fosfomycin and Critical-Illness

The spread of multidrug-resistant, extensively drug-resistant and pan-drug-resistant pathogens is causing an unprecedented public health crisis. The limited current therapeutic options led to the revival of two 'old' antibiotics - colistin and fosfomycin - for which a better understanding of their pharmacokinetics in the critically ill patient and in specific body compartments is required. Tigecycline's use in clinical practice for nonapproved indication based on its in vitro activity against problematic pathogens requires caution and probably higher doses. Furthermore, all three antibiotics should be used as part of combination regimens in order to prevent resistance and optimize outcomes. The development of new antibacterials in the near future, namely combinations of avibactam, ceftolozane/tazobactam and plazomicin, seems promising; however, they will only partially address current mechanisms of resistance.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Minocycline; Tigecycline

As treatment options for critically ill patients with multidrug-resistant bacteria diminish, older antibiotics such as fosfomycin are being investigated for use as last-resort drugs. Fosfomycin is a broad-spectrum antibiotic with activity both against Gram-positive and Gram-negative bacteria. The aim of this review was to examine the effectiveness of current fosfomycin dosing strategies in critically ill patients. These patients can be subject to pathophysiology that can impact antibiotic pharmacokinetic (PK) profiles and potentially the effectiveness of their treatment. As a hydrophilic drug with negligible protein binding, fosfomycin is eliminated almost entirely by glomerular filtration and is subject to patient renal function. If altered as seen in augmented renal clearance, renal function in a critically ill patient may lead to low blood concentrations and predispose patients to the risk of treatment failure. If altered as seen in acute kidney injury, toxic blood concentrations may develop. Fosfomycin has a volume of distribution comparable with β-lactams and aminoglycosides and may therefore increase in critically ill patients. Altered dosing strategies may be required to optimise dosing given these PK changes, although the current paucity of data on fosfomycin in critically ill patients prevents accurate dosing guidance being recommended at this time.

Topics: Anti-Bacterial Agents; Bacterial Infections; Critical Illness; Fosfomycin; Humans; Treatment Outcome

The alarming epidemic of multidrug-resistant bacteria and the reluctance of the pharmaceutical industry to invest in the development of new antibiotics have forced clinicians to reintroduce forgotten antibiotics into their practice. This review highlights the effectiveness and safety of older antibiotics when used in the treatment of infections of critically ill patients.. Polymyxins emerged as useful antibiotics for the treatment of infections due to multidrug-resistant Gram-negative bacteria, in particular Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. The nephrotoxicity and neurotoxicity associated with their use are less frequent and serious than previously reported. In addition, aerosolized polymyxins may be a useful weapon in the treatment of hospital-acquired pneumonia. Fosfomycin and chloramphenicol have a wide antimicrobial spectrum, are used extensively in Europe and Africa, respectively, and may have an expanded role in our antimicrobial arsenal. Fusidic acid remains active against various staphylococcal strains, while isepamicin (an aminoglycoside used in some European countries) is slightly more effective than amikacin against some Gram-negative bacteria.. The declining investment of the pharmaceutical industry in the development of new antibiotics and the increasing antimicrobial resistance create a fertile ground for the study and, probably, revival of older antibiotics for use, especially in critically ill patients.

Topics: Anti-Bacterial Agents; Chloramphenicol; Critical Illness; Cross Infection; Drug Resistance, Bacterial; Drug Utilization; Fosfomycin; Fusidic Acid; Gentamicins; Humans; Polymyxins

In Europe, intravenous fosfomycin (IV) is used particularly in difficult-to-treat or complex infections, caused by both Gram-positive and Gram-negative pathogens including multidrug-resistant strains. Here, we investigated the efficacy and safety of intravenous fosfomycin under real-life conditions.. Prospective, multi-center, and non-interventional study in patients with bacterial infections from 20 intensive care units (ICU) in Germany and Austria (NCT01173575).. Overall, 209 patients were included (77 females, 132 males, mean age: 59 ± 16 years), 194 of which were treated in intensive care (APACHE II score at the beginning of fosfomycin therapy: 23 ± 8). Main indications (± bacteremia or sepsis) were infections of the CNS (21.5%), community- (CAP) and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP, 15.3%), bone and joint infections (BJI, 11%), abdominal infections (11%), and bacteremia (10.5%). Most frequently identified pathogens were S. aureus (22.3%), S. epidermidis (14.2%), Enterococcus spp. (10.8%), E. coli (12.3%) and Klebsiella spp. (7.7%). At least one multidrug-resistant (MDR) pathogen was isolated from 51 patients (24.4%). Fosfomycin was administered with an average daily dose of 13.7 ± 3.5 g over 12.4 ± 8.6 days, almost exclusively (99%) in combination with other antibiotics. The overall clinical success was favorable in 81.3% (148/182) of cases, and in 84.8% (39/46) of patients with ≥ 1 MDR pathogen. Noteworthy, 16.3% (34/209) of patients developed at least one, in the majority of cases non-serious, adverse drug reaction during fosfomycin therapy.. Our data suggest that IV fosfomycin is an effective and safe combination partner for the treatment of a broad spectrum of severe bacterial infections in critically ill patients.

