Dataset Information

Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial.

ABSTRACT:

Importance

Emergency department visits for skin infections in the United States have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). For cellulitis without purulent drainage, β-hemolytic streptococci are presumed to be the predominant pathogens. It is unknown if antimicrobial regimens possessing in vitro MRSA activity provide improved outcomes compared with treatments lacking MRSA activity.

Objective

To determine whether cephalexin plus trimethoprim-sulfamethoxazole yields a higher clinical cure rate of uncomplicated cellulitis than cephalexin alone.

Design, setting, and participants

Multicenter, double-blind, randomized superiority trial in 5 US emergency departments among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess enrolled from April 2009 through June 2012. All participants had soft tissue ultrasound performed at the time of enrollment to exclude abscess. Final follow-up was August 2012.

Interventions

Cephalexin, 500 mg 4 times daily, plus trimethoprim-sulfamethoxazole, 320 mg/1600 mg twice daily, for 7 days (n = 248 participants) or cephalexin plus placebo for 7 days (n = 248 participants).

Main outcomes and measures

The primary outcome determined a priori in the per-protocol group was clinical cure, defined as absence of these clinical failure criteria at follow-up visits: fever; increase in erythema (>25%), swelling, or tenderness (days 3-4); no decrease in erythema, swelling, or tenderness (days 8-10); and more than minimal erythema, swelling, or tenderness (days 14-21). A clinically significant difference was defined as greater than 10%.

Results

Among 500 randomized participants, 496 (99%) were included in the modified intention-to-treat analysis and 411 (82.2%) in the per-protocol analysis (median age, 40 years [range, 15-78 years]; 58.4% male; 10.9% had diabetes). Median length and width of erythema were 13.0 cm and 10.0 cm. In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P = .50). In the modified intention-to-treat population, clinical cure occurred in 189 (76.2%) of 248 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 171 (69.0%) of 248 in the cephalexin group (difference, 7.3%; 95% CI, -1.0% to 15.5%; P = .07). Between-group adverse event rates and secondary outcomes through 7 to 9 weeks, including overnight hospitalization, recurrent skin infections, and similar infection in household contacts, did not differ significantly.

Conclusions and relevance

Among patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim-sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis. However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed.

Trial registration

clinicaltrials.gov Identifier: NCT00729937.

SUBMITTER: Moran GJ

PROVIDER: S-EPMC5815038 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundU.S. emergency department visits for cutaneous abscess have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). The role of antibiotics for patients with a drained abscess is unclear.MethodsWe conducted a randomized trial at five U.S. emergency departments to determine whether trimethoprim-sulfamethoxazole (at doses of 320 mg and 1600 mg, respectively, twice daily, for 7 days) would be superior to placebo in outpatients older than 12 years of age who had an uncomplicated abscess that was being treated with drainage. The primary outcome was clinical cure of the abscess, assessed 7 to 14 days after the end of the treatment period.ResultsThe median age of the participants was 35 years (range, 14 to 73); 45.3% of the participants had wound cultures that were positive for MRSA. In the modified intention-to-treat population, clinical cure of the abscess occurred in 507 of 630 participants (80.5%) in the trimethoprim-sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P=0.005). In the per-protocol population, clinical cure occurred in 487 of 524 participants (92.9%) in the trimethoprim-sulfamethoxazole group versus 457 of 533 participants (85.7%) in the placebo group (difference, 7.2 percentage points; 95% CI, 3.2 to 11.2; P<0.001). Trimethoprim-sulfamethoxazole was superior to placebo with respect to most secondary outcomes in the per-protocol population, resulting in lower rates of subsequent surgical drainage procedures (3.4% vs. 8.6%; difference, -5.2 percentage points; 95% CI, -8.2 to -2.2), skin infections at new sites (3.1% vs. 10.3%; difference, -7.2 percentage points; 95% CI, -10.4 to -4.1), and infections in household members (1.7% vs. 4.1%; difference, -2.4 percentage points; 95% CI, -4.6 to -0.2) 7 to 14 days after the treatment period. Trimethoprim-sulfamethoxazole was associated with slightly more gastrointestinal side effects (mostly mild) than placebo. At 7 to 14 days after the treatment period, invasive infections had developed in 2 of 524 participants (0.4%) in the trimethoprim-sulfamethoxazole group and in 2 of 533 participants (0.4%) in the placebo group; at 42 to 56 days after the treatment period, an invasive infection had developed in 1 participant (0.2%) in the trimethoprim-sulfamethoxazole group.ConclusionsIn settings in which MRSA was prevalent, trimethoprim-sulfamethoxazole treatment resulted in a higher cure rate among patients with a drained cutaneous abscess than placebo. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00729937.).

