Treatment Of Serious Systemic Infections Research Articles

Fosfomycin: the characteristics, activity, and use in critical care.

Fosfomycin (C3H7O4P) is a phosphonic acid derivative representing an epoxide class of antibiotics. The drug is a re-emerging bactericidal antibiotic with a wide range of actions against several Gram-positive and Gram-negative bacteria. Among the existing antibacterial agents, fosfomycin has the lowest molecular weight (138 Da), which is not structurally associated with other classes of antibiotics. In intensive care unit (ICU) patients, severe soft tissue infections (STIs) may lead to serious life-threatening problems, and therefore, appropriate antibiotic therapy and often intensive care management (ICM) coupled with surgical intervention are necessary. Fosfomycin is an antibiotic primarily utilized for the treatment of STIs in ICUs. Recently, fosfomycin has attracted renewed interest for the treatment of serious systemic infections caused by multidrug-resistant Enterobacteriaceae. In some countries, intravenous fosfomycin has been prescribed for various serious systemic infections, such as acute osteomyelitis, nosocomial lower respiratory tract infections, complicated urinary tract infections, bacterial meningitis, and bacteremia. Administration of intravenous fosfomycin can result in a sufficient concentration of the drug at different body regions. Dose modification is not required in hepatic deficiency because fosfomycin is not subjected to enterohepatic circulation.

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.

Metronidazole Single versus Multiple Daily Dosing in Serious Intraabdominal/Pelvic and Diabetic Foot Infections

The purpose of the study was to compare the clinical efficacy of once-daily versus multiple dose regimens of metronidazole in inpatients with serious/systemic Bacteroides fragilis infections, i.e., intraabdominal/pelvic and diabetic foot infections. A retrospective chart review was performed on 145 adult inpatients who received combination therapy with metronidazole for B. fragilis abdominal/pelvic infection or diabetic (deep) foot infections/osteomyelitis. Exclusion criteria included metronidazole given for indications other than those mentioned, patients who received only one dose of metronidazole, and patients who received oral metronidazole only. The 145 patients were in two groups: 66 patients in the metronidazole 1 g (i.v.) q24h (Group A) and 79 patients who received metronidazole 500 mg (i.v./p.o.) q6-8h dosing (Group B). Patient demographics included age, gender, indications of metronidazole, concomitant antibiotics, and co-morbidities. Data collection also included length of stay (LOS), antibiotic days, and clinical outcomes. The 145 patients in our study had a mean age of 66 years, 61% were female and 39% male. Most patients were being treated for definitive intraabdominal/pelvic infections (82%), or probable intraabdominal/pelvic infections (22%). Only 6% had deep diabetic foot infections of osteomyelitis (percentages exceed 100% since a patient can have more than one indication) and were included since B. fragilis is also an important pathogen in diabetic osteomyelitis. Group A patients had more concomitant antibiotics and co-morbidities (p <0.0001 and p <0.05 respectively, chi-square test for trend) than Group B patients. There were no statistically significant differences between groups A and B for LOS and antibiotic days (p = 0.42 and p = 0.92 respectively, by rank-sum test), but after adjusting for concomitant antibiotics and co-morbidities Group A patients had clinically shorter LOS and fewer antibiotic days. Unadjusted mortality and failure rates were non-significantly higher in group A (relative ratios of 12.1% / 6.3% = 1.91 and 18.2% / 10.1% = 1.80 respectively), but after adjusting for concomitant antibiotics and co-morbidities with stratification analysis, groups A and B were virtually the same (risk differences of ≤1% ). The authors conclude that for B. fragilis infections, as part of combination therapy, metronidazole 1 g (i.v.) q24h appears to be as efficacious and not inferior to multiply- dosed metronidazole regimens. Once daily metronidazole, i.e., 1 g (i.v.) q24h for the treatment of serious systemic infections where B. fragilis is an important co-pathogen (intraabdominal/pelvic and deep diabetic foot infections) has pharmacokinetic and pharmaco-economic advantages.

Lethal photosensitisation of oral bacteria and its potential application in the photodynamic therapy of oral infections.

Chemical antibacterial agents are increasingly being used in prophylactic and therapeutic regimes for dental plaque-related diseases, which are among the most common human infections. As these agents are difficult to maintain at a therapeutic concentration in the oral cavity and can be rendered ineffective by resistance development in the target organisms, there is a need to develop alternative antimicrobial approaches. Bacteria and other microbes can be sensitised to light through prior treatment with a chemical photosensitising agent. Lethal photosensitisation of a wide range of bacteria responsible for caries, periodontal diseases and root canal infections has been demonstrated using red light in conjunction with a number of photosensitisers, including Toluidine Blue, phthalocyanines and chlorins. The advantages of this approach are that bacteria can be eradicated in very short periods of time (seconds or minutes), resistance development in the target bacteria is unlikely and damage to adjacent host tissues and disruption of the normal microflora can be avoided. This approach may be a useful alternative to antibiotics and antiseptics in eliminating cariogenic and periodontopathogenic bacteria from disease lesions and for the disinfection of root canals. Not only would this be of benefit for the treatment of these diseases but, by replacing the antimicrobial agents that are currently used for such purposes, it would help to conserve our dwindling supply of antimicrobial agents that are effective in the treatment of serious systemic infections.

Intravenous Ciprofloxacin: A Position Statement by the Society of Infectious Diseases Pharmacists

Intravenous ciprofloxacin is approved for the treatment of urinary tract, bone and joint, skin and soft tissue, and lower respiratory tract infections. Few large, randomized studies comparing its effectiveness with that of other available agents exist; most of these have been published in non-peer-reviewed journal supplements. Intravenous ciprofloxacin is nearly ten times more expensive than the "equivalent" oral dose. Based on the limitations of currently available clinical data, iv ciprofloxacin does not appear to be superior, and is at best comparable in efficacy to other currently available antibiotics. Bacterial resistance, especially in serious infections secondary to P. aeruginosa and S. aureus, is becoming more prevalent. Intravenous ciprofloxacin should be considered an alternative for the treatment of infections of the urinary and lower respiratory tracts only when the following conditions exist: (1) documented bacterial resistance to less-costly regimens with proven efficacy for these indications (e.g., beta-lactams, aminoglycosides, trimethoprim/sulfamethoxazole) and known susceptibility to ciprofloxacin, (2) documented hypersensitivity to first-line agents, or (3) inability to ingest or absorb oral ciprofloxacin. Further clinical trials using higher doses are required before iv ciprofloxacin can be recommended routinely for treatment of serious systemic infections. Because of its poor activity against streptococci, marginal activity against some strains of P. aeruginosa, and the rapidly developing resistance of staphylococci, iv ciprofloxacin should not be used empirically for infections in settings (such as the intensive care unit) where these organisms are likely to be pathogenic.