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Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients
Chawangwa Modongo1, Jotam G Pasipanodya2, Nicola M Zetola3
1Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania, USA Botswana-University of Pennsylvania Partnership, Gaborone, Botswana.
Abstract:
Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis.
Insights
Cumulative amikacin exposure and therapy duration, not peak/trough levels, predict ototoxicity in multidrug-resistant tuberculosis. Monitoring cumulative area under the curve (AUC) is crucial for preventing hearing loss.
Area of Science:
- Pharmacology and Toxicology
- Infectious Diseases
- Machine Learning in Medicine
Background:
- Aminoglycosides like amikacin are vital for treating multidrug-resistant tuberculosis (MDR-TB).
- Ototoxicity is a significant adverse effect, typically monitored by World Health Organization-recommended peak and trough amikacin concentrations.
- Existing monitoring strategies may not effectively predict or prevent amikacin-induced ototoxicity.
Purpose of the Study:
- To identify clinical factors, using machine learning, that predict audiometry-confirmed ototoxicity in MDR-TB patients.
- To evaluate the predictive performance of cumulative amikacin exposure versus peak/trough concentrations for ototoxicity.
- To establish thresholds for cumulative amikacin exposure associated with specific probabilities of ototoxicity.
Main Methods:
- Classification and Regression Tree (CART) analysis was employed to identify predictors of ototoxicity.
- Probit analysis quantified the relationship between predictive factors and ototoxicity probability.
- Amikacin concentrations, therapy duration, and audiometry results were analyzed in 28 MDR-TB patients.
Main Results:
- Cumulative days of therapy and cumulative amikacin area under the concentration-time curve (AUC) were primary predictors of ototoxicity.
- Peak and trough amikacin concentrations did not predict ototoxicity; their inclusion significantly reduced model performance (AUC 0.46).
- Otoxicity probability increased sharply after 6 months, nearing maximum at 9 months; a cumulative AUC threshold for 10% ototoxicity was 87,232 days·mg·h/L.
Conclusions:
- Cumulative amikacin AUC and duration of therapy are superior predictors of ototoxicity compared to peak and trough levels.
- Clinical decision-making to minimize ototoxicity risk should prioritize monitoring cumulative amikacin exposure and treatment duration.
- These findings necessitate a shift in monitoring strategies for amikacin therapy in MDR-TB patients to improve safety.
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