A Randomized Trial of Clindamycin Versus Trimethoprim-sulfamethoxazole for Uncomplicated Wound Infection.
ABSTRACT: With the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in the United States, visits for skin infections greatly increased. Staphylococci and streptococci are considered predominant causes of wound infections. Clindamycin and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed, but the efficacy of TMP-SMX has been questioned.We conducted a randomized, double-blind, superiority trial at 5 US emergency departments. Patients >12 years of age with an uncomplicated wound infection received oral clindamycin 300 mg 4 times daily or TMP-SMX 320 mg/1600 mg twice daily, each for 7 days. We compared the primary outcome, wound infection cure at 7-14 days, and secondary outcomes through 6-8 weeks after treatment, in the per-protocol population.Subjects had a median age of 40 years (range, 14-76 years); 40.1% of wound specimens grew MRSA, 25.7% methicillin-susceptible S. aureus, and 5.0% streptococci. The wound infection was cured at 7-14 days in 187 of 203 (92.1%) clindamycin-treated and 182 of 198 (91.9%) TMP-SMX-treated subjects (difference, 0.2%; 95% confidence interval [CI], -5.8% to 6.2%; P = not significant). The clindamycin group had a significantly lower rate of recurrence at 7-14 days (1.5% vs 6.6%; difference, -5.1%; 95% CI, -9.4% to -.8%) and through 6-8 weeks following treatment (2.0% vs 7.1%; difference, -5.1%; 95% CI, -9.7% to -.6%). Other secondary outcomes were statistically similar between groups but tended to favor clindamycin. Adverse event rates were similar.In settings where MRSA is prevalent, clindamycin and TMP-SMX produce similar cure and adverse event rates among patients with an uncomplicated wound infection. Further study evaluating differential effects of antibiotics on recurrent infection may be warranted.NCT00729937.
Project description:Skin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear.We enrolled outpatients with uncomplicated skin infections who had cellulitis, abscesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The primary outcome was clinical cure 7 to 10 days after the end of treatment.A total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, defined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, -2.6 percentage points; 95% confidence interval [CI], -10.2 to 4.9; P=0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, -1.2 percentage points; 95% CI, -7.6 to 5.1; P=0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups.We found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infections, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.).
Project description:BACKGROUND:Uncomplicated skin abscesses are common, yet the appropriate management of the condition in the era of community-associated methicillin-resistant Staphylococcus aureus (MRSA) is unclear. METHODS:We conducted a multicenter, prospective, double-blind trial involving outpatient adults and children. Patients were stratified according to the presence of a surgically drainable abscess, abscess size, the number of sites of skin infection, and the presence of nonpurulent cellulitis. Participants with a skin abscess 5 cm or smaller in diameter were enrolled. After abscess incision and drainage, participants were randomly assigned to receive clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), or placebo for 10 days. The primary outcome was clinical cure 7 to 10 days after the end of treatment. RESULTS:We enrolled 786 participants: 505 (64.2%) were adults and 281 (35.8%) were children. A total of 448 (57.0%) of the participants were male. S. aureus was isolated from 527 participants (67.0%), and MRSA was isolated from 388 (49.4%). Ten days after therapy in the intention-to-treat population, the cure rate among participants in the clindamycin group was similar to that in the TMP-SMX group (221 of 266 participants [83.1%] and 215 of 263 participants [81.7%], respectively; P=0.73), and the cure rate in each active-treatment group was higher than that in the placebo group (177 of 257 participants [68.9%], P<0.001 for both comparisons). The results in the population of patients who could be evaluated were similar. This beneficial effect was restricted to participants with S. aureus infection. Among the participants who were initially cured, new infections at 1 month of follow-up were less common in the clindamycin group (15 of 221, 6.8%) than in the TMP-SMX group (29 of 215 [13.5%], P=0.03) or the placebo group (22 of 177 [12.4%], P=0.06). Adverse events were more frequent with clindamycin (58 of 265 [21.9%]) than with TMP-SMX (29 of 261 [11.1%]) or placebo (32 of 255 [12.5%]); all adverse events resolved without sequelae. One participant who received TMP-SMX had a hypersensitivity reaction. CONCLUSIONS:As compared with incision and drainage alone, clindamycin or TMP-SMX in conjunction with incision and drainage improves short-term outcomes in patients who have a simple abscess. This benefit must be weighed against the known side-effect profile of these antimicrobials. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00730028 .).
