High-dose cephalexin for cellulitis: a pilot randomized controlled trial.

BACKGROUND: Up 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. OBJECTIVES: To evaluate the feasibility of a randomized trial comparing high-dose (1000 mg) to standard-dose (500 mg) cephalexin to treat ED patients with cellulitis. METHODS: A 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. RESULTS: Of 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. CONCLUSION: This 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 REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT04471246).

RéSUMé: CONTEXTE: Jusqu'à 3% de toutes les visites aux urgences sont dues à des infections de la peau et des tissus mous, comme la cellulite non purulente. Le taux actuel d'échec du traitement est d'environ 20%. Il manque des données probantes sur la gestion optimale de la cellulite en consultation externe. OBJECTIFS: Évaluer la faisabilité d'un essai randomisé comparant la céfalexine à dose élevée (1000 mg) à la céfalexine à dose normale (500 mg) pour traiter les patients des urgences atteints de cellulite. MéTHODES: Un essai pilote contrôlé randomisé en double aveugle à bras parallèles mené dans deux services d'urgence au Canada. Les participants éligibles étaient des adultes (âge ≥ 18 ans) se présentant aux urgences avec une cellulite non purulente et déterminés par l'urgentiste traitant comme pouvant bénéficier d'une prise en charge ambulatoire par antibiotiques oraux. Les participants ont été randomisés entre la céfalexine à dose élevée et la céfalexine à dose normale, quatre fois par jour pendant 7 jours. Le résultat primaire de faisabilité était le taux de recrutement des participants (objectif ≥ 35%). Le résultat primaire préliminaire d'efficacité était l'échec du traitement antibiotique oral. RéSULTATS: Sur les 134 participants éligibles sollicités pour participer à l'essai, 69 (51,5%, IC à 95% 43,1% à 59,8%) ont été recrutés et randomisés. Après avoir exclu trois participants randomisés en raison d'un autre diagnostic, 33 participants au total ont été inclus dans chaque bras. Au total, 19 cas éligibles (14,2%) ont été manqués. Le taux de perte au suivi était de 6,1%. L'échec du traitement est survenu chez quatre patients (12,9%) dans le groupe à dose standard contre un patient (3,2%) dans le groupe à dose élevée. Une plus grande proportion de patients ont eu des effets indésirables mineurs dans le groupe à forte dose. Aucun patient n'a été hospitalisé de façon imprévue dans les 14 jours. CONCLUSION: Cet essai pilote randomisé et contrôlé comparant la céphalexine à dose élevée à la céfalexine à dose normale pour les patients des urgences atteints de cellulite a démontré un taux élevé de recrutement de participants et la faisabilité d'un essai à grande échelle. La céfalexine à forte dose a entraîné moins d'échecs thérapeutiques, mais avec une proportion plus élevée d'effets indésirables mineurs. Les résultats de ce projet pilote serviront de base à la conception d'un futur essai à grande échelle. INSCRIPTION à L'ESSAI: Cet essai a été enregistré sur ClinicalTrials.gov (NCT04471246).

Phenytoin induced Stevens-Johnson Syndrome-toxic Epidermal Necrolysis Overlap Exacerbated by Cephalexin in a 65-Year-old Neurosurgical Patient: A Rare Case Report.

OBJECTIVE: To report a rare case of drug induced overlap of Stevens-Johnson syndrome and Toxic Epidermal Necrosis Syndrome exacerbated by cephalexin. CASE PRESENTATION: In this case report, we present a 65-year-old female who had come to the hospital with complaints of Sloughing of the skin and redness all over the body with raised body temperature. She was on therapeutic Phenytoin to prevent the post-surgical complications of Communicating Hydrocephalus. After a detailed examination, it was found that the patient had misemployed with an overdose of Phenytoin. The patient was found with nikolsky sign and diagnosed as Stevens- Johnson syndrome and Toxic Epidermal Necrosis overlap. This case report emphasizes phenytoin induced Stevens-Johnson syndrome and Toxic Epidermal Necrosis syndrome exacerbated by cephalexin. CONCLUSION: By witnessing this phenomenon, we could figure out the association between cephalexin and Stevens-Johnson syndrome- Toxic Epidermal Necrosis syndrome overlap. The Immediate dismissal of the offending agent and commencement of supportive care was found to be effective.

