Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation.

BACKGROUND: 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. RESULTS: 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%). CONCLUSIONS: 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.

Pharmacodynamic Analysis of Meropenem and Fosfomycin Combination Against Carbapenem-Resistant Acinetobacter baumannii in Patients with Normal Renal Clearance: Can It Be a Treatment Option?

Background and Objective: Combination therapy may be a treatment option against carbapenem-resistant Acinetobacter baumannii (CR-AB) infections. In this study, we explored the utility of fosfomycin in combination with meropenem (FOS/MEM) against CR-AB isolates. Materials and Methods: Screening of synergistic activity of FOS/MEM was performed using the checkerboard assay. A pharmacokinetic/pharmacodynamic analysis was performed for various FOS/MEM regimens using Monte Carlo simulations. Results: The minimum inhibitory concentration (MIC) required to inhibit the growth of 50% of the isolates (MIC50) and MIC required to inhibit the growth of 90% of the isolates (MIC90) of FOS and MEM were reduced fourfold and twofold, respectively. The combination was synergistic against 14/50 isolates. No antagonism was observed. Sixteen out of fifty isolates had MEM MICs of ≤8 mg/L when subjected to combination therapy, compared to none with monotherapy. Forty-one out of 50 isolates had FOS MICs of ≤128 mg/L when subjected to combination therapy, compared to 17/50 isolates with monotherapy. The cumulative fraction response for MEM and FOS improved from 0% to 40% and 40% to 80%, with combination therapy, respectively. Conclusions: Addition of MEM improved the in vitro activity of FOS against the CR-AB isolates. FOS/MEM could be a plausible option to treat CR-AB for a small fraction of isolates.

Evaluation of pooled human urine and synthetic alternatives in a dynamic bladder infection in vitro model simulating oral fosfomycin therapy.

The impact of the bladder environment on fosfomycin activity and treatment response is uncertain. Standard laboratory media does not reflect the biomatrix of urine, where limited nutritional factors are important for growth and antimicrobial kill rates. We compared fosfomycin activity against Enterobacteriaceae in laboratory media, human urine and synthetic alternatives. Sixteen clinical isolates (8-Escherichia coli, 4-Enterobacter cloacae, 4-Klebsiella pneumoniae) were studied with broth microdilution (BMD) susceptibility, static time-kill assays and dynamic testing in a bladder infection model simulating a 3 g oral fosfomycin dose. Mueller-Hinton broth (MHB) with and without 25 mg/L glucose-6-phosphate (G6P), pooled midstream urine (MSU), pooled 24 h urine collection (24 U), artificial urine medium (AUM) and synthetic human urine (SHU) were compared. BMD susceptibility, bacterial growth and response to static fosfomycin concentrations in urine were best matched with SHU and were distinctly different when tested in MHB with G6P. Fosfomycin exposure in the bladder infection model was accurately reproduced (bias 4.7 ± 6.2%). Under all media conditions, 8 isolates (2-E. coli, 2-E. cloacae, 4-K. pneumoniae) re-grew and 4 isolates (4-E. coli) were killed. The remaining isolates (2-E. coli, 2-E. cloacae) re-grew variably in urine and synthetic media. Agar dilution MIC failed to predict re-growth, whereas BMD MIC in media without G6P performed better. Emergence of resistance was restricted in synthetic media. Overall, SHU provided the best substitute for urine for in vitro modelling of antimicrobial treatment of uropathogens, and these data have broader utility for improved preclinical testing of antimicrobials for urinary tract infections.

Relative potency of different generic brands of meropenem, colistin and fosfomycin: Implications for antimicrobial therapy and antimicrobial formulary.

There is a need of a relatively simple and inexpensive method for the determination of relative potency of various generic brands of antibiotics in comparison to original products. The current study describes an agar diffusion method which can be performed in any microbiology laboratory, is cheap (costs $2 per test) and its results can be available after overnight incubation. The results show that neither all generics are reliable nor are all generic antibiotics of poor quality.