Project description:OBJECTIVE:To assess the impact of adjunctive antibiotic therapy on uncomplicated skin abscesses. DESIGN:Systematic review and network meta-analysis. DATA SOURCES:Medline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. STUDY SELECTION:A BMJ Rapid Recommendation panel provided input on design, important outcomes and the interpretation of the results. Eligible randomised controlled trials (RCTs) included a comparison of antibiotics against no antibiotics or a comparison of different antibiotics in patients with uncomplicated skin abscesses, and reported outcomes prespecified by the linked guideline panel. REVIEW METHODS:Reviewers independently screened abstracts and full texts for eligibility, assessed risk of bias and extracted data. We performed random-effects meta-analyses that compared antibiotics with no antibiotics, along with a limited number of prespecified subgroup hypotheses. We also performed network meta-analysis with a Bayesian framework to compare effects of different antibiotics. Quality of evidence was assessed with The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS:Fourteen RCTs including 4198 patients proved eligible. Compared with no antibiotics, antibiotics probably lower the risk of treatment failure (OR 0.58, 95%?CI 0.37 to 0.90; low quality), recurrence within 1 month (OR 0.48, 95% CI 0.30 to 0.77; moderate quality), hospitalisation (OR 0.55, 95% CI 0.32 to 0.94; moderate quality) and late recurrence (OR 0.64, 95% CI 0.48 to 0.85; moderate quality). However, relative to no use, antibiotics probably increase the risk of gastrointestinal side effects (trimethoprim and sulfamethoxazole (TMP-SMX): OR 1.28, 95% CI 1.04 to 1.58; moderate quality; clindamycin: OR 2.29, 95% CI 1.35 to 3.88; high quality) and diarrhoea (clindamycin: OR 2.71, 95% CI 1.50 to 4.89; high quality). Cephalosporins did not reduce the risk of treatment failure compared with placebo (moderate quality). CONCLUSIONS:In patients with uncomplicated skin abscesses, moderate-to-high quality evidence suggests TMP-SMX or clindamycin confer a modest benefit for several important outcomes, but this is offset by a similar risk of adverse effects. Clindamycin has a substantially higher risk of diarrhoea than TMP-SMX. Cephalosporins are probably not effective.
Project description:To compare clindamycin and cephalexin for treatment of uncomplicated skin and soft tissue infections (SSTIs) caused predominantly by community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA). We hypothesized that clindamycin would be superior to cephalexin (an antibiotic without MRSA activity) for treatment of these infections.Patients aged 6 months to 18 years with uncomplicated SSTIs not requiring hospitalization were enrolled September 2006 through May 2009. Eligible patients were randomly assigned to 7 days of cephalexin or clindamycin; primary and secondary outcomes were clinical improvement at 48 to 72 hours and resolution at 7 days. Cultures were obtained and tested for antimicrobial susceptibilities, pulsed-field gel electrophoresis type, and Panton-Valentine leukocidin status.Of 200 enrolled patients, 69% had MRSA cultured from wounds. Most MRSA were USA300 or subtypes, positive for Panton-Valentine leukocidin, and clindamycin susceptible, consistent with CA-MRSA. Spontaneous drainage occurred or a drainage procedure was performed in 97% of subjects. By 48 to 72 hours, 94% of subjects in the cephalexin arm and 97% in the clindamycin arm were improved (P = .50). By 7 days, all subjects were improved, with complete resolution in 97% in the cephalexin arm and 94% in the clindamycin arm (P = .33). Fevers and age less than 1 year, but not initial erythema > 5 cm, were associated with early treatment failures, regardless of antibiotic used.There is no significant difference between cephalexin and clindamycin for treatment of uncomplicated pediatric SSTIs caused predominantly by CA-MRSA. Close follow-up and fastidious wound care of appropriately drained, uncomplicated SSTIs are likely more important than initial antibiotic choice.
