Fosfomycin Research Articles

Pharmacokinetics and bioavailability of calcium fosfomycin in post weaning piglets after oral administration

Fil: Perez, Denisa Soledad. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Tandil. Centro de Investigacion Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigacion Veterinaria de Tandil. Provincia de Buenos Aires. Gobernacion. Comision de Investigaciones Cientificas. Centro de Investigacion Veterinaria de Tandil; Argentina

Plasmid-Mediated Resistance in Enterobacteriaceae

Antimicrobial resistance is increasing worldwide, and pathogenic microorganisms that are resistant to all available antimicrobial agents are increasingly reported. Emerging plasmid-encoded extended-spectrum β-lactamases (ESBLs) and carbapenemases are increasingly reported worldwide. Carbapenemase production encoded by genes located on mobile genetic elements is typically accompanied by genes encoding resistance to other drug classes, often but not necessarily located on the same mobile element. Multiple plasmid-mediated mechanisms of resistance against the fluoroquinolones and aminoglycosides have been described, and the combination of plasmid-mediated resistance with chromosomally encoded resistance mechanisms of multiple drug classes now results in strains that are resistant to all of the main classes of commonly used antimicrobial drugs. Clinical studies of antimicrobial therapy and outcome of patients infected with ESBL- or carbapenemase-producing strains of Enterobacteriaceae compared with patients infected with susceptible strains are limited in their design but suggest a worse outcome after infection with resistant strains. Alternative options for the treatment of infections caused by carbapenem-resistant strains of Enterobacteriaceae are limited. Current strategies include colistin, fosfomycin, tigecycline and temocillin. Although in vitro testing suggests strong activity for each of these drugs against a large proportion of carbapenem-resistant strains of Enterobacteriaceae, clinical evaluations do not provide strong evidence for equivalent or improved outcome. Oral treatment with fosfomycin tromethamine is effective against lower urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli. Intravenous fosfomycin may be beneficial and safe for patients when used as part of a combination therapy in the management of severe infections caused by carbapenem-resistant Klebsiella pneumoniae. Tigecycline is only indicated for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections in Europe, and is also approved for treatment of community-acquired pneumonia in the US. Clearly, further research on the clinical and safety outcomes in the treatment of multidrug-resistant Enterobacteriaceae with these existing alternative drugs, and the development of new and unrelated drugs, are urgently warranted.

Serotype, Shiga Toxin (Stx) Type, and Antimicrobial Resistance of Stx-Producing Escherichia coli Isolated from Humans in Shizuoka Prefecture, Japan (2003^|^ndash;2007)

The serotype, Shiga toxin (Stx) type, and antimicrobial resistance patterns of 138 Stx-producing Escherichia coli (STEC) strains isolated from humans between 2003 and 2007 in Shizuoka Prefecture, Japan were characterized. The predominant O serogroups of the STEC isolates were O157, O26, and O111. Antimicrobial susceptibility testing of the STEC isolates showed that 31 of the 138 isolates (22.5%) were resistant to antibiotics. Compared to the results reported in the previous studies, a higher rate of STEC O157 isolates were susceptible to all the antimicrobial agents used in this study. However, antimicrobial susceptibility data from this study showed that antimicrobial resistance patterns have increased by 6 compared to the survey performed by Masuda et al. between 1987 and 2002 (Jpn. J. Food Microbiol., 21, 44-51, 2004). This indicates that STEC isolates have evolved to show a variety of antimicrobial resistance patterns. It is important to consider the population of isolates showing decreased susceptibility to clinically relevant drugs such as ciprofloxacin (CPFX) and fosfomycin (FOM). All the 3 STEC isolates resistant to nalidixic acid showed low susceptibility to CPFX (MIC, 0.25-0.5 μg/ml). In addition, a decreased susceptibility to FOM was clearly observed in the E. coli O26 isolates. Our findings also showed that 1 STEC O26 strain could possibly be a chromosomal AmpC β-lactamase hyperproducer. These results suggest that antimicrobial therapy may be less effective in patients with non-O157 STEC infections than in those with STEC O157 infections.

