fosfomycin and Cystic-Fibrosis

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

Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF).. To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted.. This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI).. A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values.. FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Cough; Cystic Fibrosis; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Fosfomycin; Humans; Male; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Tobramycin; Treatment Outcome; United States

Pseudomonas aeruginosa is the most frequent infectious agent in cystic fibrosis patients. P. aeruginosa resistance to first line antibiotics limits therapeutic options, but the therapeutic potential of older generation antibiotics, such as fosfomycin is under investigation. Fosfomycin does not belong to any other antibiotic class and acts by inhibiting the biosynthesis of the bacterial cell wall during the initial phases. A major problem for the use of fosfomycin against P. aeruginosa is the absence of a clinical breakpoint, the last one of 32 μg/mL was proposed in 2013 by the CA-SFM (Comité de l'Antibiogramme de la Société Française de Microbiologie).. Sixty-one strains of P. aeruginosa (thirty mucoid and thirty-one non mucoid) were collected from respiratory samples of cystic fibrosis patients. All isolates were identified by MALDI-TOF (Bruker, Bremen, Germany). Fosfomycin MICs against P. aeruginosa were measured using an automated system and confirmed by the gold standard method.. There was no significant difference between mucoid and non-mucoid strains. MIC distribution and susceptibility rates were obtained by agar dilution method and from this data we measured MIC50 and MIC90 which were equal to 32 μg/mL and 64 μg/mL, respectively. From automated method results we measured a very major error (VME), major error (ME) and categorical agreement (CA) which were equal to 0%, 11% and 89%, respectively. Comparing automated and agar dilution methods, a Cohen's kappa equal to 73% (0.726) was measured.. Our data suggest that fosfomycin has good effect against mucoid and non-mucoid strains of P. aeruginosa and automated systems can be implemented in clinical microbiology laboratories to assess fosfomycin with rapid and reproducible results.

Topics: Automation, Laboratory; Cystic Fibrosis; Fosfomycin; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

The increased prevalence of multi-drug resistant strains of P.aeruginosa and allergic reactions among adult patients with cystic fibrosis (CF) limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases.. To describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF.. A retrospective analysis of data captured prospectively, over a 2-years period, on the Unit electronic medical records for patients who received IV fosfomycin was performed. Baseline characteristics in the 12 months prior treatment, lung function, CRP, renal and liver function and electrolytes at start and end of treatment were retrieved.. 54 patients received 128 courses of IV fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effect (48%), but was well controlled with anti-emetics.. Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.

Topics: Administration, Intravenous; Adult; Anti-Bacterial Agents; C-Reactive Protein; Creatinine; Cystic Fibrosis; Drug Therapy, Combination; Female; Follow-Up Studies; Fosfomycin; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Urea

In cystic fibrosis, chronic airways infection caused by Pseudomonas aeruginosa can be treated with inhaled antibiotics such as inhaled tobramycin, aztreonam or colistin. However, biofilm formation induced by this bacterium can reduce the effectiveness of such therapies and can contribute to antibiotic resistance. Inhaled antibiotic combination might represent an optimal antibiofilm strategy in this setting. This review discusses the rationale for combining the antibiotics as well as some emerging or existing combinations. Most of the combinations except for fosfomycin/tobramycin are at an early stage of development. The latter combination was found to be effective in Phase II clinical studies and is planned to be tested in Phase III trials. The clinical data on long-term efficacy are currently missing, but the existing evidence as well as the unmet therapeutic need can prompt the further evaluation of such compounds.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Clinical Trials as Topic; Cystic Fibrosis; Drug Combinations; Fosfomycin; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Tobramycin; Treatment Outcome

