Effect of Pneumocystis jirovecii pneumonia prophylaxis on hematologic toxicity in patients receiving chemoradiation for primary brain tumors.

PURPOSE: Diffuse gliomas are managed with radiation and temozolomide; however, this therapy often results in hematologic toxicities. Patients undergoing chemoradiation also risk contracting Pneumocystis jirovecii pneumonia (PJP), and frequently receive prophylaxis against PJP during treatment. Independent of chemoradiation, some PJP prophylaxis drugs have the potential to cause myelosuppression, which could require cessation of chemotherapy. Here, we evaluate differences in the frequency of hematologic toxicities during chemoradiation when patients receive PJP prophylaxis. METHODS: This retrospective chart review evaluated patients with primary brain tumors treated with radiation and concurrent temozolomide. Analyses were performed to assess the effect of the type of PJP prophylaxis on risk for neutropenia, lymphopenia, or thrombocytopenia and the severity of these adverse effects as defined using the Common Terminology Criteria for Adverse Events. RESULTS: Of the 217 patients included in this analysis, 144 received trimethoprim-sulfamethoxazole (TMP/SMX) and 69 received pentamidine. Of the patients who received TMP/SMX, 15.3% developed an absolute neutrophil count < 1500 cells/µL compared with 7.2% of patients receiving pentamidine (p = 0.10). Platelet count < 100,000/µL occurred in 18.1% of patients who received TMP/SMX and 20.3% of patients who received pentamidine (p = 0.70). No significant differences in lymphocyte counts between therapies were seen. Severity of hematologic toxicities were similar between PJP prophylaxis groups. CONCLUSION: These findings suggest that the type of PJP prophylaxis does not significantly affect the risk for hematologic toxicity in brain tumor patients receiving radiation and temozolomide. Additional studies are merited to evaluate the higher rate of neutropenia in patients on TMP/SMX observed in this study.

Variance in Pneumocystis jirovecii prophylaxis practice for pediatric patients undergoing hematopoietic cell transplantation.

Pneumocystis jirovecii pneumonia (PJP) in hematopoietic cell transplant (HCT) recipients can be prevented by efficient prophylaxis. We surveyed HCT centers in North America to assess their PJP prophylaxis practices. Most institutions used intravenous (IV) pentamidine (29.6%) or inhaled pentamidine (14.8%); 37% institutions changed from trimethoprim/sulfamethoxazole (TMP-SMX) to another medication after conditioning; and 44% administered no PJP prophylaxis during the pre-engraftment period. Most institutions avoided using TMP-SMX during the pre-engraftment period, mainly because of concerns about myelotoxicity, despite this being the preferred PJP prophylaxis agent. There is a need to evaluate the effects of TMP-SMX on engraftment.

Therapeutic potential of pentamidine for glioma-initiating cells and glioma cells through multimodal antitumor effects.

Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.

Treatment of cutaneous leishmaniasis with a sequential scheme of pentamidine and tamoxifen in an area with a predominance of Leishmania (Viannia) guyanensis: A randomised, non-inferiority clinical trial.

OBJECTIVE: To determine whether a combination of a single intramuscular (IM) dose of pentamidine (7 mg/kg) followed by oral tamoxifen 40 mg/day for 20 days is non-inferior to three IM doses of pentamidine 7 mg/kg in the treatment of cutaneous leishmaniasis with a margin of 15%. METHODS: Phase II, randomised, controlled, open-label, non-inferiority clinical trial. Primary outcome was the complete healing of the lesions 6 months after starting treatment. Secondary outcomes were healing 3 months after starting treatment and determining the presence and severity of adverse effects (AE). RESULTS: The research was concluded with 49 patients; Leishmania (Viannia) guyanensis was the most frequent species isolated. In the primary outcome, 18 (72%) (95% CI: 52.4%-85.7%) of the 25 patients allocated to the intervention group and 24 (100%) (95% CI: 86.2%-100%) of the control group (p = 0.015) met the established criteria of cure. There was no AE with tamoxifen. CONCLUSION: Although a 72% cure rate presented by the combination of tamoxifen and pentamidine was lower than in the control group that achieved a 100% cure, it is still a safe and is a clinically relevant result. It indicates that the therapeutic scheme evaluated may be a promising option for populations in remote areas, however it should be further studied, in order to include a larger number of patients.

