fosfomycin and Pneumonia--Ventilator-Associated

We sought to evaluate published evidence regarding clinical or microbiological outcomes related to the use of inhaled antibiotics other than aminoglycosides, polymyxins and aztreonam. A systematic search of PubMed and Scopus databases as well as bibliographies of eligible articles was performed. In total, 34 eligible studies were identified. Among several inhaled β-lactams, ceftazidime was used with varying success in the prevention and treatment of ventilator-associated pneumonia (VAP) and improved clinical outcomes in chronic Pseudomonas aeruginosa lower respiratory tract infections (LRTIs) in patients with cystic fibrosis (CF) or bronchiectasis. Inhaled vancomycin, as an adjunctive therapy, was effective in treating Gram-positive VAP, whilst inhaled levofloxacin, ciprofloxacin and an inhaled combination of fosfomycin and tobramycin were associated with improved microbiological or clinical outcomes in chronic LRTI in patients with CF or bronchiectasis. In conclusion, published evidence is heterogeneous with regard to antibiotics used, studied indications, patient populations and study designs. Therefore, although the currently available data are encouraging, no safe conclusion regarding the effectiveness and safety of the drugs in question can be reached.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Bacterial Infections; beta-Lactams; Bronchiectasis; Cystic Fibrosis; Fosfomycin; Humans; Pneumonia, Ventilator-Associated; Quinolones; Respiratory Tract Infections; Treatment Outcome

Although investigations are limited, adjunctive aerosolized antibiotics have been advised in the setting of gram-negative ventilator-associated pneumonia (VAP). This study aimed to compare the efficiency of inhaled colistin with inhaled fosfomycin/tobramycin in treating VAP due to extensively drug-resistant (XDR) Acinetobacter baumannii.. This single center open-label randomized controlled trial included 60 patients who developed XDR A. bumannii VAP. Eligible participants were randomly assigned to two groups (no. 30). Regardless of the assignment, all participants received meropenem (2 g as a 3-h extended infusion every 8 h) plus intravenous colistin (a loading dose of 9 million IU and then 4.5 million IU every 12 h). The control group was given inhaled colistin (1 million IU every 8 h), and the case group received inhaled tobramycin/fosfomycin (300 mg every 12 h/80 mg every 12 h) as adjunctive therapy. The primary outcome was treatment duration, and the secondary outcomes were Clinical Pulmonary Infection Score (CPIS) trend and mortality rate in the groups. The decision to stop treatment was made by the treating physician.. The mean treatment duration was 13.73 ± 3.22 days in the colistin group and 10.85 ± 2.84 days in the tobramycin/fosfomycin group; the mean treatment duration in the latter group was lower significantly (P = 0.001). CPIS was decreased in the groups significantly (P < 0.001), but the mean changes of CPIS were significantly different between the groups, and in the inhaled tobramycin/fosfomycin group, a greater reduction (P = 0.005) was observed. Two (6.67%) patients in the control group and three (10%) patients in the case group died.. The use of inhaled tobramycin/fosfomycin in cases with XDR A. bumannii VAP was associated with a shorter treatment duration in this open-label trial.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Colistin; Fosfomycin; Humans; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Tobramycin; Treatment Outcome

Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization.. We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if < 10 days) via the investigational eFlow Inline System (PARI GmbH). The primary efficacy end point was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with gram-negative bacteria.. There were 143 patients randomized: 71 to the AFIS group, and 72 to the placebo group. Comparison of CPIS change from baseline between treatment groups was not different (P = .70). The secondary hierarchical end point of no mortality and clinical cure at day 14 or earlier was also not significant (P = .68) nor was the hierarchical end point of no mortality and ventilator-free days (P = .06). The number of deaths in the AFIS group was 17 (24%) and 12 (17%) in the placebo group (P = .32). The AFIS group had significantly fewer positive tracheal cultures on days 3 and 7 than placebo.. In this trial of adjunctive aerosol therapy compared with standard of care IV antibiotics in patients with gram-negative VAP, the AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden.. ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Adult; Aged; Amikacin; Anti-Bacterial Agents; APACHE; Chemotherapy, Adjuvant; Double-Blind Method; Female; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia, Ventilator-Associated; Treatment Outcome