Topics: Administration, Intravenous; Adult; Aged; Anti-Bacterial Agents; Austria; Bacteremia; Bacterial Infections; Critical Illness; Female; Fosfomycin; Germany; Humans; Intensive Care Units; Male; Middle Aged; Prospective Studies; Sepsis; Treatment Outcome

Intensive care unit (ICU)-acquired infections as a result of multidrug-resistant Gram-negative pathogens remain a serious problem in critically ill patients. Adult ICU patients who received intravenous fosfomycin were prospectively examined to assess its safety and effectiveness as an adjunct to the antimicrobial therapy of life-threatening infections caused by carbapenem-resistant Klebsiella pneumoniae. Fosfomycin was administered intravenously in 11 patients for treatment of hospital-acquired infections caused by carbapenem-resistant K. pneumoniae. Fosfomycin (2-4 g every 6 h) was administered in combination with other antibiotics. The mean +/- SD duration of treatment was 14 +/- 5.6 days. All patients had good bacteriological and clinical outcome of infection. All-cause hospital mortality was two out of 11 (18.2%) patients. No patient experienced adverse events related to the administration of fosfomycin. Intravenous fosfomycin may be a beneficial and safe adjunctive treatment in the management of life-threatening ICU-acquired infections caused by carbapenem-resistant K. pneumoniae.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Critical Illness; Cross Infection; Female; Fosfomycin; Humans; Infusions, Intravenous; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Prospective Studies; Treatment Outcome

The present study was undertaken to investigate the target site penetration properties of fosfomycin, an antibiotic particularly suitable for treatment of soft tissue infections (STIs) in critically ill patients.. The study population included nine patients with sepsis. Penetration of fosfomycin into the interstitial space fluid of skeletal muscle was measured using the microdialysis technique, following a single intravenous administration of 8.0 g of fosfomycin to patients. The median (range) fosfomycin area under the concentration versus time profile for plasma and skeletal muscle were 673 (459-1108) and 477 (226-860) mg x h/L (P < 0.011), respectively. Interstitial maximum concentrations were lower than plasma values (P < 0.029). Median fosfomycin concentrations in the interstitium and plasma exceeded 70 mg/L throughout the observation period of 4 h and covered MICs for Streptococcus pyogenes, Staphylococcus aureus and Pseudomonas aeruginosa. Simulation of bacterial growth inhibition of S. pyogenes, based on tissue concentration data, confirmed the bactericidal properties of fosfomycin described in previous studies.. Fosfomycin concentrations in muscle interstitium and plasma exceeded the MICs for a range of clinically relevant pathogens in critically ill patients. Thus, fosfomycin exhibits a tissue pharmacokinetic profile, which appears to offer an alternative to other broad-spectrum antibiotics in intensive care patients suffering from STI.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Computer Simulation; Critical Illness; Female; Fosfomycin; Half-Life; Humans; Male; Microbial Sensitivity Tests; Microdialysis; Middle Aged; Muscle, Skeletal; Streptococcus pyogenes

Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function.. The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%).. The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Critical Illness; Female; Fosfomycin; Humans; Kidney; Kidney Function Tests; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Tigecycline

To assess fosfomycin (FOS) elimination in patients with sepsis and acute kidney injury (AKI) undergoing slow-extended daily dialysis (SLEDD) with the Genius system in a prospective observational study. After ethics committee approval ten patients with sepsis and AKI stage 3 underwent daily SLEDD sessions of eight hours. FOS was applied i.v. at doses of 3 × 5 g per day. FOS serum levels were measured pre- and post hemofilter before, during, and after SLEDD sessions, and instantaneous clearance was calculated. In five of the patients, we analyzed FOS levels after the first dose, in the other five patients serum levels were measured during ongoing therapy. FOS was eliminated rapidly via the hemofilter. FOS clearance decreased from 152 ± 10 mL/min (start of SLEED session) to 43 ± 38 mL/min (end of SLEDD session). In 3/5 first-dose patients after 4-6 h of SLEDD the FOS serum level fell below the EUCAST breakpoint of 32 mg/L for Enterobacterales and Staphylococcus species. In all patients with ongoing fosfomycin therapy serum levels were high and above the breakpoint at all times. FOS toxicity or adverse effects were not observed. FOS serum concentrations exhibit wide variability in critically ill patients with sepsis and AKI. FOS is eliminated rapidly during SLEDD. A loading dose of 5 g is not sufficient to achieve serum levels above the EUCAST breakpoint for common bacteria in all patients, considering that T > MIC > 70% of the dosing interval indicates sufficient plasma levels. We thus recommend a loading dose of 8 g followed by a maintenance dose of 5 g after a SLEDD session in anuric patients. We strongly recommend therapeutic drug monitoring of FOS levels in critically ill patients with AKI and dialysis therapy.

