A highly polarized TH2 bladder response to infection promotes epithelial repair at the expense of preventing new infections.

Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)-skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.

The Widely Used Antimicrobial Triclosan Induces High Levels of Antibiotic Tolerance In Vitro and Reduces Antibiotic Efficacy up to 100-Fold In Vivo.

The antimicrobial triclosan is used in a wide range of consumer products ranging from toothpaste, cleansers, socks, and baby toys. A bacteriostatic inhibitor of fatty acid synthesis, triclosan is extremely stable and accumulates in the environment. Approximately 75% of adults in the United States have detectable levels of the compound in their urine, with a sizeable fraction of individuals (>10%) having urine concentrations equal to or greater than the minimal inhibitory concentration for Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). Previous work has identified connections between defects in fatty acid synthesis and accumulation of the alarmone guanosine tetraphosphate (ppGpp), which has been repeatedly associated with antibiotic tolerance and persistence. Based on these data, we hypothesized that triclosan exposure may inadvertently drive bacteria into a state in which they are able to tolerate normally lethal concentrations of antibiotics. Here we report that clinically relevant concentrations of triclosan increased E. coli and MRSA tolerance to bactericidal antibiotics as much as 10,000-fold in vitro and reduced antibiotic efficacy up to 100-fold in a mouse urinary tract infection model. Genetic analysis indicated that triclosan-mediated antibiotic tolerance requires ppGpp synthesis but is independent of growth. These data highlight an unexpected and certainly unintended consequence of adding high concentrations of antimicrobials in consumer products, supporting an urgent need to reevaluate the costs and benefits of the prophylactic use of triclosan and other bacteriostatic compounds.

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient.

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.

Metabolic risk factors in pediatric stone formers: a report from an emerging economy.

The goal of this study was to investigate metabolic risk factors in pediatric stone formers in an emerging economy. A prospective, data collection enrolled 250 children age <1-15 years at our center. Risk factors were evaluated by gender and in age groups <1-5, 6-10 and 11-15 years. Patients were evaluated for demographics, blood and 24 h urine for calcium, magnesium, phosphate, uric acid, electrolytes and additional protein, citrate, ammonia and oxalate in urine. All reported values were two sided and statistical significance was considered at p value ≤0.05. The mean age at diagnosis was 7.50 ± 3.56 years with a male to female ratio of 1.84:1. A family history of urolithiasis was found in 41 (16.4 %), urinary tract infection in 18 (7 %) and chronic diarrhea in 75 (30 %). Hypercalcemia was seen in 37 (14.8 %), hyperuricemia in 23 (9.2 %) and hyperphosphatemia in 6 (2.4 %). Urinary metabolic abnormalities were identified in 248 (98 %) of the cases. Hypocitraturia was found in 207 (82.8 %), hyperoxaluria in 62 (26.4 %), hyperuricosuria in 82 (32.8 %), hypercalciuria in 51 (20.4 %), hyperphosphaturia in 46 (18.4 %), hyperammonuria in 10 (4 %), hypocalciuria in 82 (32.8 %), and hypovolemia in 73 (29.2 %). Risk factors were similar between genders except higher rates of hyponatriuria, hypophosphaturia, and hypocalciuria in females. Hyperuricosuria, hyponatriuria, and hypovolemia were highest in 1-5 years (52, 49, 49 %) as compared to (18, 21, 12 %) those in 11-15 years (p < 0.001), respectively. This study shows that careful metabolic analysis can identify risk factors in 98 % of the children where appropriate metaphylaxis can be undertaken both for treatment and prevention of recurrence.

Evaluation by Monte Carlo simulation of levofloxacin dosing for complicated urinary tract infections caused by Escherichia coli or Pseudomonas aeruginosa.