Project description:OBJECTIVE:The aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characterize age-related maturational changes in drug disposition for the renally eliminated and hepatically metabolized antibiotic trimethoprim (TMP)-sulfamethoxazole (SMX). METHODS:We developed separate population PBPK models for TMP and SMX in children after oral administration of the combined TMP-SMX product and used sparse and opportunistically collected plasma concentration samples to validate our pediatric model. We evaluated predictability of the pediatric PBPK model based on the number of observed pediatric data out of the 90% prediction interval. We performed dosing simulations to target organ and tissue (skin) concentrations greater than the methicillin-resistant Staphylococcus aureus (MRSA) minimum inhibitory concentration (TMP 2 mg/L; SMX 9.5 mg/L) for at least 50% of the dosing interval. RESULTS:We found 67-87% and 71-91% of the observed data for TMP and SMX, respectively, were captured within the 90% prediction interval across five age groups, suggesting adequate fit of our model. Our model-rederived optimal dosing of TMP at the target tissue was in the range of recommended dosing for TMP-SMX in children in all age groups by current guidelines for the treatment of MRSA. CONCLUSION:We successfully developed a pediatric PBPK model of the combination antibiotic TMP-SMX using sparse and opportunistic pediatric pharmacokinetic samples. This novel and efficient approach has the potential to expand the use of PBPK modeling in pediatric drug development.
Project description:Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume of distribution (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.
Project description:Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used in malaria-endemic areas in human immunodeficiency virus (HIV)-infected children and HIV-uninfected, HIV-exposed children as opportunistic infection prophylaxis. Despite the known effects that TMP-SMX has in reducing clinical malaria, its impact on development of malaria-specific immunity in these children remains poorly understood. Using rodent malaria models, we previously showed that TMP-SMX, at prophylactic doses, can arrest liver stage development of malaria parasites and speculated that TMP-SMX prophylaxis during repeated malaria exposures would induce protective long-lived sterile immunity targeting pre-erythrocytic stage parasites in mice. Using the same models, we now demonstrate that repeated exposures to malaria parasites during TMP-SMX administration induces stage-specific and long-lived pre-erythrocytic protective anti-malarial immunity, mediated primarily by CD8<sup>+</sup> T-cells. Given the HIV infection and malaria coepidemic in sub-Saharan Africa, clinical studies aimed at determining the optimum duration of TMP-SMX prophylaxis in HIV-infected or HIV-exposed children must account for the potential anti-infection immunity effect of TMP-SMX prophylaxis.
Project description:BACKGROUND:Using published data, we sought to compare outcomes in patients transitioned to either oral fluoroquinolones (FQ) or trimethoprim-sulfamethoxazole (TMP-SMX) versus ß-lactams (BL's) after an initial intravenous (IV) course for gram-negative rod (GNR) bacteremia. METHODS:We conducted a systematic review of PubMed and EMBASE and published IDWeek abstracts. We included studies that reported all-cause mortality and/or infection recurrence in patients transitioned to oral FQ/TMP-SMX and BL's. RESULTS:Eight retrospective studies met inclusion criteria with data for 2,289 patients, of whom 65% were transitioned to oral FQ, 7.7% to TMP-SMX, and 27.2% to BL's. Follow up periods ranged from 21 to 90 days. All-cause mortality was not significantly different between patients transitioned to either FQ/TMP-SMX or BL's (OR 1.13; 95%CI, 0.69-1.87). Overall recurrence of infection, either bacteremia or the primary site, occurred more frequently in patients transitioned to oral BL's vs. FQ's (OR 2.05, 95% CI 1.17 to 3.61). Analysis limited to recurrent bacteremia was similarly suggestive although limited by small numbers (OR 2.32, 95% CI 0.99 to 5.44). However, based on known pharmacokinetics/pharmacodynamics, prescribed ß-lactam dosing regimens were frequently suboptimal. CONCLUSIONS:In the step-down IV to oral treatment of GNR bacteremia, we found insufficient data regarding outcomes after oral TMP-SMX; however, selection of a FQ over commonly utilized ß-lactam regimens may reduce chances of infection recurrence. While this may be a class effect, it may simply be the result of inadequate dosing of ß-lactams. Additional investigations are warranted to determine outcomes with TMP-SMX and optimized oral ß-lactam dosing regimens.