Influence of Fosfomycin to Aminoglycoside Induced Ototoxicity

Influence of Fosfomycin to Aminoglycoside Induced Ototoxicity

Lower respiratory tract of pneumoconiosis on fosfomycin antibacterial activity in vitro of fosfomycin to infected in coal worker pneumoconiosis in vitro antibacterial activity

目的 观察磷霉素对煤工尘肺下呼吸道感染耐亚胺培南鲍曼不动杆菌(IRAB)的体外抗菌活性.方法 分离住院治疗的23例煤工尘肺并发下呼吸道感染患者痰液标本中的IRAB,采用K-B纸片扩散法对IRAB进行药敏试验,观察磷霉素等16种抗生素的敏感性,同时对比IRAB与亚胺培南敏感的鲍曼不动杆菌(ISAB)的耐药性.结果 磷霉素对IRAB的敏感性最强,达78.3%,IRAB表现出较强的多重耐药性,对头孢曲松等8种药物完全耐药,除了哌拉西林、磷霉素外,IRAB的耐药性多强于ISAB.结论 磷霉素对IRAB具有良好的抗菌活性,可以使用磷霉素治疗煤工尘肺IRAB性下呼吸道感染。

Fosfomycin in vitro resistance of Escherichia coli from the community

Fosfomycin in vitro resistance of Escherichia coli from the community

Antibiotic time-lag combination therapy with fosfomycin for postoperative intra-abdominal abscesses

The first-line treatment for intra-abdominal abscess is source control. Sometimes, however, source control is too invasive for relatively small abscesses and is not feasible due to the risk of injury to some organs. Based on reports that fosfomycin (FOM) can break up biofilms to enhance the permeability of other antibiotics, we investigated the FOM time-lag combination therapy (FOM-TLCT). We enrolled 114 patients who had intra-abdominal abscess after gastrointestinal surgery and examined the efficacy of FOM-TLCT using the same therapeutic antibiotic (TA) as that which had been used previously, but had proven ineffective, at the same dose schedule. The efficacy endpoint determination was carried out as follows: among the systemic inflammatory response syndrome (SIRS)-positive cases, even after administration of TA, excellent outcome was defined as SIRS negative within 7 days of FOM-TLCT with TA without the need for other treatment, including other antibiotics or drainage. Of the 114 patients enrolled, 104 cases (SIRS positive 73; SIRS negative 31) were assessed. Ten patients were excluded; four had received TA at higher doses, three had received different TAs, and three were considered to have bacteria resistant to TAs. Among these patients, 86.3% (63/73) of the SIRS-positive cases were classified as excellent, and 90.3% (28/31) of the SIRS-negative cases were classified as effective. In total, the efficacy rate was 87.5% (91/104). The total no-response rates were 12.5% (13/104). FOM-TLCT seems to be effective for treating refractory intra-abdominal abscess.

Protective effect of Lactobacillus casei strain Shirota against lethal infection with multi-drug resistant Salmonella enterica serovar Typhimurium DT104 in mice

