Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance

Laurence Huang,Jannik Helweg-Larsen,Robert Miller,Kristina Crothers,Chiara Atzori,Thomas Benfield,Meja Rabodonirina

doi:10.3201/eid1010.030994

Abstract

Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.

Highlights

Sulfa ResistanceLaurence Huang,* Kristina Crothers,* Chiara Atzori,† Thomas Benfield,‡ Robert Miller,§ Meja Rabodonirina,¶ and Jannik Helweg-Larsen#
Infected patients with PCP is a complex issue, with multiple factors affecting death, including those related to the patient, the patient’s overall health status, the underlying HIV/AIDS, and, those specific factors related to PCP
The overall number of patients studied and the subset of patients who had Pneumocystis that contained DHPS mutations and were treated with TMP-SMX or dapsone plus trimethoprim were too small to account for these factors and to detect small differences in outcome that may be related to drug resistance

Summary

Sulfa Resistance

Laurence Huang,* Kristina Crothers,* Chiara Atzori,† Thomas Benfield,‡ Robert Miller,§ Meja Rabodonirina,¶ and Jannik Helweg-Larsen#. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations Whether these mutations confer resistance to TMPSMX or dapsone plus trimethoprim for PCP treatment remains unclear. While prophylaxis has been shown to reduce the incidence of PCP, the widespread and long-term use of TMP-SMX in HIV patients has raised concerns regarding the development of resistant organisms. Some strains of Neisseria meningitidis have acquired a DHPS gene with 10% sequence divergence, postulated by others to be due to recombination [12], whereas other Neisseria strains have acquired a chromosomal insertion, resulting in the addition of two amino acids to DHPS [13] In other organisms, such as E. coli and Plasmodium falciparum, nonsynonymous point mutations resulting in amino acid substitutions in DHPS can confer sulfa resistance [14,15]. The accumulation of additional mutations over time can confer increasing levels of sulfa resistance, as has occurred in P. falciparum [16]

Dihydropteroate Synthase Mutations in Pneumocystis

Association of Sulfamethoxazole and Dapsone with DHPS Gene Mutations

Lack of Association of Trimethoprim with DHFR Gene Mutations

Clinical Importance of DHPS Gene Mutations in Pneumocystis jirovecii