Bioequivalence of cefalexin in healthy Chinese subjects.

OBJECTIVE: An earlier three-way crossover study evaluating bioequivalence of 3 cefalexin formulations (capsule for reference, capsule and tablet for test) in healthy subjects in Malaysia showed that the intra-individual coefficients of variation were 9.25% for AUC0-t, 9.54% for AUC0-∞, and 13.90% for Cmax. It is preliminarily stated that cefalexin is not a high-variation product. The here-presented clinical study in China was carried out to analyze the pharmacokinetic properties of two preparations in fasting and postprandial condition to assess the bioequivalence of the test preparation and reference preparation when administered on a fasting and postprandial basis in healthy Chinese subjects and to observe the safety of the test preparation and reference preparation in healthy Chinese subjects. MATERIALS AND METHODS: In this trial, a total of 56 eligible subjects were randomly assigned to the fasting group and the postprandial group. The two groups were given 250 mg of the test and reference preparation, respectively. Liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was applied to determine the plasma concentration of cefalexin. PhoenixWinNonlin software (V7.0) was used to calculate the pharmacokinetic parameters of cefalexin using the non-compartmental model (NCA), and the bioequivalence and safety results were calculated by SAS (V9.4) software. RESULTS: The main pharmacokinetic parameters of the test and reference preparations were as follows, the fasting group: Cmax 12.59 ± 2.65 µg/mL, 12.72 ± 2.28 µg/mL; AUC0-8h 20.43 ± 3.47 h×µg/mL, 20.66 ± 3.38 h×µg/mL; AUC0-∞ 20.77 ± 3.53 h×µg/mL, 21.02 ± 3.45 h×µg/mL; the postprandial group: Cmax 5.25 ± 0.94 µg/mL, 5.23 ± 0.80 µg/mL; AUC0-10h 16.92 ± 2.03 h×µg/mL, 17.09 ± 2.31 h×µg/mL; AUC0-∞ 17.33 ± 2.09 h×µg/mL, 17.67 ± 2.45 h×µg/mL. CONCLUSION: The 90% confidence intervals of geometric mean ratios of test preparation and reference preparation were calculated, and the 90% confidence intervals of geometric mean ratios of Cmax, AUC0-10h, and AUC0-∞ were within the 80.00% ~ 125.00% range in both groups. Both Cmax and AUC met the pre-determined criteria for assuming bioequivalence. The test and reference products were bioequivalent after administration under fasting as well as under fed conditions in healthy Chinese subjects. This study may suggest that successful generic versions of cefalexin not only guarantee the market supply of such drugs but can also improve the safety and effectiveness and quality controllability of cefalexin through a new process and a new drug composition ratio.

A rare case of cephalexin-induced acute interstitial nephritis with hypokalemic periodic paralysis.

Drug-induced acute interstitial nephritis (AIN) is often encountered in clinical practice. Cephalexin is a first-generation cephalosporin with antimicrobial sensitivity ranging from Gram-positive to Gram-negative organisms. Cephalexin-induced AIN presenting with hypokalemic periodic paralysis (HPP) has been rarely reported. A 34-year-old female with recent history of oral cephalexin intake presented with acute onset paraplegia with deranged renal parameters and hypokalemia. She was treated conservatively with mechanical ventilator support. HPP could be a rare clinical presentation for cephalexin-induced AIN.

Bullous Pemphigoid with Atypical Skin Lesions and Acute Interstitial Nephritis: A Case Report and Focused Literature Review.