Project description:Melioidosis, an infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei, is difficult to cure. Antimicrobial treatment comprises intravenous drugs for at least 10 days, followed by oral drugs for at least 12 weeks. The standard oral regimen based on trial evidence is trimethoprim-sulfamethoxaxole (TMP-SMX) plus doxycycline. This regimen is used in Thailand but is associated with side-effects and poor adherence by patients, and TMP-SMX alone is recommended in Australia. We compared the efficacy and side-effects of TMP-SMX with TMP-SMX plus doxycycline for the oral phase of melioidosis treatment.For this multi-centre, double-blind, non-inferiority, randomised placebo-controlled trial, we enrolled patients (aged ?15 years) from five centres in northeast Thailand with culture-confirmed melioidosis who had received a course of parenteral antimicrobial drugs. Using a computer-generated sequence, we randomly assigned patients to receive TMP-SMX plus placebo or TMP-SMX plus doxycycline for 20 weeks (1:1; block size of ten, stratified by study site). We followed patients up every 4 months for 1 year and annually thereafter to the end of the study. The primary endpoint was culture-confirmed recurrent melioidosis, and the non-inferiority margin was a hazard ratio (HR) of 1.7. This study is registered with www.controlled-trials.com, number ISRCTN86140460.We enrolled and randomly assigned 626 patients: 311 to TMP-SMX plus placebo and 315 to TMP-SMX plus doxycycline. 16 patients (5%) in the TMP-SMX plus placebo group and 21 patients (7%) in the TMP-SMX plus doxycycline group developed culture-confirmed recurrent melioidosis (HR 0.81; 95% CI 0.42-1.55). The criterion for non-inferiority was met (p=0.01). Adverse drug reactions were less common in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group (122 [39%] vs 167 [53%]).Our findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline for the oral phase of melioidosis treatment, and is preferable on the basis of safety and tolerance by patients.Thailand Research Fund, the Melioidosis Research Center, the Center of Excellence in Specific Health Problems in Greater Mekong Sub-region cluster, and the Wellcome Trust.
Project description:Background:Stenotrophomonas maltophilia is a gram-negative, opportunistic infection that is usually hospital-acquired and associated with high morbidity and mortality. The reported increase in S. maltophilia infections is presumed to be due to an increase in the population at risk. Methods:We retrospectively reviewed 10-year data for S. maltophilia bacteremia in hospitalized adults at our institution to determine the population at risk, sources of infection, common complications, antimicrobial susceptibility profiles, and clinical outcome trends over the past decade. Results:Among the 98 patients analyzed, the most common source of infection was catheter-related (62, 63.3%). Most isolates (61, 65%) were resistant to ceftazidime; fewer were resistant to trimethoprim-sulfamethoxazole (TMP-SMX; 2, 2.1%) and levofloxacin (22, 23.4%). All-cause in-hospital mortality was 29.6% (29 patients). The highest mortality, 53.8%, was observed in pulmonary sources of bacteremia. Conclusions:Although TMP-SMX continues to have reliable activity in our cohort, we noted resistance to TMP-SMX in patients with recent TMP-SMX exposure, including a case with developing resistance to TMP-SMX while on therapy.