteremia and receiving daptomycin. Using a published population-pharmacokinetic model and daptomycin blood level in these patients, area under the curve (AUC) was calculated and compared to the pharmacological target. For the first patient, treated with 6 mg/kg every 48 hours due to acute renal failure and then every 24 hours, the AUC was 820 mg×h×L-1, with a minimal concentration of 23.5 mg/L confirming the right dose adjustment and the absence of underdosing. The methicillin-resistant Staphylococcus aureus (MRSA) strain was still susceptible to daptomycin, but it was not sufficient to observe a favorable outcome. For the second patient, treated with 10 mg/kg/d, the steady state residual concentration was 10.4 mg/L, and the calculated AUC value was 550 mg×h×L-1. AUC/MIC values evolved during treatment to be under the cut-off for bactericidal effects (> 800 hours), and the Staphylococcus aureus (SA) strain became daptomycin resistant. This study highlights the inter-individual pharmacokinetic variation leading sometimes to drug underdosing. Drug monitoring should be encouraged in order to avoid treatment failure.

Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens.

AIMS: Significant alterations in the pharmacokinetics (PK) of antimicrobials have been reported in critically ill patients. We describe PK parameters of imipenem in intensive care unit (ICU) patients with suspected ventilator-associated pneumonia and evaluate several dosage regimens. METHODS: This French multicentre, prospective, open-label study was conducted in ICU patients with a presumptive diagnosis of ventilator-associated pneumonia caused by Gram-negative bacilli, who empirically received imipenem intravenously every 8 h. Plasma imipenem concentrations were measured during the fourth imipenem infusion using six samples (trough, 0.5, 1, 2, 5 and 8 h). Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm in Monolix 4.2. A Monte Carlo simulation was performed to evaluate the following six dosage regimens: 500, 750 or 1000 mg with administration every 6 or 8 h. The pharmacodynamic target was defined as the probability of achieving a fractional time above the minimal inhibitory concentration (MIC) of >40%. RESULTS: Fifty-one patients were included in the PK analysis. Imipenem concentration data were best described by a two-compartment model with three covariates (creatinine clearance, total bodyweight and serum albumin). Estimated clearance (between-subject variability) was 13.2 l h(-1) (38%) and estimated central volume 20.4 l (31%). At an MIC of 4 µg ml(-1) , the probability of achieving 40% fractional time > MIC was 91.8% for 0.5 h infusions of 750 mg every 6 h, 86.0% for 1000 mg every 8 h and 96.9% for 1000 mg every 6 h. CONCLUSIONS: This population PK model accurately estimated imipenem concentrations in ICU patients. The simulation showed that for these patients, the best dosage regimen of imipenem is 750 mg every 6 h and not 1000 mg every 8 h.

Oral DAV131, a charcoal-based adsorbent, inhibits intestinal colonization by ß-lactam-resistant Klebsiella pneumoniae in cefotaxime-treated mice.

Antibiotics excreted into the intestinal tract, such as broad-spectrum cephalosporins, disrupt the indigenous microflora, affect colonization resistance (CR), and promote intestinal colonization by resistant bacteria. We tested whether oral DAV131, a charcoal-based adsorbent, would prevent colonization by a cefotaxime (CTX)-resistant Klebsiella pneumoniae strain (PUG-2) in CTX-treated mice. Mice received CTX, saline, CTX and DAV131, or saline and DAV131 for 3 days before oral challenge with 10(6) CFU of PUG-2. The fecal CTX concentrations and counts of PUG-2 were assayed. Fecal CTX disappeared when DAV131 was given concomitantly with CTX (P < 0.05), and the area under the curve of PUG-2 fecal density was significantly reduced (P < 0.01). In conclusion, reducing intestinal antibiotic exposure with DAV131 may reduce colonization by resistant strains during treatment compared to treatment with CTX only. This might open new possibilities for decreasing the impact of antibiotics on the intestinal microbiota during treatments.

Efficacy of ceftazidime-avibactam in various combinations for the treatment of experimental osteomyelitis due to Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae.