The anti-infectious activity of lactobacilli against multi-drug resistant Salmonella enterica serovar Typhimurium DT104 (DT104) was examined in a murine model of an opportunistic antibiotic-induced infection. Explosive intestinal growth and subsequent lethal extra-intestinal translocation after oral infection with DT104 during fosfomycin (FOM) administration was significantly inhibited by continuous oral administration of Lactobacillus casei strain Shirota (LcS), which is naturally resistant to FOM, at a dose of 10(8) colony-forming units per mouse daily to mice. Comparison of the anti-Salmonella activity of several Lactobacillus type strains with natural resistance to FOM revealed that Lactobacillus brevis ATCC 14869(T) , Lactobacillus plantarum ATCC 14917(T) , Lactobacillus reuteri JCM 1112(T) , Lactobacillus rhamnosus ATCC 7469(T) and Lactobacillus salivarius ATCC 11741(T) conferred no activity even when they obtained the high population levels almost similar to those of the effective strains such as LcS, Lact. casei ATCC 334(T) and Lactobacillus zeae ATCC 15820(T) . The increase in concentration of organic acids and maintenance of the lower pH in the intestine because of Lactobacillus colonization were correlated with the anti-infectious activity. Moreover, heat-killed LcS was not protective against the infection, suggesting that the metabolic activity of lactobacilli is important for the anti-infectious activity. These results suggest that certain lactobacilli in combination with antibiotics may be useful for prophylaxis against opportunistic intestinal infections by multi-drug resistant pathogens, such as DT104. Antibiotics such as FOM disrupt the metabolic activity of the intestinal microbiota that produce organic acids, and that only probiotic strains that are metabolically active in vivo should be selected to prevent intestinal infection when used clinically in combination with certain antibiotics.

Biliary bacteriology and drug resistance in patients with biliary tract infection in Jinshan area

Objective To investigate the distribution of biliary bacteriology and their sensitivity to antibiotics in patients with biliary tract infection in Jinshan area in recent 3 years.Methods Bile specimens collected from 367 patients with cholelithiasis between June 2006 and June 2009 were cultured and tested for drug sensitivity to aerobic bacteria.The results were statistically analyzed.Results One hundred and fifty-six bacterial strains were found in 142 (38.7%) bile specimens including gram negative strains (97,62.2%),gram positive strains (51,32.7% ),and fungal strains (8,5.1%).Enterococcus (17.9%) was major pathogen and follwed by Escherichia coli (12.8%),staphylococcus (11.5%),Klebsiella pneumoniae (8.3%),Pseudomonas aeruginosa (7.7%).Whereas the mixed infection was found in 26 (18.3%) specimens.The positive rate of bacterial infection was 53.1% in patients over 60 years of age (X2=8.36,P 50% ).In gram positive strains,none was resistant to Vancomycin,11.3% to fosfomycin and 11.6% to chloromycetin.They were highly resistant to Penicillins,Ampicillin and Cefazollin (>40%).ConclusionsEnterococcus,Escherichia coli,Sstaphylococcus and Klebsiella pneumoniae are commonly seen pathogens in biliary tract infection in Jinshan area.Use of Sulperazone or TZP plus Amikacin and metronidazole is recommended.Imipenem and Vancomycins may be second choice in treatment of severe biliary infection and refractory infection. Key words: Bacterial infection; Bile; Drug resistance

Comparative in vitro activity of cefditoren and other antimicrobials against Enterobacteriaceae causing community-acquired uncomplicated urinary tract infections in women: a Spanish nationwide multicenter study

