Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus (HIV)-infected patients, but little is known about the effects of this practice on the emergence of TMP-SMX-resistant bacteria. A serial cross-sectional study of resistance to TMP-SMX among all clinical isolates of Staphylococcus aureus and 7 genera of Enterobacteriaceae was performed at San Francisco General Hospital. Resistance among all isolates was <5.5% from 1979 to 1986 but then markedly increased, reaching 20.4% in 1995. This was most prominent in HIV-infected patients: resistance increased from 6.3% in 1988 to 53% in 1995. The largest increases in resistance were in Escherichia coli (24% in 1988 to 74% in 1995) and S. aureus (0% to 48%) obtained from HIV-infected patients. A rapid increase in the use of prophylactic TMP-SMX in HIV disease was also observed during this time in San Francisco and is likely responsible for the increase in TMP-SMX resistance.
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PMID:Emergence of trimethoprim-sulfamethoxazole resistance in the AIDS era. 1055 35

Based on the knowledge of the crystal structures of yeast and Escherichia coli thymidylate kinases (TmpKs) and the observation that TmpK from E. coli can phosphorylate azidothymidine monophosphate (AZT-MP) much more efficiently than either the yeast or the highly homologous human enzyme, we have engineered yeast and human TmpKs to obtain enzymes that have dramatically improved AZT-MP phosphorylation properties. These modified enzymes have properties that make them attractive candidates for gene therapeutic approaches to potentiating the action of AZT as an inhibitor of human immunodeficiency virus (HIV) replication. In particular, insertion of the lid domain of the bacterial TmpK into the human enzyme results in a pronounced change of the acceptance of AZT-MP such that it is now phosphorylated even faster than TMP.
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PMID:Modifying human thymidylate kinase to potentiate azidothymidine activation. 1058 90

Two hundred eleven adults with human immunodeficiency virus (HIV) infection hospitalized for community-acquired pneumonia, including Pneumocystis carinii pneumonia (PCP; patients), and 192 matched HIV-infected hospitalized patients without pneumonia (controls) were interviewed to determine risk factors for pneumonia. Multivariate logistic regression showed that patients were less likely than controls to have used trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.12-0.41) and more likely to have been hospitalized previously with pneumonia (OR, 6.25; CI, 3.40-11.5). Patients were also more likely than controls to have gardened (OR, 2.24; CI, 1.00-5.02) and to have camped or hiked (OR, 4.95; CI, 1.31-18.7), but stratified analysis by etiologic agent showed this association only for PCP. These findings reconfirm the efficacy of TMP-SMZ in preventing community-acquired pneumonia. In addition, hospitalization for pneumonia might represent a missed opportunity to encourage HIV-infected patients to enter into regular medical care and to adhere to prescribed antiretroviral and prophylaxis medications.
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PMID:Risk factors for community-acquired pneumonia among persons infected with human immunodeficiency virus. 1060 62

Toxoplasmic retinochoroiditis is an important opportunistic retinal infection in human immunodeficiency virus (HIV)-infected patients. It may present as diffuse necrotizing retinochoroiditis instead of a focal lesion and may be the initial manifestation of HIV infection. A 50-year-old heterosexual man presented with blurred vision in his left eye of 3 months' duration. Fundus examination revealed diffuse necrotizing retinochoroiditis, mainly at the posterior pole, with marked vitritis in the left eye. Serologic studies and aqueous fluid antibody titers indicated recent toxoplasmic infection. Positive enzyme immunoassays (EIA) and Western blot tests proved HIV infection. The retinochoroiditis and vitritis improved after an antitoxoplasmic regimen with trimethoprim-sulfamethoxazole (TMP-SMX). Nonetheless, toxoplasmic encephalitis developed 6 months after the onset of ocular toxoplasmosis and responded well to TMP-SMX. This is the first case of toxoplasmic retinochoroiditis as the initial manifestation of AIDS reported in Taiwan. We suggest that Toxoplasma infection should be included in the differential diagnosis of diffuse necrotizing retinochoroiditis and vitritis. We also recommend that adults with newly diagnosed ocular toxoplasmosis be screened for HIV infection.
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PMID:Diffuse toxoplasmic retinochoroiditis as the initial manifestation of acquired immunodeficiency syndrome. 1082 Sep 54