Intravenous fosfomycin for the treatment of multidrug-resistant pathogens: what is the evidence on dosing regimens?

INTRODUCTION: The intravenous (IV) formulation of fosfomycin has been re-introduced in clinical practice mainly to overcome treatment failures against multidrug-resistant (MDR) bacteria. Appropriate dosing schedules of the IV formulation have not yet been established. Areas covered: The mechanism of action and resistance development, commercial IV formulations, pharmacokinetic/pharmacodynamic (PK/PD) properties, IV dosing regimens for the treatment of MDR infections along with efficacy and safety issues were reviewed. Data regarding specific MDR pathogens, daily doses and patients' outcomes, gaps in the current literature, and in progress research agenda are presented. Expert opinion: The doses of fosfomycin IV range between 12 and 24 grams/day depending on the severity of infection. The efficacy and safety of the commonly administered doses have been shown mainly in observational non-comparative trials. The optimal dose ensuring maximal efficacy with minimal toxicity along with the most appropriate co-administered antibiotic(s) need further evaluation. The pharmacokinetic/pharmacodynamic parameter associated with maximum efficacy has not yet been established, although, the ratio of the area under the concentration-time curve (AUC) for the free unbound fraction of fosfomycin versus the MIC (fAUC/MIC) may be linked to optimal treatment. RCTs and other comparative studies are underway to address gaps of knowledge in adult patients and neonates.

Pharmacokinetics and Pharmacodynamics of Fosfomycin and Its Activity against Extended-Spectrum-ß-Lactamase-, Plasmid-Mediated AmpC-, and Carbapenemase-Producing Escherichia coli in a Murine Urinary Tract Infection Model.

Fosfomycin has become an attractive treatment alternative for urinary tract infections (UTIs) due to increasing multidrug resistance (MDR) in Escherichia coli In this study, we evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) indices of fosfomycin and its in vivo activity in an experimental murine model of ascending UTI. Subcutaneous administration of fosfomycin showed that the mean peak plasma concentrations of fosfomycin were 36, 280, and 750 mg/liter following administration of a single dose of 0.75, 7.5, and 30 mg/mouse, respectively, with an elimination half-life of 28 min, and urine peak concentrations of 1,100, 33,400, and 70,000 mg/liter expected to be sustained above 1 mg/liter (MIC of the test strain, NU14) for 5, 8, and 9.5 h, respectively. The optimal PK/PD indices for reducing urine colony counts (number of CFU per milliliter) were determined to be the area under the concentration-time curve/MIC from 0 to 72 h and the maximum concentration/MIC on the basis of the dose-dependent bloodstream PK and the results of an evaluation of six dosing regimens. With a dosing regimen of 15 mg/mouse twice (every 36 h), fosfomycin significantly reduced the number of CFU per milliliter of all susceptible strains in urine, including clinical MDR strains, except for one clinical strain (P = 0.062). Variable degrees of reduction were observed in the bladder and kidneys. No significant reductions in the number of CFU per milliliter were observed with the resistant strains. In conclusion, fosfomycin shows concentration-dependent in vivo activity, and the results suggest that fosfomycin is an effective alternative to carbapenems in treating MDR E. coli in uncomplicated UTIs. The data on the effectiveness of fosfomycin against the MDR isolates along with the results of PK/PD modeling should facilitate the further development of improved recommendations for its clinical use.

Fosfomycin residues in colostrum: Impact on morpho-physiology and microbiology of suckling piglets.

