Experience with a six-month regimen of Pneumocystis pneumonia prophylaxis in 122 HIV-positive kidney transplant recipients.

Anti-Pneumocystis pneumonia (PCP) prophylaxis is recommended for 3 to 6 months post-transplant in HIV-negative kidney transplant recipients. For HIV-positive kidney transplant recipients, there is no definite duration of primary prophylaxis and is often prescribed life-long. The objective of this study was to determine the incidence of PCP in HIV-positive recipients who received 6 months of prophylaxis with trimethoprim-sulfamethoxazole or an alternative agent. One hundred and twenty-two HIV-positive recipients received a kidney transplant from 2001 to 2017 at Hahnemann University Hospital. Most patients received induction immunosuppression with an IL-2 receptor antagonist, with or without intravenous immunoglobulin. Only one patient received anti-thymocyte globulin. Maintenance immunosuppression included a calcineurin-inhibitor (tacrolimus or cyclosporine), an antiproliferative agent (mycophenolate or sirolimus), and prednisone. Mean CD4 cell count was 461 ± 127 cells/uL prior to transplant and 463 ± 229 cells/µL at 6 to 12 months after transplant. None of the recipients developed PCP after a median follow-up of 2.88 years (IQR 1.16-4.87). Based on our observation, a 6-month regimen of PCP prophylaxis may be sufficient among HIV-positive recipients, similar to those without HIV infection.

Dose-Dependent Hyperkalemia Among Hospitalized, HIV-Infected Patients Receiving Sulfamethoxazole/Trimethoprim.

Background: Sulfamethoxazole-trimethoprim (SXT) therapy is commonly used in HIV-infected patients and is associated with hyperkalemia and elevated serum creatinine (SCr). Objective: The purpose of this study was to examine the frequency of hyperkalemia and elevated SCr in hospitalized, HIV-infected patients receiving SXT. Methods: This was a retrospective, single-center cohort study. HIV-infected hospitalized patients receiving a minimum of 3 consecutive days of SXT were included. Patients were grouped according to high dose (≥10 mg/kg/d) and low dose (<10 mg/kg/d) trimethoprim. The primary end point was the frequency of hyperkalemia, severe hyperkalemia, and elevated SCr. Secondary end points included an evaluation of concomitant potassium-altering medications and concomitant nephrotoxic drugs. Results: A total of 100 consecutive patients were selected from all possible patients who met inclusion criteria. Overall, 47 patients experienced at least 1 adverse drug event (ADE) of either hyperkalemia or increased SCr, with 20 patients experiencing these ADEs in the low-dose group and 27 patients experiencing these ADEs in the high-dose group (P = 0.229). The ADEs of hyperkalemia or increased SCr occurred after a shorter period (5.5 vs 8.7 days) in the high-dose group (P = 0.049). Overall frequency of elevated SCr was 24% and of elevated serum K was 36%. Hyperkalemia requiring a therapeutic intervention occurred in 12 patients in the high-dose group compared with 2 in the low-dose group (P = 0.009). Conclusion and Relevance: Rates of elevated SCr and hyperkalemia in hospitalized HIV-infected patients receiving SXT are significant. Hyperkalemia requiring intervention is more common in patients receiving high-dose SXT.

Comparison of antibiotic prophylaxis with cotrimoxazole/colistin (COT/COL) versus ciprofloxacin (CIP) in patients with acute myeloid leukemia.