Initiation of human immunodeficiency virus-1 reverse transcription requires formation of a complex containing the viral RNA, primer tRNA(3)(Lys), and reverse transcriptase. Initiation, corresponding to addition of the first six nucleotides to tRNA(3)(Lys), is distinguished from elongation by its high specificity and low efficiency (processivity). Here, we compared the inhibition of initiation and elongation of reverse transcription by 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP), the active form of 3'-azido-3'-deoxythymidine. We report the first detailed study of nucleotide binding, discrimination, and pyrophosphorolysis by the authentic initiation complex. We showed that the initiation and elongation complexes bound AZTTP and dTTP with the same affinity, while the polymerization rates were reduced by 148-160-fold during initiation. The pyrophosphorolysis rate of dTTP was reduced by the same extent, indicating that the polymerization equilibrium is the same in the two phases. The efficient unblocking of the 3'-azido-3'-deoxythymidine 5'-monophosphate (AZTMP)-terminated primer by pyrophosphorolysis significantly relieved inhibition of DNA synthesis during elongation in the presence of physiological pyrophosphate concentrations. Remarkably, although pyrophosphorolysis of dTMP and AZTMP were equally efficient during elongation, reverse transcriptase was almost totally unable to unblock the AZTMP-terminated primer during initiation. As a result, inhibition of reverse transcription by AZTTP was more efficient during initiation than elongation of reverse transcription, despite a reduced selectivity of incorporation.
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PMID:Inhibition of the initiation of HIV-1 reverse transcription by 3'-azido-3'-deoxythymidine. Comparison with elongation. 1086 29

Cyclosaligenyl-2',3'-didehydro-2', 3'-dideoxythymidine-5'-monophosphate (cycloSal-d4TMP) is a potent and selective inhibitor of human immunodeficiency virus replication in cell culture and differs from other nucleotide prodrug approaches in that it is designed to selectively deliver the nucleotide 5'-monophosphate by a controlled, chemically induced hydrolysis. Its antiviral efficacy in cell culture is at least as good as, if not superior to, that of d4T. CycloSal-d4TMP was found to lead to the efficient intracellular release of d4TMP in a variety of cell lines, including both wild-type CEM and thymidine kinase-deficient CEM/TK(-) cells. Under similar experimental conditions, exposure of CEM/TK(-) cells to d4T failed to result in significant d4TTP levels. The intracellular conversion of cycloSal-d4TMP proved to be both time and dose dependent. The half-life of d4TTP generated intracellularly from d4T- or cycloSal-d4TMP-treated CEM cells was approximately 3.5 h, and the intracellular ratios of d4TTP/d4TMP in cells exposed to cycloSal-d4TMP gradually increased from 1 to 3.4 upon prolonged incubation. Radiolabeled cycloSal-d4TMP could be separated as its two R(p) and S(p) diastereomers on high-performance liquid chromatography. The R(p) diastereomer of cycloSal-d4TMP was 3- to 7-fold more efficient in releasing d4TMP and generating d4TTP than the S(p) cycloSal-d4TMP diastereomer. This correlated well with the 5-fold more pronounced antiviral activity of the R(p) diastereomer versus the S(p) diastereomer. d4TMP is a poor substrate for the cytosolic 5'(3')-deoxyribonucleotidase (V(max)/K(m) for d4TMP: 0.08 of V(max)/K(m) for dTMP) and is only slowly hydrolyzed to d4T. This contributes to the efficient conversion of the prodrug of d4TTP.
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PMID:Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate: efficient intracellular delivery of d4TMP. 1104 39

To determine the prevalence of sexually transmitted diseases (STDs), we screened 107 human immunodeficiency virus-positive patients in Peru, where the virus is predominantly sexually transmitted. Patients had multiple risk factors for STDs, and 38% of women and 50% of men had at least 1 STD (gonorrhea, trichomoniasis, herpes simplex, anogenital warts, or syphilis seropositivity). No chlamydial infection was detected, even though infection rates in the general population are 5%-12%. Patients receiving trimethoprim-sulfamethoxazole(TMP-SMZ) for prophylaxis or treatment of respiratory infections were least likely to have cervicitis and/or urethritis (odds ratio, 0.37; 95% confidence interval, 0.15-0.89). Although not optimal treatment, administration of TMP-SMZ is effective against chlamydial infection. We speculate that the use of concomitant medications, such as TMP-SMZ, may be inadvertently preventing chlamydial infection in this population. Another finding was the presence of Trichomonas vaginalis in pharyngeal specimens of 3 men with histories of orogenital activity. This has not been previously reported and requires further study.
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PMID:Screening for sexually transmitted diseases in human immunodeficiency virus-positive patients in Peru reveals an absence of Chlamydia trachomatis and identifies Trichomonas vaginalis in pharyngeal specimens. 1122 50