Cefditoren is a third-generation orally administered cephalosporin with a broad spectrum of activity against Gram-positive and Gram-negative bacterial species. After an oral 400-mg single dose, the mean concentrations in urine are 186.5 mg/L at 2 to 4 h and 12.7 mg/L at 8 to 12 h, and it is a potential drug to be used in the treatment of urinary tract infection (UTI). We performed a multicenter nationwide study in Spain in order to determine the in vitro activity of cefditoren and other comparative agents against Enterobacteriaceae causing community-acquired uncomplicated UTI in women. From June 2008 to March 2009, 89 institutions participated in the study. A total of 2152 Enterobacteriaceae were collected and sent to a coordinating laboratory where identification and antimicrobial susceptibility testing was performed against 20 antimicrobials using an automated microdilution method (MicroScan; Siemens, Sacramento, CA). Cefditoren MICs were determined by the broth microdilution method (Clinical and Laboratory Standards Institute guidelines) using the same inoculum. Microorganisms isolated were Escherichia coli (81.8%), Klebsiella pneumoniae (7.9%), Proteus mirabilis (5.2%), and others (5.1%). A total of 51 isolates (2.4%) were extended-spectrum β-lactamase (ESBL) producers, 3 (0.1%) produced plasmidic AmpC enzymes, and 64 (2.9%) produced chromosomal AmpC. The MIC 50/MIC 90 (mg/L) of cefditoren against all isolates was 0.12/0.5. Cefditoren inhibited 96.5% of isolates at 1 mg/L and was uniformly active against all isolates with the exception of strains producing ESBLs or AmpC enzymes. The MIC 50/MIC 90 of other antimicrobials were ampicillin (AMP) >16/>16, amoxicillin/clavulanic acid (A/C) ≤8/4/16/8, cefuroxime (FUR) ≤4/8, cefotaxime ≤1/≤1, ciprofloxacin (CIP) ≤0.12/>2, trimethoprim/sulfamethoxazole (SxT) ≤2/38/>4/76, and fosfomycin (FOS) ≤16/≤16. The respective percentages of resistance were 61%, 17.2%, 5.5%, 2.3%, 20.2%, 27.4%, and 4.8%. The activity of cefditoren against Enterobacteriaceae producing community-acquired uncomplicated UTI in women was superior to that of AMP, A/C, FUR, CIP, and SxT and similar to that of FOS.

Fosfomycin: an old, new friend?

Fosfomycin (FOM) is an antibiotic which has varying application indications across the globe. European, Japanese, South African and Brazilian usage practices are much broader, involving multiple formulations of FOM than the currently limited application of FOM in the United States, where uncomplicated urinary tract infection represents the only indication for FOM-tromethamine. Based on early difficulty in determining FOMs genuine in vitro activity, there was initial skepticism about its efficacy and application range. However, in the mid 1970s, correctly executed experiments coupled with an improved understanding of microbiological concepts opened the door for broader use of FOM. During the following 40 years FOM was evaluated in pre-clinical and clinical trials in a wide range of applications and in a multitude of settings. The gathering of pharmacokinetic and pharmacodynamic data was incorporated into large scale studies in which FOM efficacy was further explored and proven. Among European nations, intravenous FOM-disodium for patients presenting with soft tissue infections, sepsis or deep seated infectious processes has become well accepted over the last two decades. The recent emergence of bacterial strains, which impede and encumber pharmacotherapy, namely, MRSA, ESBL and MSSA, lends itself to the idea of reviving long-standing, sensibly used antimicrobial agents like FOM. This review provides a comprehensive conspectus on FOM's history, mode of action, tissue penetration characteristics, resistance, antibacterial activity, combination partners and clinical uses among other facets of interest.

Multidrug-Resistant Gram-Negative Infections

The emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a challenge in the treatment of nosocomial infections. While the pharmaceutical pipeline is waning, two revived old antibacterials (colistin and fosfomycin), a newer one (tigecycline) and an 'improved' member of an existing class (doripenem) are the only therapeutic options left. The class of polymyxins, known since 1947 and represented mostly by polymyxin B and polymyxin E (colistin), has recently gained a principal role in the treatment of the most problematic MDR Gram-negative pathogens (such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Stenotrophomonas maltophilia). Future prospective studies are needed to answer important clinical questions, such as the possible benefit of combination with other antimicrobials versus monotherapy, the efficacy of colistin in neutropenic hosts and the role of inhaled colistin. As new pharmacokinetic data emerge, clarification of the pharmacokinetic/pharmacodynamic (PK/PD) profile of colistin as well as appropriate dosing seems urgent, while development of resistance must be carefully monitored. Fosfomycin tromethamine, a synthetic salt of fosfomycin discovered in 1969, has regained attention because of its in vitro activity against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and MDR P. aeruginosa. Although in use for decades in oral and parenteral formulations for a variety of infections without significant toxicity, its clinical utility in MDR infections remains to be explored in future studies. Tigecycline, the first representative of the new class of glycylcyclines, holds promise in infections from MDR K. pneumoniae (K. pneumoniae carbapenemase [KPC]- and ESBL-producing strains) and Enterobacteriaceae with various mechanisms of resistance. The in vitro activity of tigecycline against A. baumannii makes it a tempting option, as it is currently the most active compound against MDR strains along with colistin. However, the usual minimum inhibitory concentration values of this pathogen are approximately 2 mg/L and compromise clinical outcomes based on PK/PD issues. Its advantageous penetration into various tissues is useful in infections of the skin and soft tissues as well as intra-abdominal infections (official indications), whereas low serum concentrations compromise its use in bloodstream infections. Therefore, prospective studies with dose escalation are urgently needed, as well as clarification of its role in nosocomial pneumonia, after poor results in the study of ventilator-associated pneumonia. Finally, doripenem, the recently licensed member of the carbapenems (without significant spectrum alterations from the ascendant members) seems to possess a lower potential for resistance selection and a more favourable pharmacokinetic profile when given as an extended infusion. The latter strategy could prove helpful in overcoming low level resistance of A. baumannii and P. aeruginosa strains.