This clinical trial evaluated the pharmacokinetics and safety/tolerability of amikacin/fosfomycin solution using a vibrating plate nebulizer, in mechanically ventilated patients with ventilator-associated tracheobronchitis (VAT) or ventilator-associated pneumonia (VAP).. Nine adult patients were consented to receive three escalating doses of a combination of 50 mg/mL amikacin and 20 mg/mL fosfomycin; doses were separated by 24±2 hr. On day 3, patients received two blinded, randomized treatments (amikacin/fosfomycin and volume-matched placebo), separated by 2 hr. All treatments were administered with a single-patient, multitreatment nebulizer (Investigational eFlow(®) Inline Nebulizer System; PARI Pharma GmbH, positioned in the inspiratory limb tubing between the ventilator and the patient. The nebulizer remained in-line until all treatments had been delivered. Concentrations of amikacin and fosfomycin were measured in tracheal aspirate and plasma samples obtained during the 24 hr after each dose.. Fifteen minutes after dosing with the 300/120 mg amikacin/fosfomycin combination, tracheal aspirate amikacin concentrations±SD were 12,390±3,986 μg/g, and fosfomycin concentrations were 6,174±2,548 μg/g (n=6). Airway clearance was rapid. Plasma concentrations were subtherapeutic; the highest observed amikacin plasma concentration was 1.4 μg/mL, and the highest observed fosfomycin plasma concentration was 0.8 μg/mL. Administration time was approximately 2 min/mL. No adverse effects on respiratory rate, peak airway pressures, or oxygenation were observed during or following drug or placebo administration.. High tracheal aspirate concentrations of amikacin and fosfomycin were achieved in mechanically ventilated patients with VAT or VAP after aerosolized administration with an inline nebulizer system. Airway clearance was rapid. No adverse respiratory effects were noted during or following drug administration.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Aged, 80 and over; Amikacin; Anti-Bacterial Agents; Bronchitis; Double-Blind Method; Drug Combinations; Drug Monitoring; Equipment Design; Fosfomycin; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Ventilator-Associated; Respiration, Artificial; Tracheitis; Victoria

Ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) in patients hospitalized in intensive care units (ICUs) is an important and challenging complication, including in patients with coronavirus disease 2019 (COVID-19). Considering the poor lung penetration of most antibiotics, including intravenous colistin due to the poor pharmacokinetics/pharmacodynamics at the infection site, the choice of the best antibiotic regimen is still being debated.. This single-centre, observational study was conducted from March 2020 to August 2022, and included all patients hospitalized consecutively with VAP and concomitant bloodstream infection due to CRAB in the COVID-ICU. The main goal of the study was to evaluate risk factors associated with survival or death at 30 days from VAP onset. A propensity score for receiving therapy was added to the model.. During the study period, 73 patients who developed VAP and concomitant positive blood cultures caused by CRAB were enrolled in the COVID-ICU. Of these patients, 67 (91.7%) developed septic shock, 42 (57.5%) had died at 14 days and 59 (80.8%) had died at 30 days. Overall, 54 (74%) patients were treated with a colistin-containing regimen and 19 (26%) were treated with a cefiderocol-containing regimen. Cox regression analysis showed that chronic obstructive pulmonary disease and age were independently associated with 30-day mortality. Conversely, cefiderocol-containing regimens and cefiderocol + fosfomycin in combination were independently associated with 30-day survival, as confirmed by propensity score analysis.. This real-life study in patients with bacteraemic VAP caused by CRAB provides useful suggestions for clinicians, showing a possible benefit of cefiderocol and its association with fosfomycin.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacteremia; Carbapenems; Cefiderocol; Colistin; COVID-19; Fosfomycin; Humans; Pneumonia, Ventilator-Associated

The aim of this study was to evaluate the combination treatments with intravenous fosfomycin for carbapenem-resistant Klebsiella pneumoniae infections in a tertiary-care center.. Between December 24, 2018 and November 21, 2022, adult patients diagnosed with bloodstream infection or ventilator-associated pneumonia due to culture-confirmed carbapenem-resistant Klebsiella pneumoniae in the anesthesiology and reanimation intensive care units were investigated retrospectively.. There were a total of 62 patients fulfilling the study inclusion criteria. No significant difference was recorded in 14- and 30-day mortality among different types of combination regimens such as fosfomycin plus one or two antibiotic combinations. Hypokalemia (OR:5.651, 95%CI 1.019-31.330, p=0.048) was found to be a significant risk factor for 14-day mortality, whereas SOFA score at the time of diagnosis (OR:1.497, 95%CI 1.103-2.032, p=0.010) and CVVHF treatment (OR:6.409, 95%CI 1.395-29.433, p=0.017) were associated with 30-day mortality in multivariate analysis.. In our study, high mortality rates were found in patients with bloodstream infection or ventilator-associated pneumonia due to carbapenem-resistant Klebsiella pneumoniae, and no significant difference was recorded in 14- and 30-day mortality among different types of combination regimens such as fosfomycin plus one or two antibiotic combinations.