BACKGROUND The hallmark of bullous pemphigoid (BP) is widespread tense blisters arising on normal or erythematous skin, often with marked pruritus, the diagnosis of which is confirmed by direct immunofluorescence (DIF). BP is an autoimmune process that can be induced, though rarely, by medications. Drug-induced BP often has atypical clinical presentation, which requires a good understanding of other dermatological conditions with similar presentations, in particular, bullous subtype of erythema multiforme. End organ involvement warrants differentiating it from one of the severe cutaneous adverse reaction (SCAR) syndromes. CASE REPORT A 76-year-old African American male presented with extensive targetoid purplish skin lesions that clinically resembled atypical erythema multiforme, and one tense blister that raised a concern for BP. The patient presented 6 weeks after treatment with cephalexin for a urinary tract infection. Initial workup showed serum eosinophilia, acute kidney injury and eosinophiluria requiring deliberations on SCAR syndromes. A skin biopsy at an intralesional location showed a negative DIF, however, a skin biopsy at a perilesional site showed a positive DIF, confirming the diagnosis of BP. CONCLUSIONS This case demonstrates an atypical presentation of BP induced by drugs. It emphasizes the need for a greater level of awareness of diagnosis and treatment of the various entities that fall under adverse drug reactions in the elderly. It also highlights the need for appropriate choice of skin biopsy techniques (intralesional versus perilesional) to avoid misdiagnosis, as well as lessons on how to approach dermatologic conditions with end organ involvement for hospitalists and other medical professionals who routinely deal with undifferentiated disease conditions.

Clinical Outcomes of Failing to Dose-Reduce Cephalosporin Antibiotics in Older Adults with CKD.

BACKGROUND AND OBJECTIVES: Current dosing recommendations for cephalosporin antibiotics are on the basis of pharmacokinetic studies and are frequently ignored in practice. This study was undertaken to investigate the clinical outcomes of failing to dose-reduce cephalosporin antibiotics in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective cohort study conducted in Ontario, Canada using linked population-based health care databases. Nine thousand three hundred forty-seven outpatients (median age 83; interquartile range, 77-88 years; 57% women) with an eGFR<30 ml/min per 1.73 m2 and no prior history of dialysis were dispensed oral cephalexin, cefuroxime, or cefprozil between April of 2007 and March of 2016. Two thirds of the patients (6253 of 9347) received a higher than recommended daily dose of cephalexin (>1000 mg), cefuroxime (>500 mg), or cefprozil (>500 mg). The primary outcome was a hospital encounter (emergency room visit or hospital admission) with a condition listed as a possible side-effect of cephalosporins. Secondary outcomes were antibiotic treatment failure and all-cause mortality. All measures were assessed in the 30 days after cephalosporin initiation. RESULTS: Patients who received a higher than recommended dose of a cephalosporin antibiotic were similar in multiple indicators of baseline health to patients who received a reduced dose. Overall, 6% of patients presented to hospital with a possible cephalosporin side-effect, 13% failed antibiotic treatment, and 3% died. Compared with a reduced dose, receiving a higher dose of antibiotic was not associated with a different rate of side-effects (adjusted odds ratio, 1.00; 95% confidence interval, 0.84 to 1.20), treatment failure (1.01; 0.88 to 1.15), or death (0.99; 0.76 to 1.29). CONCLUSIONS: In this study we failed to demonstrate any association between the dose of cephalosporin antibiotic administered to elderly patients with CKD and the risk of side-effects leading to hospitalization, treatment failure, or mortality.

Cephalexin-induced haemolytic anaemia: A case report.

WHAT IS KNOWN AND OBJECTIVE: Drug-induced haemolytic anaemia (DIHA) is a rare condition that has been associated with a multitude of medications. Although a few cephalosporins have been commonly implicated in DIHA, cephalexin has been reported in only a few cases. CASE DESCRIPTION: We report a case of a 44-year-old woman who developed haemolytic anaemia after 5 days of therapy with cephalexin. WHAT IS NEW AND CONCLUSION: Although DIHA is rare, it should not be overlooked in the differential diagnosis. This case adds to the limited number of reports of cephalexin-induced haemolytic anaemia.

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

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, ß-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.

[Evaluation and characterization of 125 patients with a history of reaction to beta-lactams]. / Evaluación y caracterización de 125 pacientes con antecedentes de reacción a betalactámicos.