Dose Estimation for Renal-excretion Drugs in Neonates and Infants Based on Physiological Development of Renal Function

We established dose estimation formulae for renal-excretion drugs using the glomerular filtration rate (GFR), tubular secretion clearance (Sc), and unbound fraction of drug in plasma (fp) as a renal function index of physiological development in neonates and infants not more than 2 years of age. A dose ratio of (DC/DA)=clearance ratio of (CLC/CLA) congruent with(fpC.GFRC)/(fpA.GFRA) for neonates and infants/adults was applied to drugs with fp.GFR>Sc, while DC/DA=CLC/CLA congruent with(beta.BSAC+fpC.GFRC)/(beta.BSAA+fpA.GFRA) was applied to drugs with Sc>fp.GFR using the coefficient of each drug (beta) and body surface area (BSA). Validity of the estimation formulae was investigated in drugs with fp.GFR>Sc such as vancomycin (VCM), arbekacin (ABK), fosfomycin (FOM) and norfloxacin (NFLX), and in drugs with Sc>fp.GFR such as digoxin (DGX) and amoxicillin (AMPC). First, we compared the clearance ratio (CLC/ CLA) of VCM, ABK, and DGX estimated by our method with those calculated using the Japanese population clearance values and those estimated allometrically (BSAC/BSAA). Next, we compared the established doses of all drugs investigated with the doses for neonates and infants calculated from the conventional dose estimation methods for children and our estimation formulae, and evaluated our method. As a result, favorable consistency was observed in the CL ratio for all drugs, and the doses of VCM, FOM, NFLX and AMPC calculated from our estimation formulae approximated the established doses. In conclusion, the validity of the dose estimation method using pharmacokinetic factors related to physiological development (i.e., GFR, fp, Sc) for renal-excretion drugs in neonates and infants was demonstrated.

Effects of Azithromycin in Combination with Vancomycin, Daptomycin, Fosfomycin, Tigecycline, and Ceftriaxone on Staphylococcus epidermidis Biofilms