Trimethoprim-sulfamethoxazole (TMP-SMZ) is widely prescribed as prophylaxis for Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus (HIV)-infected persons. Its efficacy against other infections has not been thoroughly evaluated. To compare the risk for infectious diseases for persons who were prescribed TMP-SMZ with that for patients who were not prescribed TMP-SMZ, we examined data collected from the medical records of HIV-infected patients (January 1990 through September 1999) who were enrolled in the Adult and Adolescent Spectrum of HIV Disease Project. During intervals when patients had CD4(+) T lymphocyte counts of <200 cells/microL (19,081 persons; 22,801 person-years), prescription of TMP-SMZ was associated with significant protection from toxoplasmosis, salmonellosis, infection with Haemophilus species, invasive or any staphylococcal infection, and PCP, but not from Shigella, pneumococcal or nonpneumococcal Streptococcus, Klebsiella, or Pseudomonas species. We demonstrate that prescription of TMP-SMZ for PCP prophylaxis in persons with HIV infection is associated with significantly decreased risk for several infectious diseases. These findings may be of interest to HIV prevention programs in resource-poor countries.
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PMID:Prophylaxis with trimethoprim-sulfamethoxazole for human immunodeficiency virus-infected patients: impact on risk for infectious diseases. 1143 10

Prophylaxis against Pneumocystis carinii pneumonia (PCP) is an essential part of the management of children with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). No dose-ranging studies were ever performed; therefore, the amount of trimethoprim-sulfamethoxazole (TMP-SMX) needed to suppress PCP in children with HIV/AIDS is not known. The dose recommended by the Centers for Disease Control (CDC) has been thought to be just above the threshold needed for prevention, based on anecdotal breakthrough PCP in cancer patients who were improperly dosed. We have been giving prophylaxis based on body weight rather than surface area, and this, combined with growth of our children, has led to a large experience with dosages lower than the currently recommended 150 mg/m2. The medical records of children with HIV who met CDC guidelines for institution of PCP prophylaxis were reviewed. To ascertain the per square meter (m2) dosage each child was receiving, body surface area was calculated from height and weight measurements. Dosages were recalculated every 6 months and at each dosage change. Data regarding PCP infection, bacterial infections, and side effects of TMP-SMX were extracted. Data were compiled from 1,719.5 child-months of TMP-SMX prophylaxis, including 1,532.5 child-months below the currently recommended dose. Sixty-seven percent of our child-months were at or below two-thirds the CDC recommended dose. There were no cases of proven or suspected PCP. Incidence of other serious bacterial infections was low. Bacteremia and sepsis with Streptococcus pneumoniae was the most common proven bacterial infection, at a rate of 5.5 episodes per 100 child-years. The incidence of bacterial infection did not vary by the dose of TMP-SMX. TMP-SMX prophylaxis was well tolerated; most reactions were mild and self-limited and did not recur with re-institution of the drug. Only 6.1% of this cohort had TMP-SMX prophylaxis discontinued due to perceived toxicity. These data show that the currently recommended dose of TMP-SMX (150 mg/m2) may not be required to prevent PCP in children with HIV/AIDS. The drug is well tolerated at all dosage levels. The incidence of serious bacterial infection in this cohort of patients did not depend upon the amount of TMP-SMX prescribed. A prospective, controlled clinical trial of low-dose TMP-SMX for children with HIV infection is warranted.
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PMID:Successful prophylaxis against Pneumocystis carinii pneumonia in HIV-infected children using smaller than recommended dosages of trimethoprim-sulfamethoxazole. 1153 Jul 67

Trimethoprim-sulfamethoxazole (TMP-SMZ) is the most effective Pneumocystis carinii pneumonia (PCP) prophylactic agent, but adverse reactions are common among human immunodeficiency virus (HIV)-infected patients and limit its use. This randomized, double-blind controlled trial compared 2 methods of TMP-SMZ reintroduction, 6-day dose escalation and direct rechallenge, for PCP prophylaxis in HIV-infected patients who had experienced previous treatment-limiting reactions. The primary end point was the ability to take single-strength TMP-SMZ daily for 6 months. Seventy-five percent of the dose-escalation group and 57% of the direct-rechallenge group continued to receive daily single-strength TMP-SMZ for 6 months (P= .014). Among premature discontinuations, 58% of the dose-escalation group and 70% of the direct-rechallenge group were due to adverse reactions. None of these reactions was serious. This study provides evidence that it is possible to successfully reintroduce TMP-SMZ to a significant proportion of HIV-infected patients who have experienced mild-to-moderate treatment-limiting adverse reactions.
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PMID:Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis Carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. 1157 13


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