Cited by 172Pneumocystis jirovecii pneumonia detection and treatmentPneumonia and Respiratory InfectionsHIV/AIDS drug development and treatment

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Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients.

Kazanjian, Powel, Locke, Amy B., Hossler, Paul A., Lane, Brian R., Bartlett, Marilyn S., Smith, James W., Cannon, Mark, Meshnick, Steven R.·1998·AIDS

DOI 10.1097/00002030-199808000-00009

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Abstract

BACKGROUND: Failures of prophylaxis against Pneumocystis carinii pneumonia (PCP) in AIDS patients do occur, but no evidence for drug resistance has yet been presented. OBJECTIVE: To determine whether mutations in the sulfa and sulfone drug target are associated with failure of prophylaxis using a sulfa-containing agent. METHODS: Portions of the gene for P. carinii dihydropteroate synthase (DHPS), the sulfa and sulfone target, from 27 patients (20 of whom had AIDS) diagnosed with PCP between 1976 and 1997 were amplified using polymerase chain reaction and sequenced. Seven of the 27 patients (all of whom had AIDS) were receiving sulfa or sulfone drugs as prophylaxis for PCP. RESULTS: Mutations were found at only two amino-acid positions and were significantly more common in patients who received sulfa/sulfone prophylaxis. Mutations were observed in five (71%) out of seven isolates from AIDS patients receiving sulfa/sulfone as prophylaxis compared with only two (15%) out of 13 specimens from AIDS patients who did not (P = 0.022). No mutations were seen in isolates from seven non-HIV-infected patients, none of whom were on prophylaxis. Mutations were only observed in specimens obtained in 1995-1997. CONCLUSIONS: Mutations in two amino-acid positions were significantly more common in AIDS patients with PCP who failed sulfa/sulfone prophylaxis. These amino acids appeared to be directly involved in both substrate and sulfa binding, based on homology to the Escherichia coli DHPS crystal structure. Thus, the results were consistent with the possibility that mutations in the P. carinii DHPS are responsible for some of the failures of sulfa/sulfone prophylaxis in AIDS patients.

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Authors: Kazanjian, P., Locke, A. B., Hossler, P. A., Lane, B. R., Bartlett, M. S., Smith, J. W., Cannon, M., & Meshnick, S. R.
Affiliations: University of Michigan (US)
Indiana University (US)
ORCID: Kazanjian, Powel
Locke, Amy B.
Lane, Brian R.
Smith, James W.
Venue: AIDS
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 1998-05
Volume: 12
Issue: 8
Pages: 873-878
ISSN: 0269-9370 (ISSN-L)
DOI: 10.1097/00002030-199808000-00009
OpenAlex: W2027990333
Cited by: 171
References: 20
Citations by year: 2025: 2 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 3 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 5 · 2015: 5 · 2014: 4 · 2013: 6 · 2012: 6
FWCI: 12.18
Type: journal article
Language: en
Open access: closed
Locations: AIDS (publishedVersion)
PubMed (publishedVersion)
Funders: University of Michigan
National Institutes of Health (5r01ai031775-05)
National Institute of Allergy and Infectious Diseases (R01-AI 31775)
Topics: Health Sciences › Medicine › Epidemiology › Pneumocystis jirovecii pneumonia detection and treatment
Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords: Pneumocystis carinii, Pneumocystis carinii pneumonia, dihydropteroate synthase, dhps mutations, drug resistance, prophylaxis failure, amino acid substitutions
MeSH terms: Adolescent, Adult, Aged, Amino Acid Sequence, Anti-Infective Agents, Child, Dapsone, Dihydropteroate Synthase, Drug Resistance, Microbial, Female, Humans, Infant, Male, Middle Aged, Mutation, Pneumocystis, Pneumonia, Pneumocystis, Trimethoprim, Sulfamethoxazole Drug Combination, Polymerase Chain Reaction, AIDS-Related Opportunistic Infections, Treatment Failure, Sequence Analysis, DNA

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Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients.

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