Topics: Adult; Anti-Bacterial Agents; Carbapenems; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Pneumonia, Ventilator-Associated; Retrospective Studies; Sepsis

In vitro and clinical studies using parenteral fosfomycin have suggested the possibility of using this drug against infections caused by MDR microorganisms. The aim of this study was to describe a case series of patients treated with fosfomycin who had severe infections caused by pan-drug-resistant Gram-negative bacteria.. We describe a prospective series of cases of hospitalized patients with infections caused by Gram-negative bacteria resistant to β-lactams and colistin, treated with 16 g of fosfomycin daily for 10-14 days. Isolates were tested for antimicrobial susceptibility and synergism of fosfomycin with meropenem. We tested for resistance genes and performed typing using PCR and WGS.. Thirteen patients received fosfomycin (seven immunosuppressed); they had bloodstream infections (n = 11; 85%), ventilator-associated pneumonia (n = 1; 8%) and surgical site infection (n = 1; 8%), caused by Klebsiella pneumoniae (n = 9), Serratia marcescens (n = 3) and Pseudomonas aeruginosa (n = 1). Overall, eight (62%) patients were cured. Using time-kill assays, synergism between fosfomycin and meropenem occurred in 9 (82%) of 11 isolates. Typing demonstrated that K. pneumoniae were polyclonal. Eight patients (62%) had possible adverse events, but therapy was not discontinued.. Fosfomycin may be safe and effective against infections caused by pan-drug-resistant Gram-negative microorganisms with different antimicrobial resistance mechanisms and there seems to be synergism with meropenem.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Drug Synergism; Drug-Related Side Effects and Adverse Reactions; Female; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Middle Aged; Pneumonia, Ventilator-Associated; Sepsis; Surgical Wound Infection; Young Adult

Topics: Amikacin; Anti-Bacterial Agents; Fosfomycin; Humans; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Amikacin; Anti-Bacterial Agents; Fosfomycin; Humans; Pneumonia, Ventilator-Associated; Ventilators, Mechanical

The amikacin-fosfomycin inhalation system (AFIS), a combination of antibiotics administered with an in-line nebulizer delivery system, is being developed for adjunctive treatment of ventilator-associated pneumonia (VAP). The in vitro characterization of amikacin-fosfomycin (at a 5:2 ratio) described here included determining resistance selection rates for pathogens that are representative of those commonly associated with VAP (including multidrug-resistant strains) and evaluating interactions with antibiotics commonly used intravenously to treat VAP. Spontaneous resistance to amikacin-fosfomycin (5:2) was not observed for most strains tested (n, 10/14). Four strains had spontaneously resistant colonies (frequencies, 4.25 × 10(-8) to 3.47 × 10(-10)), for which amikacin-fosfomycin (5:2) MICs were 2- to 8-fold higher than those for the original strains. After 7 days of serial passage, resistance (>4-fold increase over the baseline MIC) occurred in fewer strains (n, 4/14) passaged in the presence of amikacin-fosfomycin (5:2) than with either amikacin (n, 7/14) or fosfomycin (n, 12/14) alone. Interactions between amikacin-fosfomycin (5:2) and 10 comparator antibiotics in checkerboard testing against 30 different Gram-positive or Gram-negative bacterial strains were synergistic (fractional inhibitory concentration [FIC] index, ≤ 0.5) for 6.7% (n, 10/150) of combinations tested. No antagonism was observed. Synergy was confirmed by time-kill methodology for amikacin-fosfomycin (5:2) plus cefepime (against Escherichia coli), aztreonam (against Pseudomonas aeruginosa), daptomycin (against Enterococcus faecalis), and azithromycin (against Staphylococcus aureus). Amikacin-fosfomycin (5:2) was bactericidal at 4-fold the MIC for 7 strains tested. The reduced incidence of development of resistance to amikacin-fosfomycin (5:2) compared with that for amikacin or fosfomycin alone, and the lack of negative interactions with commonly used intravenous antibiotics, further supports the development of AFIS for the treatment of VAP.

Topics: Amikacin; Anti-Bacterial Agents; Bacteria; DNA Mutational Analysis; Drug Combinations; Drug Interactions; Drug Resistance, Bacterial; Drug Synergism; Fosfomycin; Humans; Kinetics; Microbial Sensitivity Tests; Mutation; Pneumonia, Ventilator-Associated

Topics: Carbapenems; Colistin; Cross Infection; Doripenem; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Retrospective Studies; Time Factors