BACKGROUND: Optimal treatment of carbapenemase-producing Enterobacterales (CPE) bone infections is poorly defined. This study evaluated the efficacy of the novel beta-lactam-beta-lactamase inhibitor-ceftazidime-avibactam (CAZ-AVI)-with different antibiotic combinations in an experimental model of CPE osteomyelitis. METHODS: KPC-99YC is a clinical strain of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae with intermediate susceptibility to meropenem (MIC 4 mg/L), gentamicin (MIC 0.25 mg/L), colistin (MIC 0.25 mg/L), fosfomycin (MIC 4 mg/L) and ceftazidime-avibactam (MIC 1 mg/L). Time-kill curves were performed at 4x MIC. Osteomyelitis was induced in rabbits by tibial injection of 2×108 CFU of KPC-99YC. Six groups started treatment 14 days later for 7 days: control, colistin, CAZ-AVI, CAZ-AVI plus gentamicin, CAZ-AVI plus colistin and CAZ-AVI plus fosfomycin. Antibiotic dosages were selected to simulate plasma concentrations obtained in humans. Treatment was evaluated according to bone cultures quantified in log10 CFU. RESULTS: In vitro, CAZ-AVI plus colistin or gentamicin were rapidly bactericidal in contrast with CAZ-AVI plus fosfomycin. In vivo, compared with controls, colistin alone (P = 0.045) and CAZ-AVI alone or in combination significantly lowered bone bacterial counts (P < 0.001). Bone sterilisation was achieved in 67% and 100% of animals with combinations of CAZ-AVI plus colistin or gentamicin (P = 0.001 and P < 0.001, respectively) whereas other treatments were no different from controls. CAZ-AVI plus gentamicin provided greater bone bacterial reduction than CAZ-AVI plus colistin (P = 0.033). No CAZ-AVI-resistant strains emerged in treated rabbits, regardless of combination. CONCLUSIONS: CAZ-AVI plus gentamicin was the best effective combination therapy. Combinations with CAZ-AVI appear to be a promising treatment of KPC-producing Klebsiella pneumoniae osteomyelitis.

Cefiderocol Treatment for Severe Infections due to Difficult-to-Treat-Resistant Non-Fermentative Gram-Negative Bacilli in ICU Patients: A Case Series and Narrative Literature Review.

Cefiderocol (FDC) is a siderophore cephalosporin now recognized as a new weapon in the treatment of difficult-to-treat-resistant (DTR) Gram-negative pathogens, including carbapenemase-producing enterobacterales and non-fermentative Gram-negative bacilli (GNB). This article reports our experience with an FDC-based regimen in the treatment of 16 extremely severe patients (invasive mechanical ventilation, 15/16; extracorporeal membrane oxygenation, 9/16; and renal replacement therapy, 8/16) infected with DTR GNB. Our case series provides detailed insight into the pharmacokinetic profile and the microbiological data in real-life conditions. In the narrative review, we discuss the interest of FDC in the treatment of non-fermentative GNB in critically ill patients. We reviewed the microbiological spectrum, resistance mechanisms, pharmacokinetics/pharmacodynamics, efficacy and safety profiles, and real-world evidence for FDC. On the basis of our experience and the available literature, we discuss the optimal FDC-based regimen, FDC dosage, and duration of therapy in critically ill patients with DTR non-fermentative GNB infections.

Cefoxitin as an alternative to carbapenems in a murine model of urinary tract infection due to Escherichia coli harboring CTX-M-15-type extended-spectrum ß-lactamase.

We investigated the efficiency of the cephamycin cefoxitin as an alternative to carbapenems for the treatment of urinary tract infections (UTIs) due to Escherichia coli producing CTX-M-type extended-spectrum ß-lactamases. The susceptible, UTI-inducing E. coli CFT073-RR strain and its transconjugant CFT073-RR Tc (pbla(CTX-M-15)), harboring a bla(CTX-M-15) carrying-plasmid, were used for all experiments. MICs of cefoxitin (FOX), ceftriaxone (CRO), imipenem (IMP), and ertapenem (ETP) for CFT073-RR and CFT073-RR Tc (pbla(CTX-M-15)) were 4 and 4, 0.125 and 512, 0.5 and 0.5, and 0.016 and 0.032 µg/ml, respectively. Bactericidal activity was similarly achieved in vitro against the two strains after 3 h of exposure to concentrations of FOX, IMI, and ETP that were 2 times the MIC, whereas CRO was not bactericidal against CFT073-RR Tc (pbla(CTX-M-15)). The frequencies of spontaneous mutants of the 2 strains were not higher for FOX than for IMP or ETP. In the murine model of UTIs, mice infected for 5 days were treated over 24 h. Therapeutic regimens in mice (200 mg/kg of body weight every 3 h or 4 h for FOX, 70 mg/kg every 6 h for CRO, 100 mg/kg every 2 h for IMP, and 100 mg/kg every 4 h for ETP) were chosen in order to reproduce the percentage of time that free-drug concentrations above the MIC are obtained in humans with standard regimens. All antibiotic regimens produced a significant reduction in bacterial counts (greater than 2 log(10) CFU) in kidneys and bladders for both strains (P < 0.001) without selecting resistant mutants in vivo, but the reduction obtained with CRO against CFT073-RR Tc (pbla(CTX-M-15)) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producing E. coli.