Staphylococcal biofilms on surgical implants are the underlying cause of a lack of response to antimicrobial treatment. We investigated the effects of vancomycin (VAN), daptomycin (DAP), fosfomycin (FOS), tigecycline (TGC), and ceftriaxone (CRX), alone and in combination with azithromycin (AZI), on established biofilms of Staphylococcus epidermidis. Biofilms were studied using the static microtiter plate model with established S. epidermidis biofilms, with an initial inoculum of 10(6)/ml in 96-well polystyrene flat-bottom microtiter plates. Biofilms were inoculated with VAN, DAP, FOS, TGC, or CRX at two concentrations, alone or in combination with AZI (2, 512, or 1,024 mg/liter). To assess the reduction in biomass, the optical density ratio (ODr), calculated as (optical density [OD] of the treated biofilm)/(OD of the untreated biofilm, taken as 1), was used. For antibacterial efficacy, the viable bacterial count was used. Reductions in the biofilm ODr were observed for VAN (15 and 40 mg/liter) and FOS (200 mg/liter) only (ODr [mean +/- standard deviation] for VAN at 15 and 40 mg/liter, 0.77 +/- 0.32 and 0.8 +/- 0.35, respectively; ODr for FOS at 200 mg/liter, 0.78 +/- 0.26; P < 0.05), but not for DAP (2 and 5 mg/liter), TGC (0.2 and 2 mg/liter), or CRX (600 and 2,400 mg/liter). The addition of AZI had no further effect on the ODr, but a significant reduction of bacterial growth was achieved with high doses of AZI plus TGC or AZI plus CRX (a 3-log count reduction for AZI at 1,024 mg/liter plus CRX at 600 mg/liter and for AZI at 512 or 1,024 mg/liter plus CRX at 2,400 mg/liter; a 2-log count reduction for AZI at 512 or 1,024 mg/liter plus TGC at 2 mg/liter [P < 0.05]). No significant reduction in bacterial growth was observed for FOS (50 and 200 mg/liter), DAP (2 and 5 mg/liter), or TGC (0.2 mg/liter) in combination with AZI. None of the antibiotics at either concentration reduced the bacterial count of the biofilms when used alone. Thus, the use of a combination of AZI plus TGC, FOS, or CRX at high concentrations has little effect on biofilm density but significantly reduces bacterial growth.

Fosfomycin Suppresses Chemokine Induction in Airway Epithelial Cells Infected with Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) infects airway epithelial cells, causing bronchiolitis and pneumonia. Inflammation is mediated by various cytokines secreted from RSV-infected airway epithelial cells, and it promotes the pathogenesis of RSV-related diseases. Fosfomycin (FOF) is approved as a treatment for various bacterial infectious diseases, including respiratory infectious diseases, in Japan. FOF is suggested to exhibit immunomodulatory effects on lipopolysaccharide-stimulated monocytes and T lymphocytes, in addition to its antimicrobial activity. We investigated the effect of FOF on the cytokine production of an airway epithelial cell line, A549, infected with RSV. RSV-induced cytokines, such as regulated on activation, normal T-cell expressed and secreted (RANTES), interleukin-8 (IL-8), and IL-6, in infected A549 cells. We found that FOF decreased the levels of RSV-induced RANTES and IL-8 but not the level of RSV-induced IL-6. The RANTES promoter was activated by RSV infection. Site-directed mutagenesis analysis of the RANTES promoter showed that NF-kappaB-binding motifs had a critical role in RSV-induced RANTES promoter activity. A luciferase reporter gene assay and a DNA-binding assay indicated that FOF suppressed the NF-kappaB activity induced by RSV infection. These results demonstrate that FOF treatment suppresses the RSV-induced transcription of the chemokines RANTES and IL-8 in airway epithelial cells.

Characterization of β-lactam antibiotic-induced vancomycin-resistant MRSA (BIVR) in a patient with septicemia during long-term vancomycin administration

