The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients.
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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In the citing paper
“These DHPS gene mutations were rarely found in clinical isolates before the early 1990s (19,20,22).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [19]
In the citing paper
“Nevertheless, seven of the nine studies found that most HIV-infected patients with a diagnosis of PCP who had been prescribed TMP-SMX or dapsone for PCP prophylaxis had Pneumocystis that contained DHPS mutations (range 19%–80%, Table 2) (19–24,30).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [19]
In the citing paper
“Several studies have consistently demonstrated a significant association between the use of TMP-SMX or dapsone for PCP prophylaxis in HIV-infected persons and the presence of DHPS gene mutations (Table 2) (19–25,30).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [19]
In the citing paper
“Sulfa medications appear to exert selective pressure on Pneumocystis (18), as the DHPS gene is more likely to display mutations in highly conserved regions in patients with PCP who have previously been exposed to sulfa medications (19–25).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [19]
In the citing paper
“Both patients with DHPS mutations who were treated with TMP-SMX responded to treatment.”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [19]
Citations
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Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase
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A Meta-analysis of the Relative Efficacy and Toxicity of Pneumocystis carinii Prophylactic Regimens
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Research works printed but not linked: 2
- 1992, MMWR, 41, 1
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Cited by
Sorted by citations
A New Name for Pneumocystis from Humans and New Perspectives on the Host-Pathogen Relationship
Stringer, J. R., Beard, C. B., Miller, R. F., & Wakefield, A. E. (2002) · Emerging infectious diseases · doi:10.3201/eid0809.020096 · Cited by 488
Colonization by Pneumocystis jirovecii and Its Role in Disease
Morris, A. M., & Norris, K. A. (2012) · Clinical Microbiology Reviews · doi:10.1128/cmr.00013-12 · Cited by 432
Alanio, A., Hauser, P. M., Lagrou, K., Melchers, W. J. G., Helweg‐Larsen, J., Matos, O., Cesaro, S., Maschmeyer, G., Einsele, H., Donnelly, J. P., et al. (2016) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkw156 · Cited by 420
Trimethoprim-Sulfamethoxazole Revisited
Masters, P. A., O’Bryan, T. A., Zurlo, J. J., Miller, D. Q., & Joshi, N. (2003) · Archives of Internal Medicine · doi:10.1001/archinte.163.4.402 · Cited by 426
Helweg-Larsen, J., Benfield, T. L., Eugen-Olsen, J., Lundgren, J. D., & Lundgren, B. (1999) · The Lancet · doi:10.1016/s0140-6736(99)03320-6 · Cited by 274
Metadata
- 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)
- Venue
- AIDS
- Published
- 1998-05
- Volume
- 12
- Issue
- 8
- Pages
- 873-878
- ISSN
- 0269-9370 (ISSN-L)
- 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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