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patients in the United States is approximately 25%. Little is known about the relative proportion of hospital- versus community-associated strains or the antimicrobial susceptibility of MRSA in different CF centers. We hypothesized that the majority of MRSA isolates obtained from children with CF are those endemic in the hospital and that those associated with community acquisition (SCCmec IV) would be more resistant than typically seen in non-CF MRSA isolates.. We studied MRSA strains from seven pediatric CF centers to determine the clonal distribution based on DNA sequencing of the staphylococcal protein A gene (spa typing), the type of staphylococcal chromosomal cassette mec (SCCmec), and the proportion of strains with Panton-Valentine leukocidin (PVL). Antimicrobial susceptibility to systemic and topical antibiotics was compared between different MRSA types.. We analyzed 277 MRSA isolates from unique patients (mean age 11.15 ± 4.77 years, 55% male). Seventy % of isolates were SCCmec II PVL negative and the remainder SCCmec IV. Overall 17% MRSA strains were PVL positive (all SCCmec IV). Spa typing of 118 isolates showed most of the SCCmec II strains being t002, while SCCmec IV PVL positive isolates were t008, and SCCmec IV PVL negative isolates represented a variety of spa-types. The proportions of SCCmec II strains and spa-types were similar among centers. Overall rates of resistance to trimethoprim-sulfamethoxazole (4%), tetracycline (7%), tigecycline (0.4%), linezolid (0.4%) as well as fosfomycin (0.4%), fusidic acid (3%), and mupirocin (1%) were low. No strains were resistant to vancomycin. SCCmec II strains had higher rates of resistance to ciprofloxacin and clindamycin (P < 0.001) than SCCmec IV strains.. In this U.S. study, most MRSA isolates in the pediatric CF population were SCCmec II PVL negative. Rates of resistance were low, including to older and orally available antibiotics such as trimethoprim-sulfamethoxazole.

Topics: Acetamides; Adolescent; Anti-Bacterial Agents; Bacterial Proteins; Bacterial Toxins; Bronchoscopy; Child; Child, Preschool; Cohort Studies; Cystic Fibrosis; DNA, Bacterial; Exotoxins; Female; Fosfomycin; Fusidic Acid; Humans; Leukocidins; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Minocycline; Molecular Typing; Mupirocin; Oxazolidinones; Penicillin-Binding Proteins; Pharynx; Pneumonia, Staphylococcal; Sequence Analysis, DNA; Sputum; Staphylococcal Infections; Staphylococcal Protein A; Tetracycline; Tigecycline; Trimethoprim, Sulfamethoxazole Drug Combination; United States

Although antibiotics from different classes are frequently prescribed in combination to prevent the development of resistance amongst Cystic Fibrosis (CF) respiratory pathogens, there is a lack of data as to the efficacy of this approach. We have previously shown that a 4:1 (w/w) combination of fosfomycin and tobramycin (F:T) has excellent activity against CF pathogens with increased activity under physiologically relevant anaerobic conditions. Therefore, the aim of this study was to determine whether F:T could delay or prevent the onset of resistance compared to either fosfomycin or tobramycin alone under aerobic and anaerobic conditions. The frequency of spontaneous mutants arising following exposure to fosfomycin, tobramycin and F:T was determined for clinical Pseudomonas aeruginosa and MRSA isolates under aerobic and anaerobic conditions. The effect of sub-inhibitory concentrations of fosfomycin, tobramycin and F:T on the induction of resistance was also investigated, with the stability of resistance and fitness cost associated with resistance assessed if it developed. P. aeruginosa and MRSA isolates had a lower frequency of spontaneous mutants to F:T compared to fosfomycin and tobramycin under both aerobic and anaerobic conditions. There was a maximum two-fold increase in F:T MICs when P. aeruginosa and MRSA isolates were passaged in sub-inhibitory F:T for 12 days. In contrast, sequential resistance to fosfomycin and tobramycin developed quickly (n = 3 days for both) after passage in sub-inhibitory concentrations. Once developed, both fosfomycin and tobramycin resistance was stable and not associated with a biological fitness cost to either P. aeruginosa or MRSA isolates. The results of this study suggest that F:T may prevent the development of resistance compared to fosfomycin or tobramycin alone under aerobic and physiologically relevant anaerobic conditions. F:T may be a potential treatment option in CF patients chronically colonised by MRSA and/or P. aeruginosa.