We evaluated, by Monte Carlo simulation, 500-mg once-daily, 100-mg thrice-daily, 200-mg twice-daily, and 200-mg thrice-daily dose regimens of levofloxacin (LVFX), for the ratio of area under the concentration-time curve for 24 h (AUC(0-24)) to minimum inhibitory concentration (MIC) (AUC(0-24)/MIC) and the ratio of maximum plasma concentration (C(max)) to MIC (C(max)/MIC), which predict microbiological outcomes, and the C(max)/MIC, which inhibits fluoroquinolone resistance selection, in complicated urinary tract infections (UTIs) with Escherichia coli or Pseudomonas aeruginosa. Monte Carlo simulation was performed for 10000 cases using the pharmacokinetic data of patients with complicated UTIs and the LVFX MIC distributions for E. coli or P. aeruginosa clinical strains. The probabilities of achieving the AUC(0-24)/MIC target (66.2-67.9%) and the C(max)/MIC target (64.5-67.5%) to eradicate E. coli were similar among the 4 regimens. In eradication of P. aeruginosa, the 200-mg thrice-daily and the once-daily dose regimens produced higher probabilities of achieving the AUC(0-24)/MIC target (57.5%) and C(max)/MIC target (55.1%), respectively. For the probabilities of achieving the C(max)/MIC targets that prevent the emergence of fluoroquinolone resistance, the once-daily dose regimen (66.8%) did not differ from the other multiple-dose regimens (62.3-66.2%) in E. coli, whereas the former regimen (44.2%) was superior to the latter regimens (10.8-31.7%) in P. aeruginosa. The 500-mg once-daily dose regimen of LVFX, which produced the larger AUC(0-24) and higher C(max), could ensure the efficacy of eradication of uropathogens and reduce the risk of fluoroquinolone resistance selection in complicated UTIs.

A risk-benefit assessment of levofloxacin in respiratory, skin and skin structure, and urinary tract infections.

As a class, the quinolone antibacterials can no longer be assumed to be both effective and relatively free of significant adverse effects. Recent safety issues with newer generation fluoroquinolones, and concerns regarding drug-use associated bacterial resistance have made all drugs in this class subject to intense scrutiny and further study. Levofloxacin is a second generation fluoroquinolone with a post marketing history of well tolerated and successful use in a variety of clinical situations. Quinolones as a class cause a variety of adverse effects, including phototoxicity, seizures and other CNS disturbances, tendonitis and arthropathies, gastrointestinal effects, nephrotoxicity, prolonged QTc interval and torsade de pointes, hypo- or hyperglycaemia, and hypersensitivity reactions. Levofloxacin has been involved in only a few case reports of adverse events, which include QTc prolongation, seizures, glucose disturbances, and tendonitis. Levofloxacin has been shown to be effective at dosages of 250mg to 500mg once-daily in clinical trials in the management of acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, community-acquired pneumonia, skin and skin structure infections, and urinary tract infections. There are data suggesting that levofloxacin may promote fluoroquinolone resistance among the Streptococcus pneumoniae, and that clinical failures may result from this therapy. Other data suggest that fluoroquinolones with lower potency against Pseudomonas aeruginosa than ciprofloxacin, such as levofloxacin, may drive class-wide resistance to this pathogen. Levofloxacin is an effective drug in many clinical situations, but its cost is significantly higher than amoxicillin, erythromycin, or first and second generation cefalosporins. Because of the propensity to select for fluoroquinolone resistance in the pneumococcus and potentially other pathogens, levofloxacin should be an alternative agent rather than a drug-of-choice in routine community-acquired respiratory tract, urinary tract, and skin or skin structure infections. In areas with increasing pneumococcal beta-lactam resistance, levofloxacin may be a reasonable empiric therapy in community-acquired respiratory tract infections. Similarly, in patients with risk factors for infectious complications or poor outcome, levofloxacin may be an excellent empiric choice in severe community-acquired respiratory tract infections, urinary tract infections, complicated skin or skin structure infections, and nosocomial respiratory and urinary tract infections. Better clinical data are needed to identify the true place in therapy of the newer fluoroquinolones in common community-acquired and nosocomial infections. Until then, these agents, including levofloxacin, might best be reserved for complicated infections, infection recurrence, and infections caused by beta-lactam or macrolide-resistant pathogens.