PURPOSE: Recent meta-analyses showed that antibiotic prophylaxis in patients with neutropenia after chemotherapy reduced the incidence of fever and mortality rate. Fluoroquinolones appear to be most effective and well tolerated. Thus, in April 2008, we changed our antibiotic prophylaxis regimen from cotrimoxazole/colistin (COT/COL) to the fluoroquinolone ciprofloxacin (CIP) in patients with acute myeloid leukemia (AML). The aim of this retrospective study was to compare efficacy and development of bacterial resistance with two different prophylaxis regimens over a time period of more than 4 years. METHODS: Induction chemotherapy courses given for AML during the antibiotic prophylaxis period with COT/COL (01/2006-04/2008) and CIP (04/2008-06/2010) were retrospectively analyzed with a standard questionnaire. RESULTS: Eighty-five courses in the COT/COL group and 105 in the CIP group were analyzed. The incidence of fever was not significantly different (COT/COL 80 % vs CIP 77 %; p = 0.724). Also, the rate of microbiologically documented infections was nearly the same (29 vs 26 %; p = 0.625). In addition, there was no significant difference in the incidence of clinically documented infections (11 vs 19 %; p = 0.155) or in the rates of detected gram-positive and gram-negative bacteria. Of note, there was no increase in resistance rates or cases with Clostridium difficile-associated diarrhea in the CIP group. CONCLUSION: The antibiotic prophylaxis with CIP compared to COT/COL in AML was similarly effective with no increase in bacterial resistance. COT/COL may have the advantages of providing additional prophylaxis against Pneumocystis jirovecii pneumonia and leaving fluoroquinolones as an additional option for treatment of febrile neutropenia.

[Effects of Fructus Psoralea and Brucea javanica on the level of IL-2 and NK cell in rats infected with Pneumocystis carinii].

SD rat model of PCP was established by subcutaneous injection with dexamethasone. The treatment groups received Fructus Psoralea (FP, 10.0 mg/kg), Brucea javanica (BJ, 1.2 mg/kg) and a mixture of the two Chinese herbs(FP 5mg/kg, BJ 0.6 mg/kg) respectively. By means of detecting the level of IL-2 in sera and NK cells in spleens, the effect of FP and BJ on the level of IL-2 and NK cells in rats with Pneumocystis carinii pneumonia (PCP) was observed, with SMZco treatment group (TMP 50 mg/kg, SMZ 250 mg/kg) and groups of infected and normal rats as controls. Compared with the infected group, the level of IL-2(526.1 +/- 5.5) pg/ml and NK cells (27.1% +/- 0.8%) significantly increased in the FP group (P < 0.01), followed by the FP/BJ combination group [(314.7 +/- 6.7) pg/ml, 22.9% +/- 0.9%) (P < 0.05)], and BJ group [(285.4 +/- 6.1) pg/ml, 20.7% +/- l.0%) (P < 0.05)]. Chinese herbs Fructus Psoralea and Brucea javanica show an immune regulatory action on the PCP rats.

Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection.

The safety and efficacy of a fixed 25 mg pyrimethamine-500 mg sulfadoxine combination supplemented with 15 mg folinic acid twice a week as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis was evaluated in 106 patients infected with the human immunodeficiency virus. All patients had a CD4+ T-lymphocyte count of less than 100 cells/microl at study entry. Efficacy in this single-arm open-label prospective study was analyzed on an as-treated basis. No patient received highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. PCP developed in four patients, one of whom had been noncompliant. No PCP episode occurred in the first year. Probabilities of freedom from PCP were 0.97 (95%CI, 0.92-1) after 24 months and 0.93 (95%CI, 0.84-1) after 36 months. Of 74 (69.8%) patients positive for anti-toxoplasma IgG antibodies, one noncompliant patient developed toxoplasmic encephalitis after 24 months. Allergic reactions were observed in 18 (17%) patients and resulted in permanent discontinuation in 7 (6.6%) patients. One (0.9%) patient who had continued prophylaxis despite progressive hypersensitivity reactions developed a serious adverse reaction (Stevens-Johnson syndrome). The median survival of study participants was 29 months, with relentless progression of AIDS accounting for most deaths. The prophylaxis regimen studied appeared safe and effective for primary prophylaxis of PCP and toxoplasmic encephalitis. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance. Efficacy and safety compare favorably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients failing or intolerant to approved regimens.

Pneumocystis carinii dihydropteroate synthase but not dihydrofolate reductase gene mutations correlate with prior trimethoprim-sulfamethoxazole or dapsone use.