It was reported that some methicillin-resistant Staphylococcus aureus (MRSA) show resistance to vancomycin (VCM) and beta-lactam antibiotics; thus, they are termed beta-lactam antibiotic-induced VCM-resistant MRSA (BIVR). The VCM resistance of MRSA is induced by the administration of beta-lactam antibiotics, but this phenomenon can be difficult to detect in the clinical laboratory. We detected the BIVR strain in a 64-year-old man who had had a ventilator tube inserted directly into the windpipe during long-term VCM therapy. The patient was diagnosed with MRSA pneumonia and septicemia on July 5, 2007, and sulbactam/ampicillin (SBT/ABPC) was administered for 5 days. However, the fever recurred, and administration of VCM was resumed for 7 days from July 19. Fever developed again, and VCM was administered again for 14 days from September 30. BIVR and VCM-low-sensitive MRSA were isolated from blood on October 18 and 22, although the VCM trough concentration was 10.2 microg/ml. On October 27, we changed to a combination of fosfomycin (FOM) and arbekacin (ABK), and thereafter the fever quickly decreased and the clinical symptoms abated. We isolated five MRSA strains from the blood of the patient, three strains of VCM-sensitive MRSA, one strain of BIVR, and one strain of a VCM-low-sensitive MRSA. The DNA band patterns determined by pulsed-field gel electrophoresis were completely identical except for the VCM-low-sensitive MRSA, which was missing one band. Furthermore, the VCM-low-sensitive MRSA became sensitive to beta-lactam antibiotics. Our results indicate the possibility that long-term VCM therapy is one of the factors that allow BIVR or VCM-low-sensitive MRSA to emerge, and this allows VCM therapy for MRSA to fail.

Prevalence of Avian Influenza Virus Subtype H5n1 in Waterfowl in West Java Province of Indonesia

are commonly associated with neonatal diarrhea and dysentery in calves. It is important to determine minimal inhibitory concentrations(MICs) for the treatment of animals including human with E. coli infections. A total of 160 strains from 158 diarrheic cattle(1 day to 11 years old) were examined between April 1999 and December 2001 in Japan. The isolates were tested about characteristic pathogenic genes (stx1, stx 2, and eaeA) by polymerase chain reaction. Pathogenic E. coli were tested in vitro for their susceptibility against 18 antimicrobial agents [ampicillin(ABPC), amoxicillin(AMPC), penicillin G(PCG), gentamycin(GM), kanamycin(KM), erythromycin(EM), tetracycline(TC), oxytetracycline(OTC), chloramphenicol(CP), bicozamycin(BCM), fosfomycin(FOM), sulfadimethoxine(SMT), oxolinic acid(OXA), nalidixic acid(NA), enrofloxacin(EFLX), norfloxacin(NFLX), colistin(CL) and trimethoprim-sulfamethoxazole(TMP-S)] using the guidelines of the Clinical and Laboratory Standards Institute(CLSI). The results showed that the E. coli strains at MIC90 were susceptible to EFLX and GM but were resistant to EM, TC, OTC, CP, PCG, AMPC, ABPC and KM. In the case of PCG, the first peak is at the 16—32 g/ml level which is already considered a resistant value but another peak was demonstrated at a much higher MIC (>512 g/ml). The results suggested that E. coli may be still continued to develop stronger resistance.

Community Infections Caused by Extended-Spectrum β-Lactamase–Producing Escherichia coli

Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli is an increasingly important group of community pathogens worldwide. These organisms are frequently resistant to many of the antimicrobial agents usually recommended for the treatment of infections caused by E coli, such as penicillins, cephalosporins, fluoroquinolones, and trimethoprim-sulfamethoxazole. Data concerning risk factors, clinical features, and therapeutic options for such infections are scarce. A case-control study was performed to investigate the risk factors for all types of community-acquired infections caused by ESBL-producing E coli in 11 Spanish hospitals from February 2002 to May 2003. Controls were randomly chosen from among outpatients with a clinical sample not yielding ESBL-producing E coli. The clinical features of these infections were investigated in the case patients. The efficacy of fosfomycin tromethamine and amoxicillin-clavulanate potassium was observationally studied in patients with cystitis. A total of 122 cases were included. Risk factors selected by multivariate analysis included the following: age older than 60 years; female sex; diabetes mellitus; recurrent urinary tract infections (UTIs); previous invasive procedures of the urinary tract; follow-up in outpatient clinic; and previous receipt of aminopenicillins, cephalosporins, and fluoroquinolones. Urinary tract infections accounted for 93% of the cases; 6% of the patients were bacteremic and 10% needed hospitalization. The cure rate of patients with cystitis was 93% with fosfomycin therapy (all isolates were susceptible); among patients treated with amoxicillin-clavulanate, cure rates were 93% for those with susceptible isolates (minimum inhibitory concentration < or =8 microg/mL) and 56% for those with intermediate or resistant isolates (minimum inhibitory concentration > or =16 microg/mL) (P = .02). In predisposed patients, ESBL-producing E coli is a notable cause of community-acquired infection, and particularly UTI. Fosfomycin and amoxicillin-clavulanate appear to be effective for cystitis caused by susceptible isolates.