Topics: Acute Kidney Injury; Aged; Critical Illness; Dose-Response Relationship, Drug; Drug Monitoring; Enterobacter; Female; Fosfomycin; Hemodynamics; Hemofiltration; Humans; Male; Middle Aged; Prospective Studies; Renal Dialysis; Sepsis

Topics: Anti-Bacterial Agents; beta-Lactamases; Blood; Critical Illness; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Urine

The purpose of the study was to determine the optimal dosing regimen of intravenous fosfomycin for the treatment of Pseudomonas aeruginosa (PA) based on PK/PD targets.. A total of 120 PA isolates were recovered from various clinical specimens at university hospital in Thailand. Minimum Inhibitory Concentrations (MICs) of all the isolates were determined by the E-test method. PK parameters were obtained from a published study. Monte Carlo simulation was performed to calculate the percentage of target attainment (PTA) and cumulative fraction of response (CFR).. MIC90 of fosfomycin alone, fosfomycin in combination with carbapenem, carbapenems alone and carbapenems in combination with fosfomycin were >1,024, 1,024, >32 and 32μg/ml, for multidrug resistant (MDR)-PA and 512, 128, 8 and 3μg/ml respectively, for non-MDR PA. Approximately 40% of the non-MDR PA were carbapenem-resistant strains. For non-MDR PA with CRPA, fosfomycin 16g continuous infusion in combination with carbapenems provided %PTA of approximately 80 and %CFR of > 88. While, %PTA and %CFR > 90 were achieved with fosfomycin 24g/day prolonged infusion in combination with carbapenem.. Prolonged infusion of fosfomycin 16 - 24g combined with extended carbapenem infusion could be used in non-MDR PA treatment with CRPA.

Topics: Anti-Bacterial Agents; Carbapenems; Critical Illness; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fosfomycin; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections; Thailand

A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, using hydrophilic interaction liquid chromatography (HILIC) chromatography for the analysis of fosfomycin in human plasma and urine, has been developed and validated. The plasma method uses a simple protein precipitation using a low volume sample (10 μL) and is suitable for the concentration range of 1 to 2000 μg/mL. The urine method involves a simple dilution of 10 μL of sample and is suitable for a concentration range of 0.1 to 10 mg/mL. The plasma and urine results, reported, respectively, are for recovery (68, 72%), inter-assay precision (≤9.1%, ≤8.1%) and accuracy (range -7.2 to 3.3%, -1.9 to 1.6%), LLOQ precision (4.7%, 3.1%) and accuracy (1.7% and 1.2%), and includes investigations into the linearity, stability and matrix effects. The method was used in a pilot pharmacokinetic study of a critically ill patient receiving i.v. fosfomycin, which measured a maximum and minimum plasma concentration of 222 μg/mL and 172 μg/mL, respectively, after the initial dose, and a maximum and minimum plasma concentration of 868 μg/mL and 591μg/mL, respectively, after the fifth dose. The urine concentration was 2.03 mg/mL after the initial dose and 0.29 mg/mL after the fifth dose.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Critical Illness; Drug Administration Schedule; Drug Monitoring; Drug Stability; Fosfomycin; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Injections, Intravenous; Limit of Detection; Molecular Structure; Pilot Projects; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry

This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CLCR) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (Vc) described the data adequately. Calculated CLCR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, Vc of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

Topics: Aged; Anti-Bacterial Agents; APACHE; Biological Availability; Critical Illness; Drug Administration Schedule; Female; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Greece; Humans; Intensive Care Units; Male; Middle Aged; Models, Statistical; Multiple Organ Failure; Opportunistic Infections

Fosfomycin is active in vitro against extensively drug-resistant (XDR) and pandrug-resistant (PDR) Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase-producing strains; however, the in vivo effectiveness against such pathogens is almost unknown. A multicentre, observational, prospective case-series study was performed in 11 ICUs. All consecutive fosfomycin-treated patients suffering from XDR or PDR fosfomycin-susceptible, microbiologically documented infections were recorded. Clinical and microbiological outcomes were assessed. A safety analysis was performed. In total, 68 patients received fosfomycin during the study period, 48 of whom were considered suitable for effectiveness analysis based on predefined criteria. Bacteraemia and ventilator-associated pneumonia were the main infections. Carbapenemase-producing K. pneumoniae and P. aeruginosa were isolated in 41 and 17 cases, respectively. All isolates exhibited an XDR or PDR profile, being fosfomycin-susceptible by definition. Fosfomycin was administered intravenously at a median dose of 24g/day for a median of 14 days, mainly in combination with colistin or tigecycline. Clinical outcome at Day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively. All-cause mortality at Day 28 was 37.5%. Bacterial eradication was observed in 56.3% of cases. Fosfomycin resistance developed in three cases. The main adverse event was reversible hypokalaemia. In conclusion, fosfomycin could have a place in the armamentarium against XDR and PDR Gram-negative infections in the critically ill. Resistance development during therapy, which has been a matter of concern in previous studies, did not occur frequently. The necessity of combination with other antibiotics requires further investigation.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tigecycline; Treatment Outcome