Recent studies of the human Pneumocystis carinii dihydropteroate synthase (DHPS) gene suggest that P. carinii is developing resistance to sulfamethoxazole (SMX) and dapsone. To explore whether P. carinii is also developing resistance to trimethoprim (TMP), the human P. carinii dihydrofolate reductase (DHFR) gene was cloned, DHFR and DHPS genes in 37 P. carinii isolates from 35 patients were sequenced, and the relationship between TMP-SMX or dapsone use and gene mutations was analyzed. The DHFR gene sequences were identical in all isolates except 1 with a synonymous substitution. In contrast, the DHPS gene sequences showed mutations in 16 of the 37 isolates; prior sulfa/sulfone prophylaxis was associated with the presence of these mutations (P<.001). In addition to suggesting that there is less selective pressure on DHFR than on DHPS, this study reinforces the hypothesis that mutations in the DHPS gene are likely involved in the development of sulfa resistance in P. carinii.

Clinical aspects of Pneumocystis carinii pneumonia in HIV-infected patients: 1997.

In 1997 in Europe P. carinii pneumonia is largely a disease of individuals who are either unaware of their HIV serostatus or who decline prophylaxis despite knowing they are HIV positive. Although fibre optic bronchoscopy and bronchoalveolar lavage is the diagnostic 'gold standard' polymerase chain reaction (PCR) amplification applied to oropharyngeal washings appears to have a moderate to high diagnostic yield. With further development this may provide a truly non-invasive diagnostic test. There is a clear need for an inherently more effective regimen for prophylaxis both for those with adverse reactions (ADR) to co-trimoxazole and also for those with low CD4 lymphocyte counts. Ideally, new drug regimens should afford cross-prophylaxis against bacterial, mycobacterial and other fungal infections. Given the high frequency of ADR to co-trimoxazole when used as treatment for P. carinii pneumonia, there is also a need for effective, non-toxic alternative therapies.

San Francisco group demonstrates the ability of combination anti-HIV therapy to lower PHT.

AIDS: The Bay Area Perinatal AIDS Center (BAPAC) offers prenatal and HIV specialty care for HIV-positive women and for children. In the past two and a half years, BAPAC has treated 60 pregnant women, none of whom have transmitted HIV to their infants. The 62 infants born during this period will be followed for at least two years. Karen Beckerman, a physician at BAPAC, attributes the ideal transmission rate to combination therapy in the mothers, and to giving the babies AZT in compliance with ACTG 076 for six weeks. The infants also receive prophylactic treatment for Pneumocystis carinii pneumonia (PCP). Mothers in the program have seen some rises in viral load or have begun experiencing drug resistance, complicated by compliance issues. The program demonstrates the importance of counseling, testing, and aggressive treatment in women, and notes that outcomes are better when women receive care from staff experienced in dealing with HIV treatment issues.^ieng

Anecdotal reports: elderberry extract plus chondroitin and glucosamine sulfate and Thy-mate reduces viral load to non-detectable levels in 10 days.

AIDS: Several HIV patients offer anecdotal reports in which they attribute significant viral load reductions to taking elderberry extract. Thy-Mate was also used. Case studies from six patients are presented. In an interview, Steven Rahn describes his self-imposed treatment and its effect on his viral load. Another case discusses reports of dicalcium phosphate, a binding agent found in some dietary supplements such as glucosamine, inhibiting absorption of the supplements. Other cases are described, and contact information is included.^ieng

The tolerance for zidovudine plus thrice weekly or daily trimethoprim-sulfamethoxazole with and without leucovorin for primary prophylaxis in advanced HIV disease. California Collaborative Treatment Group.