Topics: Adult; Aerobiosis; Anaerobiosis; Anti-Bacterial Agents; Culture Media; Cystic Fibrosis; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mutation Rate; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Tobramycin

The activity of aminoglycosides, which are used to treat Pseudomonas aeruginosa respiratory infection in cystic fibrosis (CF) patients, is reduced under the anaerobic conditions that reflect the CF lung in vivo. In contrast, a 4:1 (wt/wt) combination of fosfomycin and tobramycin (F:T), which is under investigation for use in the treatment of CF lung infection, has increased activity against P. aeruginosa under anaerobic conditions. The aim of this study was to elucidate the mechanisms underlying the increased activity of F:T under anaerobic conditions. Microarray analysis was used to identify the transcriptional basis of increased F:T activity under anaerobic conditions, and key findings were confirmed by microbiological tests, including nitrate utilization assays, growth curves, and susceptibility testing. Notably, growth in subinhibitory concentrations of F:T, but not tobramycin or fosfomycin alone, significantly downregulated (P < 0.05) nitrate reductase genes narG and narH, which are essential for normal anaerobic growth of P. aeruginosa. Under anaerobic conditions, F:T significantly decreased (P < 0.001) nitrate utilization in P. aeruginosa strains PAO1, PA14, and PA14 lasR::Gm, a mutant known to exhibit increased nitrate utilization. A similar effect was observed with two clinical P. aeruginosa isolates. Growth curves indicate that nitrate reductase transposon mutants had reduced growth under anaerobic conditions, with these mutants also having increased susceptibility to F:T compared to the wild type under similar conditions. The results of this study suggest that downregulation of nitrate reductase genes resulting in reduced nitrate utilization is the mechanism underlying the increased activity of F:T under anaerobic conditions.

Topics: Anaerobiosis; Anti-Bacterial Agents; Bacterial Proteins; Cystic Fibrosis; Drug Combinations; Fosfomycin; Gene Expression Regulation, Bacterial; Humans; Isoenzymes; Lung; Microbial Sensitivity Tests; Nitrate Reductase; Nitrates; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Transcription, Genetic

There is a need for new antibiotics or combination of antibiotics that possess activity against increasingly resistant cystic fibrosis (CF) respiratory pathogens such as Pseudomonas aeruginosa and MRSA.. The antimicrobial activity of a novel 4:1 (w/w) fosfomycin:tobramycin (F:T) combination against CF respiratory pathogens under both aerobic and anaerobic conditions was determined by MIC, time-kill and biofilm studies, and compared with activity of fosfomycin and tobramycin, individually.. F:T and fosfomycin had excellent activity against P. aeruginosa and were more active than tobramycin against P. aeruginosa under anaerobic conditions with lower MIC(50), MIC(90) and geometric mean values. F:T (p<0.001) and fosfomycin (p<0.001) MICs for P. aeruginosa were significantly lower under anaerobic conditions with tobramycin MICs significantly higher (p<0.001). F:T and fosfomycin also had high activity against MRSA with both being more active than tobramycin. In time-kill studies, F:T was rapidly bactericidal against all 15 P. aeruginosa and 3/5 MRSA isolates tested. F:T also demonstrated bactericidal activity against P. aeruginosa grown in biofilm under both aerobic and anaerobic conditions.. F:T has promising in vitro antimicrobial activity against MRSA and P. aeruginosa with greater activity under anaerobic conditions similar to those found in the CF lung.

Topics: Anti-Bacterial Agents; Biofilms; Colony Count, Microbial; Cystic Fibrosis; Drug Combinations; Fosfomycin; Humans; Lung; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Tobramycin

Thymidine-dependent small-colony variants (TD-SCVs) of Staphylococcus aureus can be isolated from the airway secretions of patients suffering from cystic fibrosis (CF) and are implicated in persistent and treatment-resistant infections. These characteristics, as well as the variety of mutations in the thymidylate synthase-encoding thyA gene which are responsible for thymidine dependency, suggest that these morphological variants are hypermutable. To prove this hypothesis, we analyzed the mutator phenotype of different S. aureus phenotypes, in particular CF-derived TD-SCVs, CF-derived isolates with a normal phenotype (NCVs), and non-CF NCVs. The comparative analysis revealed that the CF isolates had significantly higher mutation rates than the non-CF isolates. The TD-SCVs, in turn, harbored significantly more strong hypermutators (mutation rate > or = 10(-7)) than the CF and non-CF NCVs. In addition, antimicrobial resistance to non-beta-lactam antibiotics, including gentamicin, ciprofloxacin, erythromycin, fosfomycin, and rifampin, was significantly more prevalent in TD-SCVs than in CF and non-CF NCVs. Interestingly, macrolide resistance, which is usually mediated by mobile genetic elements, was conferred in half of the macrolide-resistant TD-SCVs by the point mutation A2058G or A2058T in the genes encoding the 23S rRNA. Sequence analysis of mutS and mutL, which are involved in DNA mismatch repair in gram-positive bacteria, revealed that in hypermutable CF isolates and especially in TD-SCVs, mutL was often truncated due to frameshift mutations. In conclusion, these data provide direct evidence that TD-SCVs are hypermutators. This hypermutability apparently favors the acquisition of antibiotic resistance and facilitates bacterial adaptation during long-term persistence.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Phenotype; Sequence Analysis, DNA; Staphylococcal Infections; Staphylococcus aureus; Thymidine

