Treatment of Experimental Pneumocystis carinii Pneumonia with Analogs of Pentamidine

Seven analogs of pentamidine were tested for their activity against an immunosuppressed rat model of Pneumocystis carinii pneumonia. Structural alterations of the pentamidine molecule included variations of the alkyl chain linking the two p-amidino phenoxy moieties and relocation of the amidine groups from the para to the meu position on the phenoxy rings. All analogs of pentamidine were active against P. carinii pneumonia when compared to a saline-treated control group. One derivative, 1, 4-di(4'-amidinophenoxy)butanc, proved to be statistically more active than the parent drug.     

Treatment and prophylaxis for Pneumocystis carinii pneumonia

Without treatment, Pneumocystis carinii pneumonitis is almost always fatal in the immunocompromised host. Here, Walter Hughes discusses proven and potential treatments, and methods of chemoprophylaxis in high-risk patients. Two drugs, pentamidine isethionate and trimethoprimsulfamethoxazole, are equally effective therapeutically - permitting the recovery of approximately 75% of patients - but the latter drug combination is preferred because of its lower toxicity and fewer adverse effects. The pneumonitis can be prevented by prophylactic administration of trimethoprim-sulfamethoxazole. Other drugs with proven efficacy or under study include Fansidar, dapsone, trimetrexate and difluoromethylornithine.     

Identification and Characterization of an Endo/exonuclease in Pneumocystis carinii that is Inhibited by Dicationic Diarylfurans with Efficacy Against Pneumocystis Pneumonia

ABSTRACT Dicationic diarylfurans and dicationic carbazoles are under development as therapeutic agents against opportunistic infections. While their ability to bind to the minor groove of DNA has been established, the complete mechanism of action has not. We demonstrate here that an effective diarylfuran, 2,5-bis[4-(N-isopropylguanyl)phenyl]furan. inhibits an endo/exonuclease activity present in Pneumocystis carinii, Cryptococcus neoformans, Candida albicans , and Saccharomyces cerevisiae. This activity was purified from the particulate fraction of P. carinii. The enzyme requires Mg⁺⁺ or Mn⁺⁺, and shows preferences for single- over double stranded DNA and for AT-rich over GC-rich domains. A panel of 12 dicationic diarylfurans and eight dicationic carbazoles, previously synthesized, were evaluated for inhibition of the purified nuclease and for efficacy against Pneumocystis pneumonia in rats. Among the diarylfurans, potency of nuclease inhibition, in vivo antimicrobial activity, and DNA binding strength were all strongly correlated (p < 0.001). These findings suggest that one target for antimicrobial action of the diarylfurans may be a nucleolytic or other event requiring unpairing of DNA strands. Dicationic carbazoles which were strong nuclease inhibitors all displayed anti- Pneumocystis activity in vivo, but there were also noninhibitory carbazoles with in vivo efficacy.     

Pneumocystis Pneumonia: Epidemiology and Options for Prophylaxis in Non-HIV Immunocompromised Pediatric Patients

The pediatric population of non-HIV immunocompromised patients at risk for Pneumocystis pneumonia (PCP) continues to increase. While prophylactic therapy can be highly effective in preventing this opportunistic pathogen, identifying the at-risk populations appropriate for use of prophylaxis and navigating the risks and benefits of each therapeutic option can be challenging. In this article, the available epidemiology for baseline rates of PCP is presented for a variety of non-HIV immunocompromised pediatric populations. Additionally, the comparative effectiveness and side effect profiles for trimethoprim/sulfamethoxazole, dapsone, atovaquone, and pentamidine are discussed. Institutions are encouraged to review the data and to establish and implement a local practice guideline for PCP prophylaxis that can be monitored for effectiveness over time. An example of a standardized practice guideline is suggested.     

Propagation and Purification of Rat Pneumocystis carinii in Short-Term Cell

A short-term cell culture is used to propagate and purify rat-derived Pneumocystis carinii (Pc). An aliquot of pelleted material washed out of the lungs of rats with moderate to severe Pc pneumonia is cultured for 7 to 10 days on the adherent mink lung cell line Mv 1 Lu, and the rest of the material is frozen down in medium with 10% glycerol. Although it has not been established that substantial multiplication of Pc occurs in culture, the Pc organisms harvested from the supernatant at the end of the culture period arc relatively free of both host and feeder cells. This is in marked contrast with the lung wash inoculum in which the Pc organisms arc heavily contaminated with rat cells and enmeshed in a highly sticky material. Lung wash preparations frozen down in glycerol and stored at −70.°C for as long as 6 months or more can be successfully cultured upon thawing with no apparent loss of viability of the Pc organisms.     

Prophylaxis and Treatment of Pneumocystis jiroveci Pneumonia in Lymphoma Patients Subjected to Rituximab-Contained Therapy: A Systemic Review and Meta-Analysis

Pneumocystis jiroveci pneumonia (PCP) is frequently reported in lymphoma patients treated with rituximab-contained regimens. There is a trend toward a difference in PCP risk between bi- and tri-weekly regimens. The aims of this systemic review and meta-analysis were to estimate the risk for PCP in these patients, compare the impact of different regimens on the risk, and evaluate the efficacy of prophylaxis. The cohort studies with incept up to January 2014 were retrieved from the Cochrane Library, Medline, Embase, and Web of Science databases. Studies that compared the incidence of PCP in patients with and without rituximab treatment were conducted. Studies that reported the results of prophylaxis were concentrated to evaluate the efficacy of prophylaxis. Fixed effect Mantel-Haenszel model was chosen as the main analysis method. Funnel plots were examined to estimate the potential selection bias. Egger’s test and Begg’s test were used for the determination of possible small study bias. Eleven cohort studies that met the inclusion criteria were finally included. Results indicated that rituximab was associated with a significantly increased risk for PCP (28/942 vs 5/977; risk ratio: 3.65; 95% confidence interval 1.65 to 8.07; P=0.001), and no heterogeneity existed between different studies (I²=0%). Little significant difference in PCP risk was found between bi-weekly and tri-weekly regimens (risk ratio: 3.11; 95% confidence interval 0.92 to 10.52, P=0.068). PCP risk was inversely associated with prophylaxis in patients treated with rituximab (0/222 vs 26/986; risk ratio: 0.28; 95% confidence interval 0.09 to 0.94; P=0.039). In conclusion, PCP risk was increased significantly in lymphoma patients subjected to rituximab-contained chemotherapies. Difference in PCP risk between bi-weekly and tri-weekly regimens was not significant. Additionally, prophylaxis was dramatically effective in preventing PCP in rituximab-received lymphoma patients, suggesting that rituximab should be recommended for these patients.     

卡氏肺孢子虫感染小鼠动物模型的研究

采用肾上腺皮质激素的方法在国产昆明小鼠成功诱导卜氏肺孢子虫感染,在54只实验鼠中,47只发现虫体,阳性率为87．03％,表明该方法可透用于建立卡氏肺孢子虫感染的小鼠动物模型,并具有简便,经济等优点。