{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:13:09Z","timestamp":1790799189101,"version":"4.1.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2014,10,1]],"date-time":"2014-10-01T00:00:00Z","timestamp":1412121600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR)<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>prompted the reintroduction of<jats:italic>para<\/jats:italic>-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR\/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR\/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, neither potential drug interactions nor the effects of HIV infection are known. Potential drug-drug interaction with PAS and the effect of HIV infection was examined in 73 pulmonary tuberculosis patients; 22 (30.1%) were HIV coinfected. Forty-one pulmonary MDR or XDR tuberculosis patients received 4 g PAS twice daily, and in a second crossover study, another 32 patients were randomized, receiving 4 g PAS twice daily or 8 g PAS once daily. A PAS population pharmacokinetic model in two dosing regimens was developed; potential covariates affecting its pharmacokinetics were examined, and Monte Carlo simulations were conducted evaluating the pharmacokinetic-pharmacodynamic index. The probability of target attainment (PTA) to maintain PAS levels above MIC during the dosing interval was estimated by simulation of once-, twice-, and thrice-daily dosing regimens not exceeding 12 g daily. Concurrent efavirenz (EFV) medication resulted in a 52% increase in PAS clearance and a corresponding &gt;30% reduction in mean PAS area under the concentration curve in 19 of 22 HIV-<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>-coinfected patients. Current practice recommends maintenance of PAS concentrations at \u22651 \u03bcg\/ml (the MIC of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>), but the model predicts that at only a minimum dose of 4 g twice daily can this PTA be achieved in at least 90% of the population, whether or not EFV is concomitantly administered. Once-daily dosing of 12 g PAS will not provide PAS concentrations exceeding the MIC over the entire dosing interval if coadministered with EFV, while 4 g twice daily ensures concentrations exceeding MIC over the entire dosing interval, even in HIV-infected patients who received EFV.<\/jats:p>","DOI":"10.1128\/aac.03073-14","type":"journal-article","created":{"date-parts":[[2014,8,12]],"date-time":"2014-08-12T06:36:28Z","timestamp":1407825388000},"page":"6242-6250","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["Pharmacokinetics of<i>para<\/i>-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis"],"prefix":"10.1128","volume":"58","author":[{"given":"Lizanne","family":"de Kock","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherwin K. 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