Fosfomycin is a broad-spectrum bactericidal antibiotic widely used in pig farms for the treatment of a wide variety of bacterial infections. In this study, the elimination of disodium fosfomycin in colostrum/milk of the sow and the impact of this antibiotic on the microbiota and intestinal morpho-physiology of suckling piglets were analyzed. The average amount of fosfomycin eliminated in colostrum (after administration of 15 mg/kg IM) during the first 10 hr postpartum was 0.85 µg/ml, and the mean residual amount ingested by the piglets was 0.26 mg/kg. The elimination profile of fosfomycin concentrations in colostrum occurs at a time of profound changes in the morpho-physiology of the gastrointestinal tract of the piglet. However, the studied concentrations did not produce imbalances on the microbiota or on the morpho-physiology of the gastrointestinal tract of the piglet. Concentrations of fosfomycin were maintained in the mammary gland above the MIC for more than 8 hr for pathogenic bacteria of productive importance. This would indicate that fosfomycin may be considered safe for the specific treatment of bacterial infectious processes in sows during the peri- and postpartum period. This first study with disodium fosfomycin stimulates awareness in the proper use of antimicrobials at farrowing.

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrum-beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC0-∞) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R2 = 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli, K., pneumoniae and P. aeruginosa, respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.

Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy.

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 108 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 108 to 109 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.

Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation.

OBJECTIVE: 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. METHOD: 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). RESULTS: 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. CONCLUSIONS: Prolonged infusion of fosfomycin 16 - 24g combined with extended carbapenem infusion could be used in non-MDR PA treatment with CRPA.

Strategies for the treatment of polymyxin B-resistant Acinetobacter baumannii infections.

In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category using CLSI interpretive criteria. Pharmacodynamic evaluation found that for a FOF minimum inhibitory concentration (MIC) of ≤16µg/mL, treatment both by bolus dosing and prolonged infusion achieved adequate PTA, whilst for MIC=32µg/mL only infusion achieved adequate PTA. For a MEM MIC of 4µg/mL, only the bolus treatment scheme with 1.5g q6h and the infusion schemes with 1.0g q8h, 1.5g q6h and 2.0g q8h achieved PTA ≥0.9. Results of antimicrobial and pharmacodynamic analyses can assist in treating infections caused by multidrug-resistant A. baumannii. However, in vivo clinical studies are essential to evaluate the true role of these compounds, including intravenous antimicrobial FOF therapy.

Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance.

The aim of this study was to improve the understanding of the pharmacokinetic-pharmacodynamic relationships of fosfomycin against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli strains that have different fosfomycin MICs. Our methods included the use of a hollow fiber infection model with three clinical ESBL-producing E. coli strains. Human fosfomycin pharmacokinetic profiles were simulated over 4 days. Preliminary studies conducted to determine the dose ranges, including the dose ranges that suppressed the development of drug-resistant mutants, were conducted with regimens from 12 g/day to 36 g/day. The combination of fosfomycin at 4 g every 8 h (q8h) and meropenem at 1 g/q8h was selected for further assessment. The total bacterial population and the resistant subpopulations were determined. No efficacy was observed against the Ec42444 strain (fosfomycin MIC, 64 mg/liter) at doses of 12, 24, or 36 g/day. All dosages induced at least initial bacterial killing against Ec46 (fosfomycin MIC, 1 mg/liter). High-level drug-resistant mutants appeared in this strain in response to 12, 15, and 18 g/day. In the study arms that included 24 g/day, once or in a divided dose, a complete extinction of the bacterial inoculum was observed. The combination of meropenem with fosfomycin was synergistic for bacterial killing and also suppressed all fosfomycin-resistant clones of Ec2974 (fosfomycin MIC, 1 mg/liter). We conclude that fosfomycin susceptibility breakpoints (≤64 mg/liter according to CLSI [for E. coli urinary tract infections only]) should be revised for the treatment of serious systemic infections. Fosfomycin can be used to treat infections caused by organisms that demonstrate lower MICs and lower bacterial densities, although relatively high daily dosages (i.e., 24 g/day) are required to prevent the emergence of bacterial resistance. The ratio of the area under the concentration-time curve for the free, unbound fraction of fosfomycin versus the MIC (fAUC/MIC) appears to be the dynamically linked index of suppression of bacterial resistance. Fosfomycin with meropenem can act synergistically against E. coli strains in preventing the emergence of fosfomycin resistance.