PURPOSE: Trimethoprim-sulfamethoxazole (TMP/SMX) is the preferred agent for prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients with HIV infection, but frequent adverse events limit its usefulness. Intermittent dosing and supplementation with leucovorin have been tried in attempts to improve tolerance. We evaluated these strategies in persons with advanced HIV disease. METHOD: One hundred seven patients were enrolled. All had HIV infection, < 200 CD4+ lymphocytes per mm3, and no history of PCP. Fifty-two were randomized to TMP/SMX twice daily (BID); of these, 26 were randomized to leucovorin with each dose. Fifty-five patients were randomized to TMP/SMX (BID) 3 times per week; of these, 27 were randomized to leucovorin with each dose. All patients took zidovudine concurrently. RESULTS: The 24-week risk of discontinuation due to protocol-defined limiting toxicity was 24% with thrice-weekly TMP/SMX versus 42% with daily TMP/SMX (risk ratio 0.4; 95% CI 0.2 to 1.0). The risks of discontinuation for any reason were 41% and 59% (risk ratio 0.4; 95% CI 0.2 to 0.8). Clinical toxicity, such as headache and gastrointestinal distress, accounted for the observed difference in tolerance between dosing regimens. The 24-week risk of discontinuation due to protocol-defined toxicity was 33% in both the leucovorin and non-leucovorin groups (risk ratio 1.1; 95% CI 0.5 to 2.5). The risks of discontinuation for any reason were 53% and 47% (risk ratio 0.8; 95% CI 0.3 to 1.7). CONCLUSION: Intermittent therapy with TMP/SMX BID thrice weekly is better tolerated than daily BID therapy. Leucovorin use does not improve tolerance for chronic TMP/SMX dosing in AIDS, even among patients taking tablets daily.

Low-dose trimethoprim-sulfamethoxazole alone and in association with zidovudine for prevention and treatment of murine Pneumocystis carinii pneumonia.

Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) alone was found to be as effective as low-dose TMP-SMX plus zidovudine and standard-dose TMP-SMX alone in preventing and treating Pneumocystis carinii pneumonia (PCP) in an immunosuppressed-rat model. Zidovudine alone had no preventive or curative effect on PCP. We conclude that the initially reported reduced incidence of PCP in human immunodeficiency virus-infected patients treated with zidovudine alone is not due to anti-P. carinii activity of zidovudine. Furthermore, the clinical efficacy of low-dose TMP-SMX for the prevention and treatment of PCP should be further investigated.

Antipneumocystis activity of water-soluble lipopeptide L-693,989 in rats.

Water-soluble lipopeptide L-693,989 was evaluated for its antipneumocystis activity in rats. Rats from colonies with latent Pneumocystis carinii infections were immunosuppressed with dexamethasone for 6 weeks to facilitate the development of acute P. carinii pneumonia (PCP). After 6 weeks, the rats were maintained on dexamethasone and were treated twice daily for 4 days with various concentrations of L-693,989. At a dose of 0.15 mg/kg of body weight, the compound effectively eliminated 90% of the cysts in 4 days. Trophozoite forms of P. carinii were still present in these animals, as determined by using a P. carinii-specific DNA probe. A 3-week therapy study showed that the trophozoite load did not expand during treatment and that the trophozoites already present at the initiation of therapy appeared to persist. This may be a consequence of the stage specificity of the compound for cyst development and the severe immunosuppressive effects of dexamethasone on rats. When evaluated as a daily parenteral prophylactic agent, L-693,989 was effective in preventing the development of both P. carinii cysts and trophozoites, demonstrating its potential for use in prophylaxis and implying that the cyst stage of P. carinii is an obligatory step in trophozoite multiplication. The foamy exudate commonly associated with P. carinii infections was absent in the lungs of rats on prophylaxis. The compound was also evaluated via oral administration and was found to have a 90% effective dose of 32 mg/kg for therapy of acute infections and 5 mg/kg for daily prophylaxis.

Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial.