BACKGROUND: Reactions to beta-lactams are frequent and it is difficult to establish the relationship between the drug and symptoms. OBJECTIVE: To describe the clinical characteristics and explore the immunological mechanisms of patients with suspected adverse reaction to beta-lactams. METHODS: Retrospective study of patients with a history of beta-lactam reaction and tests for reactions to drugs. RESULTS: Out of 125 patients, 71 were women (56.8%); 73 had a history of immediate reaction and 52 delayed reaction; 590 allergy tests were done: specific IgE measurement, skin prick, patch, and provocation tests. The drugs most often related were amoxycillin, in 62 patients (49.6%), crystalline penicillin in 17 (13.6%), benzathine penicillin in 15 (12%), and cefalexin in 13 (10.4%). The severity of the reaction was mild in the majority (82%). 7.7% had a history of anaphylaxis and 10.8% sought care for a positive penicillin skin test, without history of reaction. Only 6.7% resulted in a positive test. More than 62% began testing two years after the reaction for which they sought care. CONCLUSIONS: The clinical history is insufficient to determine allergy to beta-lactams. In our sample, few patients with a history of beta-lactam reaction had evidence of immune-mediated reactions.

Antecedentes: Las reacciones a betalactámicos son frecuentes y es difícil establecer la relación entre el medicamento y los síntomas. Objetivo: Describir las características clínicas y explorar los mecanismos inmunológicos de pacientes con sospecha de reacción adversa a betalactámicos. Métodos: Estudio retrospectivo de pacientes con antecedentes de reacción a betalactámicos y pruebas para reacción con medicamentos. Resultados: De 125 pacientes, 71 eran mujeres (56.8%); 73 tenían historia de reacción inmediata y 52 de reacción tardía; Se realizaron 590 pruebas de alergia: medición de IgE específica, pruebas intradérmicas, de parche y de provocación. Los medicamentos más relacionados fueron amoxicilina, en 62 pacientes (49.6%), penicilina cristalina en 17 (13.6%), penicilina benzatínica en 15 (12%) y cefalexina en 13 (10.4%). La severidad de la reacción fue leve en la mayoría (82%). 7.7% tuvo antecedente de anafilaxia y 10.8% consultaba por una prueba cutánea con penicilina positiva, sin antecedente de reacción. Solo 6.7% resultó con una prueba positiva. Más de 62% inició los estudios dos años después de la reacción por la que consultó. Conclusiones: La historia clínica es insuficiente para determinar la alergia a betalactámicos. En nuestra muestra, pocos pacientes con antecedente de reacción a betalactámicos tuvo evidencia de reacciones inmunológicamente mediadas.

Thrombotic thrombocytopenic purpura in a postoperative patient taking cephalexin responding to plasmapheresis: A case report and review of cephalosporin-induced TTP.

The clinical presentation of thrombotic thrombocytopenic purpura (TTP) is often atypical delaying diagnosis and treatment. A number of drugs have been implicated in the development of TTP, including cyclosporine, tacrolimus, clopidogrel, and quinine. To our knowledge, only three cases of cephalosporin-induced TTP have been described, with two of these cases occurring with these use of cephalexin. We herein describe a case of TTP occurring in a postoperative patient taking cephalexin, requiring plasmapheresis. Following plasmapheresis, the patient's mental status and platelet count significantly improved. J. Clin. Apheresis 31:473-475, 2016. © 2015 Wiley Periodicals, Inc.

ß-lactam-associated eosinophilic colitis.

A 42-year-old man with a history of childhood asthma presented with a 2-week history of watery diarrhoea and marked peripheral eosinophilia in the setting of recent use of cephalexin. His colonoscopy revealed patchy colitis. Biopsies were consistent with eosinophilic colitis. Two months later he received a course of amoxicillin resulting in recurrence of peripheral eosinophilia. Given the time-frame of ß-lactam administration to symptom onset and elimination of all other precipitating causes, he was diagnosed with ß-lactam-associated eosinophilic colitis. The patient's symptoms resolved and peripheral eosinophil count decreased with no specific treatment. Eosinophilic colitis is a rare heterogeneous condition, the pathogenesis of which is likely to be an interplay between environmental and genetic factors. It can be secondary to a helminthic infection or a drug reaction and has been associated with ulcerative colitis. If secondary causes of eosinophilic colitis have been excluded, the mainstay of treatment is with corticosteroids.

Pharmacokinetics and pharmacodynamics of oral cephalexin in children with osteoarticular infections.

BACKGROUND: Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection. METHODS: Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L. RESULTS: Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (T>MIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively. CONCLUSIONS: Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.