Fosfomycin-daptomycin and other fosfomycin combinations as alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.

The efficacy of daptomycin, imipenem, or rifampin with fosfomycin was evaluated and compared with that of daptomycin-rifampin in a tissue cage model infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Strain HUSA 304 was used. The study yielded the following results for MICs (in µg/ml): fosfomycin, 4; daptomycin, 1; imipenem, 0.25; and rifampin, 0.03. The study yielded the following results for minimum bactericidal concentration (MBC) (in µg/ml): fosfomycin, 8; daptomycin, 4; imipenem, 32; and rifampin, 0.5. Daptomycin-rifampin was confirmed as the most effective therapy against MRSA foreign-body infections. Fosfomycin combinations with high doses of daptomycin and rifampin were efficacious alternative therapies in this setting. Fosfomycin-imipenem was relatively ineffective and did not protect against resistance.

Resistencia antimicrobiana en aislados clínicos de Pseudomonas aeruginosa / Antimicrobial resistance in clinical patterns of Pseudomonas aeruginosa

Pseudomonas aeruginosa es un microorganismo oportunista frecuentemente implicado en infecciones de origen nosocomial que presenta resistencia natural y adquirida a muchos de los antimicrobianos de uso clínico. Se llevo a cabo un estudio de resistencias a antimicrobianos de 3.029 aislamientos de P. aeruginosa de enfermos intra y extrahospitalarios en el periodo 2005-2010. La metodología utilizada fue, el método semiautomatizado WIDER I (Soria Melguizo), para la identificación de las especies y para el estudio de sensibilidades a antimicrobianos. Se consideraron los criterios de sensibilidad y resistencia recomendados por el grupo MENSURA. En nuestro hospital existe un mantenimiento relativo de la sensibilidad antimicrobiana de P. aeruginosa en el periodo 2005-2010, con un aumento de esta en amikacina, gentamicina y cefalosporinas. Existen diferencias de porcentajes de sensibilidades entre las cepas de origen intrahospitalario y extrahospitalario, salvo para fosfomicina y tobramicina. Destacamos la importancia de realizar estudios locales de la sensibilidad y resistencias de P. aeruginosa en cada zona, de forma periódica para poder valorar las diferentes pautas terapéuticas, no siendo posible extrapolar los datos de las diferentes regiones españolas(AU)

Pseudomonas aeruginosa is an opportunistic microorganism that is frequently the cause of nosocomial infections. Multiple mechanisms are involved in its natural and acquired resistance to many of the antimicrobial agents commonly used in clinical practice. We performed an antibiotic resistance study on P. aeruginosa isolated from intrahospitalary and extrahospitalary samples between 2005 and 2010 years. We included in the study a global amount of 3,029 P. aeruginosa isolates from clinical samples received at University Hospital Reina Sofia. Microbiology Service in Córdoba (Spain). Semiautomatic system WIDER I for strains identification and sensibility testing was employed. We considered susceptibility and resistance criteria recommended by MENSURA group. Results of the analysis showed that P. aeruginosa maintanied similar levels of antimicrobial susceptibility during the period 2005-2010, with increased susceptibility to amikacin, gentamicin and cefalosporins. There were also important differences in the degree of susceptibility between intrahospital and extrahospital strains during 2010 year, except for tobramicin and fosfomycin. The intrahospital difference in susceptibility was also evaluated, emphasizing the importance of periodically surveillance of susceptibility and resistance patterns of P. aeruginosa, in each setting in order to evaluate different therapeutic guidelines, because it is not always advisable to extrapolate data from different regions(AU)