BACKGROUND: Prophylaxis with low-dose trimethoprim-sulfamethoxazole has been shown to be cost-effective in the prevention of urinary tract infections, pyelonephritis, urosepsis, and pneumocystis pneumonia in renal transplant recipients. Ciprofloxacin, effective against almost all urinary tract pathogens in this patient population, represents a promising alternative prophylactic agent for patients unable to tolerate trimethoprim-sulfamethoxazole due to toxicity. METHODS: We conducted a randomized, double-blind trial to compare low-dose trimethoprim-sulfamethoxazole with ciprofloxacin for the prevention of urinary tract infections in renal transplant recipients. Patients received either ciprofloxacin (250 mg) or trimethoprim-sulfamethoxazole (80 mg trimethoprim, 400 mg sulfamethoxazole) daily for 6 months following transplantation. Treatment was considered successful if patients completed the 6-month course and 3-month follow-up period without evidence of urinary tract infection or drug-related toxicities. RESULTS: Of 103 eligible patients, 51 received ciprofloxacin and 52 received trimethoprim-sulfamethoxazole. At 6 months, treatment was successful in 75% (38 of 51) receiving ciprofloxacin and 71% (37 of 52) treated with trimethoprim-sulfamethoxazole (P = 0.87, relative risk 1.04, 95% confidence limits 0.83 to 1.33). Thirteen patients (25%) receiving trimethoprim-sulfamethoxazole withdrew from the study-4 for resistant urinary tract infection and 9 for drug-related toxicity, while 3 (6%) of the patients receiving ciprofloxacin withdrew because of drug-related toxicity (P = 0.016, relative risk of urinary tract infection or adverse event 0.24, 95% confidence limits 0.07 to 0.78). At 9 months, all 38 patients who completed the 6-month course of ciprofloxacin remained free of urinary tract infection, while an additional 4 patients who had received trimethoprim-sulfamethoxazole prophylaxis (total of 8 patients over the 9 months) developed urinary tract infections (P = 0.006, Fisher's exact test for urinary tract infection alone). Pneumocystis pneumonia occurred in a total of 7 (14%) patients who were randomized to ciprofloxacin, but 2 of the 7 had withdrawn from the study at least 2 weeks prior to the diagnosis of pneumocystis pneumonia. There were no cases of pneumocystis pneumonia in patients receiving trimethoprim-sulfamethoxazole (P = 0.006). Following completion of the study, monthly aerosolized pentamidine administered in conjunction with ciprofloxacin has provided complete protection against urinary tract infection and pneumocystis pneumonia in 30 transplant recipients unable to tolerate trimethoprim-sulfamethoxazole therapy. CONCLUSIONS: Ciprofloxacin is at least as effective as trimethoprim-sulfamethoxazole in the prevention of urinary tract infection in renal transplant recipients, and is better tolerated. Ciprofloxacin prophylaxis is associated with a higher incidence of pneumocystis pneumonia than is trimethoprim-sulfamethoxazole therapy. An uncontrolled follow-up study suggests that ciprofloxacin prophylaxis combined with monthly aerosolized pentamidine may be efficacious in preventing both urinary tract infection and pneumocystis pneumonia in renal transplant recipients.

Models for evaluating compounds for activity against Pneumocystis carinii.

Cultures and animal models have been developed to provide reproducible and uniform systems for evaluation of compounds for effects on Pneumocystis carinii. The culture model allows rapid low-cost screening of drugs for activity against trophozoite forms. The animal models allow testing of efficacy for prophylaxis and therapy of Pneumocystis carinii pneumonia.

Synergistic anti-Pneumocystis carinii effects of erythromycin and sulfisoxazole.

Pneumocystis carinii pneumonitis was effectively prevented in 90% of immunosuppressed rats by the administration of 100 mg of erythromycin and 300 mg/kg/day of sulfisoxazole. All of the untreated control and erythromycin-treated animals developed the infection and 80% of rats given sulfisoxazole alone had the pneumonitis. A similar pattern of response occurred when the drugs were used therapeutically for rats with established P. carinii pneumonitis. The erythromycin and sulfisoxazole ratio of 1:3 was the most effective of several dose combinations tested. The established safety record from three decades of clinical use of this drug combination plus the broad spectrum of coverage for other causes of diffuse pneumonitis such as Chlamydia, Mycoplasma, and Legionella warrant further study of erythromycin-sulfisoxazole in AIDS patients.