Tuberculosis (TB) remains a major global health challenge despite the availability of effective antimicrobial therapy and standardized multidrug treatment regimens. Although current treatment approaches achieve favorable outcomes in many patients, considerable variability in treatment response, bacterial clearance, relapse, and treatment failure persists. Such variability cannot be explained solely by drug efficacy and instead reflects the complex biological environment in which anti-tuberculosis therapy operates. Treatment outcomes are influenced by multiple interconnected determinants, including host-related factors, pharmacological variability, lesion heterogeneity, and pathogen-specific characteristics. Host factors such as immune status, diabetes, HIV infection, and malnutrition can significantly alter disease progression and therapeutic response. Pharmacokinetic variability may result in substantial differences in systemic and tissue drug exposure among patients receiving similar guideline-based treatment regimens. At the site of infection, heterogeneous lesion microenvironments influence drug penetration and bacterial survival, while pathogen-related factors, including bacterial burden, persistence, drug tolerance, and antimicrobial resistance, further contribute to variability in treatment outcomes. Understanding the interplay among host, pathogen, lesion, and pharmacological factors provides important opportunities for improving treatment precision and therapeutic effectiveness. This review examines the major determinants influencing tuberculosis treatment outcomes and discusses emerging precision-therapy strategies, including therapeutic drug monitoring, patient stratification, lesion-informed treatment approaches, and host-directed interventions. Recognizing and addressing biological variability may represent an important step toward more individualized and effective tuberculosis management.
Background Aminoglycosides are widely used in dual antipseudomonal therapy for acute pulmonary exacerbations in cystic fibrosis (CF). Due to altered pharmacokinetics in CF, achieving recommended pharmacokinetic/pharmacodynamic (PK/PD) targets is challenging and the impact of target attainment on clinical outcomes remains unclear. Objectives To evaluate whether currently recommended aminoglycoside dosing regimens in CF achieve PK/PD targets in clinical practice, and whether target attainment correlates with clinical improvements in CF patients. Design/methods A two-year, single-center cohort study was conducted in adult CF patients receiving aminoglycoside during acute exacerbation. Aminoglycoside levels were obtained to estimate PK parameters. Clinical symptoms and pulmonary function were assessed at admission (baseline) and discharge. Results Fourteen treatment courses were analyzed among nine patients. Amikacin (n=10, mean dose 30.9 ± 2 mg/kg), or gentamicin (n=4, mean dose 10.5 ± 0.7 mg/kg) were administered. The target C max :MIC ratio of 8-10 was achieved in 50% of amikacin courses and none of the gentamicin courses. Most patients improved clinically, evident by symptoms’ resolution and increased ppFEV 1 . Target attainment was associated with a numerically greater ppFEV 1 improvement, though not statistically significant (P=0.29). Conclusions The pre-defined PK/PD target was attained in less than half of the cases treated, underscoring the need for optimized dosing strategies. Nonetheless, clinical improvement occurred regardless of target attainment. This highlights the need of larger randomized controlled studies to define the relationship between aminoglycoside PK/PD target achievement and clinical outcomes among CF patients.
Enterococcal bacteremia and endovascular infections remain difficult to treat because of intrinsic antimicrobial tolerance, increasing resistance, and frequent involvement of high-inoculum or deep-seated infection. While β-lactams generally demonstrate limited bacterial killing activity against enterococci when used alone, accumulating experimental and clinical data suggest that selected β-lactams may enhance the activity of companion agents, particularly daptomycin. This narrative review summarizes the mechanistic rationale, preclinical evidence, and available clinical data supporting adjunctive β-lactams for enterococcal bacteremia and endovascular infections. The strongest clinical evidence supports ampicillin plus ceftriaxone for Enterococcus faecalis infective endocarditis, whereas emerging data suggest that selected β-lactams may potentiate high-dose daptomycin against vancomycin-resistant Enterococcus faecium . Proposed mechanisms include complementary penicillin-binding protein inhibition, alterations in cell envelope physiology, increased antimicrobial binding, and suppression of resistance emergence. However, available clinical data are derived largely from retrospective studies and remain heterogenous with respect to patient populations, infectious syndromes, β-lactam selection, dosing strategies, and treatment duration. Current evidence favors a phenotype-directed approach rather than routine combination therapy for all enterococcal bloodstream infections. Adjunctive β-lactams appear most justifiable in patients with persistent bacteremia, endovascular infection, high-inoculum disease, elevated daptomycin minimum inhibitory concentrations, prosthetic material, or other features associated with microbiologic failure or relapse, whereas uncomplicated bacteremia may derive limited benefit. Important questions remain regarding optimal patient selection, β-lactam choice, and duration of therapy. Given the practical and financial barriers to conducting randomized trials in this population, mechanistic, translational, and observational studies will likely remain the foundation of real-world clinical decision-making.
Candida auris osteomyelitis is an uncommon manifestation but poses a major therapeutic challenge because of limited antifungal options and management data. We report a case of a patient with multidrug resistant C. auris osteomyelitis resistant to azoles, echinocandins, and amphotericin B who was managed with aggressive surgical debridement and fosmanogepix obtained through an expanded access protocol. The patient achieved complete wound healing with clinical improvement. This case highlights the potential role of fosmanogepix as part of a multidisciplinary approach for difficult-to-treat multidrug resistant C. auris osteomyelitis and underscores the need for further clinical and pharmacokinetic studies evaluating its use in bone infections.
Histoplasmosis is a fungal infection caused by the true pathogen Histoplasma capsulatum that closely resembles tuberculosis, can infect immunocompetent as well as immunocompromised people, and remains poorly characterised in Uganda. This narrative review, guided by SANRA, brings together the Ugandan evidence across ecology, epidemiology, clinical presentation, diagnosis and treatment, and identifies where the evidence is absent. Exposure has been documented in Uganda for more than five decades, from pre-HIV histoplasmin foci near the Nile and Lake Victoria to a documented outbreak among visitors to a Ugandan rainforest traced to a bat-infested tree, and to antigen-positive patients in recent Kampala cohorts. The most substantial national evidence, a prospective study of 332 persons with advanced HIV disease across nine facilities, found histoplasmosis in 2.4 percent, all probable cases, with relatively good survival among untreated patients but with five of eight cases entangled with current or prior tuberculosis. This review therefore does not claim a large hidden burden of disseminated disease in that population. It argues instead that the question has not been asked of the right patients with the right test. No Ugandan study has screened patients under investigation for tuberculosis, a population in which antigen prevalence elsewhere in Africa has reached 24 percent, and none has tested for chronic pulmonary histoplasmosis, the form most often misdiagnosed as tuberculosis, in the large Ugandan population with post-tuberculous lung damage, where chronic pulmonary aspergillosis is already established. Whether antigenuria in advanced HIV disease warrants antifungal therapy in the absence of symptoms remains contested. An unvalidated screening pathway is proposed, requiring prospective evaluation and set out as separate algorithms for people living with HIV and HIV-negative individuals, that reflexes antigen testing onto a urine specimen already collected, includes GeneXpert-positive patients because co-infection is common, offers Giemsa microscopy of skin and oronasal lesion smears and, where antigen assays are unavailable, of other specimens, reserves antibody testing for suspected chronic pulmonary disease, and treats symptomatic rather than incidental antigen positivity. Research priorities are set out against the ISHAM 2030 targets.
