Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

HIV and tuberculosis: partners in crime.

BACKGROUND: Tuberculosis is the commonest infection detected in HIV-infected individuals worldwide. AIM: The aim of this study is to describe the clinical, bacteriologic and radiological spectrum of tuberculosis (TB) in the setting of human immunodeficiency virus (HIV) infection in a tertiary care centre in Mumbai. METHODS: A total of 8640 HIV-infected individuals were screened for tuberculosis routinely from January 1998 to December 2003, using clinical examination, chest X-ray and abdominal ultrasonography, sputum smears for acid-fast bacilli (AFB) and culture on Lowenstein-Jensen medium. RESULTS: TB was detected in 8078 (93.5%) patients of whom 3393 (42%) had pulmonary, 3514 (43.5%) had extrapulmonary TB and 1171 (14.5%) had disseminated disease. One thousand two hundred thirty eight patients (36.5%) showed AFB in sputum, while 1154 (34%) showed growth on culture medium and 4174 had radiographic involvement. In 781 (67%) individuals disseminated disease coexisted with pulmonary involvement. All 8078 coinfected patients were treated with anti-TB therapy (ATT), of whom 6422 patients (79.5%) showed one or more adverse events. Gastritis was the commonest complaint followed by hepatitis and skin rashes. ATT resistance was detected in 482 individuals. CONCLUSION: Tuberculosis is the commonest opportunistic infection (OI) in HIV positive patients in India, showing a higher prevalence of extrapulmonary and disseminated TB and adverse events due to ATT. Early recognition of concurrent OIs and their adequate treatment and prophylaxis is essential.

Penicillium marneffei infection: an AIDS-defining illness.

A 29-year-old HIV seropositive male patient from Manipur presented with fever, cough, weight loss and asymptomatic papules and nodules all over the body. Differential diagnoses of secondary syphilis, histoplasmosis, cryptococcosis and penicilliosis were considered. Histopathological and mycological study of the skin biopsy tissue, and blood culture confirmed the diagnosis of penicilliosis. Although penicilliosis, an AIDS-defining illness, is restricted to Southeast Asia, more and more cases are being recognized in non-endemic countries.