Etiología y sensibilidad de los uropatógenos identificados en infecciones urinarias bajas no complicadas de la mujer (Estudio ARESC): implicaciones en la terapia empírica / Etiology and sensitivity of uropathogens identified in uncomplicated lower urinary tract infections in women (ARESC Study): implications on empiric therapy

Pacientes y método: Estudio multicéntrico ARESC de 9 hospitales españoles, que incluyó de forma consecutiva 803 mujeres, de edades entre 18 y 65 años, con cistitis no complicada, con el fin de identificar la etiología y evaluar su sensibilidad a 9 antimicrobianos. Resultados: De 803 pacientes consecutivas con ITU baja no complicada, fueron finalmente incluidas 784 pacientes. El urocultivo fue positivo en el 87,7% de las muestras. De un total de 650 uropatógenos, Escherichia coli (E. coli) fue el más frecuente (79,2%), seguido por Staphylococcus saprophyticus (4,4%), Proteus mirabilis (4,3%), Enterococcus faecalis (3,2%) y Klebsiella pneumoniae (2,3%). E. coli mostró una elevada sensibilidad a fosfomicina (97,2%), nitrofurantoína (94,1%) y algo menor a ciprofloxacino (88,1%). Las tasas de resistencia a fluorquinolonas fueron más elevadas en mujeres postmenopáusicas (17 frente a 10%). E. coli sigue presentando unas elevadas resistencias a ampicilina (65%) y a cotrimoxazol (34%), y en la actualidad, aproximadamente un 25% de las cepas son resistentes a amoxicilina/clavulánico y cefuroxima. Conclusiones: En España se observan elevados índices de resistencia de E. coli a antibióticos de amplio uso. Fosfomicina y nitrofurantoína preservan una elevada actividad in vitro. Considerando otros aspectos prácticos, como la posología (una sola dosis) y la influencia del consumo total de quinolonas sobre los niveles de resistencia en enterobacterias y en otros microorganismos, fosfomicina trometamol representa una alternativa empírica de primera elección para la cistitis no complicada de la mujer (AU)

Background and objective: To determine the etiology and susceptibility of uropathogens identified in women with uncomplicated lower urinary tract infections (UTI). Patients and methods: In a multicenter study (ARESC) in 9 Spanish hospitals, 803 female patients with uncomplicated cystitis were consecutively enrolled and evaluated to identify the uropathogens and their susceptibility to 9 antimicrobials.Results: Of 803 patients with uncomplicated cystitis, 784 patients were included. A positive urine culture was found in 87.7% of the samples. Of the 650 pathogens isolated, Escherichia coli (E. coli) was the most frequent (79.2%) followed by Staphylococcus saprophyticus (4.4%), Proteus mirabilis (4.3%), Enterococcus faecalis (3.2%) and Klebsiella pneumoniae (2.3%). E. coli showed a high rate of susceptibility to phosphomycin (97.2%), nitrofurantoin (94.1%) and somewhat lower to ciprofloxacin (88.1%). Fluorquinolone resistance rates were higher among postmenopausal women (17 versus 10%). E. coli was highly resistant to ampicillin (65%) and cotrimoxazole (34%) and 25% of the strains were resistant to amoxicillin/clavulanalic acid and cefuroxime. Conclusions: In Spain, E. coli shows high resistance rates to widely used antimicrobial antibiotics. Phosphomycin and nitrofurantoin have a high in vitro activity. Taking into account practical aspects such as convenience (only one dose), and the influence of the amount of fluorquinolone use on enterobacteriaceae and other microorganisms resistance levels, phosphomycin trometamol represents the option of first choice for the empirical treatment of uncomplicated cystitis in women (AU)

Pharmacokinetics of disodium fosfomycin in broilers and dose strategies to comply with its pharmacodynamics versus Escherichia coli.