Project description:BackgroundSkin 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.MethodsWe 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.ResultsA 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.ConclusionsWe 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:BackgroundMelioidosis, 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.MethodsFor 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.FindingsWe 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%]).InterpretationOur 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.FundingThailand 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:ObjectivesTrimethoprim-sulfamethoxazole (TMP-SMX)-associated severe acute respiratory distress syndrome (ARDS) has gone underrecognized. We propose the first disease definition and clinical evaluation for a novel adverse drug reaction (ADR) based on a series of recently identified rare cases of life-threatening ADRs.DesignA retrospective study was conducted. All medical records were evaluated. Available pathology samples were sent to Massachusetts General for clinical consultation. Blood samples from surviving patients were obtained and human leukocyte antigen (HLA) analysis was performed by the Children's Mercy Hospital Genomic Center and Vanderbilt University Medical Center.SettingU.S. ICUs, 1996-2021.PatientsNineteen young patients (10-37) were identified. Patients were previously healthy, with no preexisting pulmonary disease, no other cause for respiratory failure, and no chronic history of smoking/vaping.InterventionsNone.Measurements and main resultsThrough our retrospective analysis, we analyzed clinical characteristics associated with TMP-SMX. Pathology samples were reviewed, and HLA analysis was performed on available samples by the study team or as standard of care at treatment hospitals in some cases. In 19 critically ill patients, we identified a pattern of severe respiratory failure requiring ICU admission, mechanical ventilation, and frequent extracorporeal membrane oxygenation use. We describe the first three-part clinical diagnosis and evaluation strategy: 1) Clinical definition: Unexplained severe respiratory failure in a patient receiving greater than or equal to 6 days of TMP-SMX at treatment dose (not prophylaxis). TMP-SMX ARDS is a diagnosis of exclusion. 2) Genetic association: One hundred percent of currently available TMP-SMX respiratory failure patient genomic data, ( n = 11) have been carriers of both HLA-B*07:02 and HLA-C*07:02 alleles. HLA allele evaluation could be considered in patients with suspected TMP-SMX respiratory failure. 3) Lung pathology: A unique pulmonary pathologic pattern of lung injury termed diffuse alveolar injury with delayed epithelialization has been observed in these cases. In suspected cases, surgical lung biopsy early in the clinical course could be considered.ConclusionsTMP-SMX is a commonly prescribed antibiotic. However, we find it imperative to share this relatively rare but life-threatening condition with clinicians as the mortality rate approaches 40%.

Project description:BackgroundUp to 3% of all Emergency Department (ED) visits are due to skin and soft tissue infections such as non-purulent cellulitis. The current treatment failure rate is approximately 20%. Evidence is lacking regarding the optimal outpatient management of cellulitis.ObjectivesTo evaluate the feasibility of a randomized trial comparing high-dose (1000 mg) to standard-dose (500 mg) cephalexin to treat ED patients with cellulitis.MethodsA parallel arm double-blind randomized controlled pilot trial conducted at two EDs in Canada. Eligible participants were adults (age ≥ 18 years) presenting to the ED with non-purulent cellulitis and determined by the treating emergency physician to be eligible for outpatient management with oral antibiotics. Participants were randomized to high-dose or standard-dose cephalexin four times daily for 7 days. The primary feasibility outcome was participant recruitment rate (target ≥ 35%). The preliminary primary effectiveness outcome was oral antibiotic treatment failure.ResultsOf 134 eligible participants approached for trial participation, 69 (51.5%, 95% CI 43.1 to 59.8%) were recruited and randomized. After excluding three randomized participants due to an alternate diagnosis, 33 participants were included in each arm. Nineteen eligible cases (14.2%) were missed. Loss to follow-up was 6.1%. Treatment failure occurred in four patients (12.9%) in the standard-dose arm versus one patient (3.2%) in the high-dose arm. A greater proportion had minor adverse events in the high-dose arm. No patients had an unplanned hospitalization within 14 days.ConclusionThis pilot randomized controlled trial comparing high-dose to standard-dose cephalexin for ED patients with cellulitis demonstrated a high participant recruitment rate and that a full-scale trial is feasible. High-dose cephalexin had fewer treatment failures but with a higher proportion of minor adverse effects. The findings of this pilot will be used to inform the design of a future large trial.Trial registrationThis trial was registered at ClinicalTrials.gov (NCT04471246).