High doses of the oral antibiotic rifampin did not improve survival outcomes in adults with tuberculous (TB) meningitis compared with standard therapy, finds a randomized controlled clinical trial published in the New England Journal of Medicine.

Meningitis is the most severe complication of TB, occurring when the bacteria reaches the brain. Despite antibiotic treatment, roughly half of TB meningitis patients die or incur severe, permanent damage. Previous research has shown that small amounts of rifampin, the most powerful antibiotic against TB, can reach the brain. But those studies did not explore the link between higher doses of rifampin and reduced mortality.

Mortality greater in high-dose group

For the study, led by researchers at Makerere University in Kampala, Uganda, 499 adults with confirmed TB meningitis in Indonesia, Uganda, and South Africa were assigned to receive either the standard treatment of four antibiotics (isoniazid, pyrazinamide, ethambutol, and 10 milligrams per kilogram [mg/kg] of rifampin) or the same regimen with a higher dose of rifampin (35 mg/kg). 

After six months, the trial found no evidence that higher-dose rifampin improved survival. In fact, mortality was greater in the higher-dose group (44.6%) than in the standard-dose group (40.7%). 

“It was, of course, disappointing that this is not the solution,” study coauthor Reinout van Crevel, MD, PhD, of the University of Oxford, said in a press release. “But these are important results—we now know we need to take a different path. That’s how science works.”

It’s unclear why the higher-dose rifampin group had worse outcomes, but one hypothesis is that the stronger dose may lead to a dysregulated immune response. Follow-up studies are underway to investigate why high-dose rifampin had no benefit.

Therapies that better control the inflammatory response of TB meningitis are urgently needed, say the researchers. Van Crevel will focus future research on tumor necrosis factor (TNF) inhibitors, a type of medication that blocks inflammation. 

“These drugs are sometimes used later in treatment of tuberculous meningitis when corticosteroids fail. But no one has used TNF inhibitors at the start of treatment—when most patients die,” he said. “That’s what we will investigate in the next clinical trial.”

More than two-thirds of retail medicine outlets in sub-Saharan Africa (SSA) regularly dispense antibiotics without a prescription, according to a study published today in JAC-Antimicrobial Resistance.

To evaluate current antimicrobial stewardship (AMS) practices in regulated retail medicine settings, which include community pharmacies, accredited drug dispensing outlets (ADDOs), and patient proprietary medicine vendors (PPMVs), British and Nigerian researchers conducted a review and meta-analysis of 26 studies examining the types of AMS interventions that are available in those settings, the factors that facilitate or hinder the implementation of such interventions, and the level of knowledge about antimicrobial resistance (AMR) and AMS activities among regulated retail medicine staff. They also analyzed data on antibiotic dispensing practices.

"The success of AMS programmes led by community pharmacists in LMICs [low- and middle-income countries] including SSA, is hindered by factors like limited AMR and AMS knowledge, time constraints, and inadequate resources," the study authors wrote. "Therefore, this study aimed to analyse existing studies to examine the knowledge, practices and challenges in delivering AMS interventions in regulated retail medicine settings across SSA."

68% of retail medicine outlets dispense antibiotics without a prescription

While the review found that community pharmacists generally have an awareness of the role that inappropriate antibiotic use plays in AMR, knowledge gaps among ADDO and PPMV staff, who have limited formal training, were more pronounced. Few studies documented AMS activities that have been implemented in these settings. Furthermore, in the 10 studies with extractable numeric data, the reported prevalence of non-prescription antibiotic dispensing ranged from 9% to 97%, with a median prevalence of 67.5%. 

Community pharmacies and medicine vendors reported dispensing antibiotics on demand for common self-limiting illnesses, including respiratory infections, diarrhea, and urinary tract infections. Non-prescription antibiotic prescribing was driven by patient demand, economic motives, and weak regulatory enforcement, the researchers found.

The authors say the findings reveal a "concerning disconnect" between knowledge of appropriate antibiotic use and actual dispensing behaviors, along with substantial barriers to proper AMS in these settings. 

"Our findings also suggest that while foundational knowledge exists, transforming awareness into consistent best practices requires addressing systemic educational and resource barriers in community pharmacy settings," they wrote.