The objective of this study was to determine, in broilers, which modality of disodium fosfomycin (DF) administration and at what dose the best pharmacokinetic (PK) profile could be obtained, taking as reference a 110 field bacterial strains of Escherichia coli minimum inhibitory concentration survey. The DF was administered via drinking water either ad libitum or at a higher concentration having 1 h of water restriction to build up thirst in the birds (loading dose). Dosages tested were 10, 20, 40, and 80 mg/kg per administration, either once or twice daily. Birds included were 24-d-old Cornish broilers randomly assigned to 16 groups of 200 birds per group and 3 replicates per group. The PK of DF was determined after ad libitum administration of either a single- or double-loading dose or after an initial loading dose followed by ad libitum medication. Also, PK after i.v. administration was studied in separate groups. Serial blood samplings were performed in all groups. Serum obtained was analyzed for DF and a possible active metabolite by means of a microbiological agar diffusion assay. The DF showed a short elimination half-life (approximately 2 h after oral loading administration) with a rapid clearance (1.23 to 1.42 mL/kg per h). Apparent volume of distribution-area under the curve values were also low (10 and 80 mg/kg=0.25 L/kg and 0.22 L/kg, respectively). Considering a minimum inhibitory concentration level that inhibited 90% of total strains of 8 µg/mL for E. coli, it is concluded that single-loading administration at 10, 20, 40, and 80 mg/kg complies poorly with sustained serum concentrations over a dosing interval of 24 h. Doses of 10 and 20 mg/kg twice a day also were insufficient to attain therapeutic concentrations. Useful serum concentrations of DF to treat outbreaks of susceptible E. coli require an initial loading dose of 40 mg/kg, followed by an ad libitum medication of 40 mg/kg 8 h later (80 mg/kg per d).

Fosfomicina trometamol. Dosis múltiples como pauta larga en el tratamiento de las infecciones urinarias bajas / Fosfomycin trometamol: Multiple-dose regimen for the treatment of lower urinary tract infections

Introducción. El tratamiento de las infecciones urinarias del tracto inferior no complicadas se realiza con pautas de tratamiento cortas. En otras circunstancias no está tan clara la pauta que hay que seguir. Cuando la infección urinaria del tracto inferior no se produce en una mujer joven, la recomendación terapéutica es la utilización de antibióticos durante al menos 7 días, y son las quinolonas y el cotrimoxazol los antibióticos utilizados con mayor frecuencia. Pero debido al porcentaje de resistencias de los microorganismos implicados en este tipo de infecciones, es aconsejable evaluar otras pautas de tratamiento, de forma que habría que evaluar, entre otros, el uso de antibióticos con un menor índice de resistencias como fosfomicina trometamol, en períodos de tratamiento más largos que el uso tan extendido en dosis única. Métodos. Desde los datos de eliminación urinaria de fosfomicina obtenidos en voluntarios sanos en un estudio previo, se han simulado las concentraciones de este antibiótico en orina tras la administración de 2 dosis. Se ha calculado el intervalo más idóneo para mantener concentraciones urinarias por encima del punto de corte de Escherichia coli para fosfomicina (16 mg/l), uno de los microorganismos implicados con mayor frecuencia en este tipo de infecciones. Resultados. Las concentraciones de fosfomicina en orina se mantienen por encima del punto de corte durante 161 h cuando se administran 2 dosis de 3 g de fosfomicina trometamol separadas 72 h. Éste supone un tiempo de eficacia del 96% en un período total de 7 días. Conclusión. La pauta teórica, desde el punto de vista farmacocinético, para conseguir concentraciones de fosfomicina en orina por encima del punto de corte de E. coli es la administración de 2 dosis de 3 g de fosfomicina trometamol separadas 72 h (AU)