Fosfomycin tromethamine as second agent for the treatment of acute, uncomplicated urinary tract infections in adult female patients in The Netherlands?

Uncomplicated urinary tract infections (UTIs) are common among female patients. According to the national guidelines of the Dutch College of General Practitioners (GPs), the drugs of first and second choice as therapy for UTIs are nitrofurantoin and trimethoprim with resistance percentages of 2% and 23%, respectively. The third choice is fosfomycin tromethamine for which no current resistance data from The Netherlands are available. The aim of this study was to determine these resistance percentages. During 2003-04, urine samples were collected from a representative sample of 21 general practices spread over The Netherlands, the Sentinel Stations of The Netherlands Institute for Health Services Research (NIVEL). Escherichia coli isolated from female patients visiting their GP with symptoms of an acute, uncomplicated UTI were used. Fosfomycin tromethamine susceptibility was determined by Etests. An MIC of fosfomycin tromethamine of 64 mg/L or lower was considered to indicate susceptibility, and MIC values of 96 mg/L or higher were considered to indicate resistance. E. coli ATCC 25922 was used as a reference strain. In total, 1705 E. coli strains were tested, of which 11 (0.65%) were resistant to fosfomycin tromethamine. The MIC(50) and MIC(90) values for this population were 1 and 4 mg/L, respectively. Within the inhibition zone of 162 susceptible E. coli, resistant mutant colonies were observed, of which after repetition of the susceptibility testing 68 were resistant. In total, 79 (5%) strains were resistant to fosfomycin tromethamine. There was no cross-resistance observed between fosfomycin tromethamine and other antimicrobial agents tested previously. The high in vitro susceptibility to fosfomycin tromethamine in this population and the lack of cross-resistance between fosfomycin tromethamine and other agents together with the extensive global clinical experience support the choice of the national guidelines of the Dutch College of GPs to include fosfomycin tromethamine as a therapeutic option in general practice for uncomplicated UTIs.

Role of Fosfomycin Tromethamine in Modulating Non-Specific Defence Mechanisms in Chronic Uremic Patients towards ESBL-Producing Escherichia Coli

Antimicrobial agents and polymorphonuclear cells (PMNs) have the potential to interact in such a way that improve the therapy for infectious diseases. In immunocompromised patients highly susceptible to microbial infections with high morbidity and mortality, several metabolic and functional alterations in PMNs, mostly related to microbicidal activity, are observed. Therefore, the antibiotic of choice should have a good antimicrobial effect without impairing host defences. The aim of this study is to evaluate in vitro effects of sub-inhibiting fosfomycin tromethamine (FT) concentrations on the primary functions of PMNs from healthy subjects and immunocompromised patients (haemodialysed and renal transplant recipients), against an ESBL-producing Escherichia coli, the most common aetiological agent in urinary tract infections (UTIs). FT is considered a first line drug in the eradication of UTIs due to its appropriate antimicrobial spectrum, oral bioavailability and minimal risk of microbial resistance. Our results provide evidence that FT is able to induce enhancement of the depressed phagocytic response of PMNs from patients on chronic haemodialysis and from renal transplant recipients, restoring their primary functions in vitro against ESBL-producing E. coli. All these data permit the conclusion that uremic-infected patients might additionally benefit from the immunomodulating properties of FT.