Flexible Development Programs for Antibacterial Drugs to Address Unmet Medical Needs.

The US Food and Drug Administration recognizes the unmet medical need for antibacterial drugs to treat serious bacterial diseases caused by resistant pathogens for which effective therapies are limited or lacking. The agency also recognizes that designing and conducting clinical trials to assess the safety and efficacy of drugs to treat resistant infections is challenging, especially for drugs only active against a single or a few bacterial species, and that a more flexible development program might be appropriate. In this article, we discuss several regulatory considerations for flexible development programs for antibacterial drugs intended to meet an unmet medical need. As an example, we use the recent approval of sulbactam for injection and durlobactam for injection (XACDURO) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.

Long-Term Risk of Acute Myocardial Infarction, Stroke, and Death With Outpatient Use of Clarithromycin: A Retrospective Cohort Study.

In a retrospective cohort study of patients enrolled in the UK Clinical Practice Research Datalink during 2000-2013, we evaluated long-term risks of death, stroke, and acute myocardial infarction (AMI) in adults prescribed clarithromycin. Patients were outpatients aged 40-85 years, who were prescribed clarithromycin (n = 287,748), doxycycline (n = 267,729), or erythromycin (n = 442,999), or Helicobacter pylori eradication therapy with a proton pump inhibitor, amoxicillin, and either clarithromycin (n = 27,639) or metronidazole (n = 14,863). We analyzed time to death, stroke, or AMI with Cox proportional hazards regression. The long-term hazard ratio for death following 1 clarithromycin versus 1 doxycycline prescription was 1.29 (95% confidence interval (CI): 1.21, 1.25), increasing to 1.62 (95% CI: 1.43, 1.84) for ≥5 prescriptions of clarithromycin versus ≥5 prescriptions for doxycycline. Erythromycin showed smaller risks in comparison with doxycycline. Stroke and AMI incidences were also increased after clarithromycin but with smaller hazard ratios than for mortality. For H. pylori eradication, the hazard ratio for mortality following clarithromycin versus metronidazole regimens was 1.09 (95% CI: 1.00, 1.18) overall, and it was higher (hazard ratio = 1.65, 95% CI: 0.88, 3.08) following ≥2 prescriptions in subjects not on statins at baseline. Outpatient clarithromycin use was associated with long-term mortality increases, with evidence for a similar, smaller increase with erythromycin.

Predicting CD4 count using total lymphocyte count: a sustainable tool for clinical decisions during HAART use.

Understanding the total lymphocyte count (TLC)-CD4 count relationship could aide design predictive instruments for making clinical decisions during antiretroviral therapy, especially in underserved resource-poor settings. We performed multiple regression analyses to assess the prediction of CD4 count using TLC on 771 participants with 4,836 visits. In linear and logistic regression TLC, hemoglobin, gender, history of AIDS, and weight predicted CD4 count and CD4 < 200, respectively, before and after highly active antiretroviral therapy (HAART) use. On HAART, the adjusted odds ratios (OR) for TLC < 1500 (optimal TLC cutoff) were 5.1 (95%CI 4.0, 6.5; P < 0.001), and off HAART, 4.6 (95%CI 3.4, 6.2: P < 0.001) with high predictive power. TLC predicts CD4 count and CD4 < 200 cells/microL well during HAART. Including the additional factors improves performance. TLC is simple and inexpensive and can be used in many ways to develop clinical decision-making tools in underserved resource-poor settings during HAART therapy.

Cryptococcal Meningitis in an HIV-Positive Pregnant Woman.

Cryptococcal meningitis is uncommon in pregnant HIV-infected women. The clinical care of an HIV-1 positive pregnant woman with cryptococcal meningitis whose pathology has been previously reported is reviewed to highlight the treatment of the disease and some of the challenges associated with antifungal therapy during pregnancy, including the teratogenicity of antifungal agents, their variable pharmacokinetics in pregnancy, the lack of well-defined treatment duration for such infections, and host factors including compliance. This patient's disease relapsed due to nonadherence after an initial course of intravenous amphotericin. Subsequently, she was successfully treated, with a favorable fetal outcome, with another 2 weeks of amphotericin B, followed by consolidation and maintenance with fluconazole and antiretroviral treatment. This case highlights and reviews the complexities of the management of cryptococcal meningitis in HIV-infected pregnant women.

Propionibacterium skull osteomyelitis treated with daptomycin.

Propionibacterium acnes (P. acnes) is emerging as a pathogen in postneurosurgical infections. A case of cranial bone flap infection due to P. acnes successfully treated with daptomycin is presented. This case demonstrates the potential of daptomycin as an option in the treatment of P. acnes.

Haemophilus influenzae CAPD peritonitis in an HIV-infected patient.

Haemophilus influenzae is a rare causative organism of CAPD peritonitis. This is a report of the first case of H. influenzae CAPD peritonitis in a host with HIV. The patient was successfully treated with a two-week course of intraperitoneal ampicillin. Peritoneal dialysis catheter removal was not required.