Introduction. A short antibiotic regimen is recommended for the treatment of uncomplicated lower urinary tract infection. Nevertheless, the treatment to follow in other situations is not so clearly defined. When the person affected by lower urinary tract infection is not a young woman, it is recommended to treat at least 7 days, and quinolones or cotrimoxazole are the antibiotics most often used. However, because of the frequency of drug resistance in this type if infection, it is advisable to apply antibiotics with lower rates of resistance, such as fosfomycin trometamol, for longer treatment periods than the often-used single dose. Methods. Using the data on urinary elimination of fosfomycin after a single dose obtained in a prior study in healthy volunteers, we simulated the urinary concentrations of this antibiotic following administration of two doses. In addition, we calculated the interval of administration required to achieve urinary concentrations greater than 16 mg/L, the critical concentration of sensitivity for Escherichia coli, one of the most commonly implicated microorganisms in these infections. Results. Fosfomycin concentrations in urine persisted above the defined cut-off for 161 hours after administration of two 3-g doses of fosfomycin trometamol, 72 hours apart. This implied an efficacy time of 66% in a period of 7 days. Conclusion. From the pharmacokinetic viewpoint, the optimum dosage of fosfomycin trometamol to achieve appropriate urinary concentrations along 7 days is administration of two 3-g doses, 72 hours apart (AU)

Fosmidomycin for the treatment of malaria.

In malaria parasites, isoprenoids are synthesised by the mevalonate independent 1-deoxy- D-xylulose 5-phosphate (DOXP) pathway. Fosmidomycin, a natural antibiotic originally developed for the treatment of bacterial infections, represents an inhibitor of DOXP reductoisomerase, an essential enzyme of this pathway. In recent clinical studies it was shown that fosmidomycin is effective in curing uncomplicated Plasmodium falciparum malaria in humans. The treatment was well tolerated and resulted in a fast parasite and fever clearance. However, the high rate of recrudescence precludes the use of fosmidomycin as a monotherapy. In drug combination studies, synergy of fosmidomycin with clindamycin was observed. Clinical studies with a fosmidomycin-clindamycin combination are currently ongoing.

In vivo activity and pharmacodynamics of cefotaxime or ceftriaxone in combination with fosfomycin in fibrin clots infected with highly penicillin-resistant Streptococcus pneumoniae.

Using a clinical pneumococcal strain for which MICs were 2, 0.5, 0.5, and 16 mg/liter for penicillin, cefotaxime, ceftriaxone, and fosfomycin, respectively, we studied the efficacies of these antibiotics alone and in combination in one or two doses or in continuous infusion over 6 h in the treatment of the prolonged (48-h) experimental fibrin clot infections in rabbits. Doses were chosen to obtain low antibiotic concentrations. We observed the highest bacterial reductions (change in log10 CFU per gram) with the following five regimens: combination of cefotaxime plus fosfomycin given in two divided doses 6 h apart (each at 50 mg/kg of body weight given intravenously (4.2 +/- 0.7 CFU/g), ceftriaxone (8 mg/kg given once intravenously) along with one or two doses of fosfomycin (3.79 +/- 0.6 and 3.95 +/- 0.5 CFU/g), cefotaxime alone administered in two divided doses (3.6 +/- 0.4 CFU/g), and a 6-h continuous infusion of cefotaxime (100 mg/kg) with fosfomycin (100 mg/kg) (3.5 +/- 0.4 CFU/g). The bacterial reductions obtained with these five regimens were all higher than those obtained with the other regimens tested (P < 0.05). The time of bacterial regrowth was significantly delayed with the two doses of the cefotaxime-fosfomycin regimens (23.2 +/- 11 h) compared with those with the other combinations (P < 0.05). The rate of bacterial regrowth with this regimen was even lower than that observed with cefotaxime alone given in two doses (P < 0.05). By a multivariate analysis, the most important independent parameters for efficacy were the maximal concentrations of beta-lactam antibiotics and the residual concentration of fosfomycin and, for the combinations, the log of the area under the concentration-time curve/MIC ratio for beta-lactam antibiotics. From these findings, the combinations cefotaxime or ceftriaxone plus fosfomycin could be proposed for the treatment of infections caused by highly penicillin-resistant pneumococci.