Topics: Adult; Anti-Bacterial Agents; Cystic Fibrosis; Female; Fosfomycin; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Treatment Outcome; Young Adult

Patients with cystic fibrosis can develop multi-resistant organisms and may have poor intravenous access making antibiotic treatment difficult. This case discusses the successful use of fosfomycin via the subcutaneous route in a paediatric patient with cystic fibrosis.

Topics: Adolescent; Anti-Bacterial Agents; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Female; Fosfomycin; Humans; Injections, Subcutaneous; Pseudomonas Infections; Staphylococcal Infections

Increasing resistance to standard antibiotics has been demonstrated in CF patients colonised by Pseudomonas aeruginosa. The antibiotic Fosfomycin has a unique mode of action against this organism, and may protect against aminoglycoside mediated renal and ototoxic effects. However, there is little published experience of this drug in IV form, and it is not licensed for use in the UK.. In combination with other antibiotics, we used Fosfomycin to treat 30 pulmonary exacerbations in 15 adult CF patients colonised by P. aeruginosa, mainly multiresistant strains. All patients gave informed consent. We cultured sputum prior to treatment and measured spirometry, renal function, and symptoms before and after treatment, and recorded any side effects.. One patient developed nausea and Fosfomycin treatment was withdrawn. The remaining patients showed clinical resolution of their chest exacerbations (mean FEV1% predicted: pre 41.1 vs. post 49.4, P<0.001). Although there was a statistical increase in plasma urea (pre 3.9 mmol/l vs. post 4.3, P<0.03), this was still within the normal range. Plasma creatinine was unchanged.. This study shows that IV Fosfomycin is well tolerated by adult patients with CF and can be useful in the treatment of those colonised with multiresistant P. aeruginosa.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Creatinine; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Fosfomycin; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum

We report a very unusual adverse effect--fosfomycin-induced repeat liver toxicity--in a female adult with cystic fibrosis (CF).

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Cystic Fibrosis; Female; Fosfomycin; Hepatomegaly; Humans; Liver; Liver Diseases; Recurrence

Pseudomonas aeruginosa remains the most common respiratory pathogen causing morbidity and mortality in cystic fibrosis (CF) patients. The in-vitro activity of ciprofloxacin and fosfomycin (calcium and tromethamine salts) in combination against P. aeruginosa isolates from CF patients, all of whom had received previous courses of ciprofloxacin, was evaluated by agar plate dilution chequerboard technique. The concentrations of drugs used were those that would be achieved in patients by oral and intravenous (fosfomycin only) routes. Synergy, taking into account fosfomycin concentrations achievable intravenously, was found against 60% of P. aeruginosa isolates. With concentrations achieved after an oral dose, 17% of isolates were synergistically inhibited. Time-kill experiments confirmed these findings. Ciprofloxacin MICs against resistant P. aeruginosa were reduced to achievable sputum and serum levels in the presence of fosfomycin. However, in progressive resistance studies fosfomycin failed to delay the development of resistance to ciprofloxacin. The combinations of ofloxacin/fosfomycin and ciprofloxacin/fosmidomycin were also tested, but showed minimal synergy. No antagonism was observed with any combination. Fosfomycin, ciprofloxacin and azlocillin in triple combination did not show synergy. The antimicrobial combinations tested against P. cepacia isolates from CF patients were indifferent. The combination of ciprofloxacin and fosfomycin may be clinically useful in selected P. aeruginosa pulmonary exacerbations in cystic fibrosis patients, particularly as an oral out-of-hospital treatment alternative or in cases where MICs for ciprofloxacin are elevated.

Topics: Ciprofloxacin; Cystic Fibrosis; Drug Synergism; Fosfomycin; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Cystic Fibrosis; Female; Fosfomycin; Humans; Male; Pseudomonas Infections