Bioanalytical methods for pharmacokinetic studies of antileishmanial drugs.

Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to conduct pharmacokinetic (PK) analysis. This review provides a comprehensive overview of published validated bioanalytical assays for the quantification of antileishmanial drugs amphotericin B, miltefosine, paromomycin, pentamidine, and pentavalent antimonials in human matrices. The applicability of the assays for leishmaniasis clinical trials as well as their relevance to PK studies with emphasis on the choice of matrix, calibration range, sample volume, sample preparation, choice of internal standards, separation, and detection was discussed for each antileishmanial drug. Given that no published bioanalytical methods included multiple antileishmanial drugs in a single assay although antileishmanial shortened combination regimens currently were under investigation, it was recommended to combine various drugs in a single bioanalytical method. Furthermore, bioanalytical method development regarding target site matrix as well as applying microsampling strategies was recommended to optimize future clinical PK studies in leishmaniasis.

Pneumocystis jirovecii Pneumonia Prophylaxis with Intravenous Pentamidine in Adult Allogeneic Hematopoietic Stem Cell Transplant Patients.

The purpose of this single-center retrospective case series was to evaluate the efficacy and safety of 300-mg once-monthly intravenous (IV) pentamidine prophylaxis in 702 adult allogeneic hematopoietic stem cell transplant (HSCT) patients. We observed no cases of Pneumocystis jirovecii pneumonia (PJP) following IV pentamidine administration. Breakthrough Nocardia and Toxoplasma infections were observed in 7 (1%) and 5 (0.7%) patients, respectively. The most commonly reported adverse event was nausea. Monthly IV pentamidine is a reasonable alternative to trimethoprim-sulfamethoxazole (TMP-SMX).

Pentamidine inhibits proliferation, migration and invasion in endometrial cancer via the PI3K/AKT signaling pathway.

BACKGROUND: Pentamidine has been reported to have many pharmacological effects including anti- protozoal, anti-inflammatory, and anti-tumor activities. The aim of this study is to investigate the potential therapeutic role of Pentamidine and molecular mechanisms of Pentamidine on PI3K/AKT signaling pathway underlying the anti-tumor properties in endometrial cancer. METHODS: Our study was carried out in the central laboratory of Harbin Medical University from 2019 to 2021. Human endometrial cancer cell lines Ishikawa and HEC-1A were treated with Pentamidine. The proliferation ability of cells was investigated by MTS and colony formation assays. The cell cycle distribution was detected by flow cytometry. Cell migration and invasion were analyzed by using the wound healing assay and Transwell assay. Western blotting was performed to measure the levels of AKT, p-AKT, MMP-2, and MMP-9. RESULTS: Our results revealed that treatment of Pentamidine inhibited proliferation, migration and invasion of Ishikawa and HEC-1A endometrial cancer cells. Mechanistic investigation showed that Pentamidine inhibited PI3K/AKT signaling pathway and also reduced the expression of MMP-2 and MMP-9. In addition, co-treatment with PI3K kinase inhibitor LY294002 and Pentamidine leaded to increased repression of cell viability and the protein expression of p-AKT in Ishikawa cells. CONCLUSIONS: Pentamidine suppresses PI3K/AKT signaling pathway, and inhibits proliferation, migration and invasion of EC cells. These findings suggested that Pentamidine might be a potential candidate for treating EC through PI3K/AKT pathway.

High incidence of Pneumocystis jirovecii pneumonia in allogeneic hematopoietic cell transplant recipients in the modern era.

BACKGROUND: International guidelines for Pneumocystis jirovecii pneumonia (PJP) prevention recommend prophylaxis for ≥6 months following allogeneic hematopoietic cell transplantation, and longer in patients with graft-versus-host disease (GVHD) or on immunosuppressive therapy (IST). These recommendations are based on cohorts of patients who did not routinely receive anti-thymocyte globulin (ATG) for GVHD prophylaxis. METHODS: We performed a retrospective chart review of 649 patients, all of whom received ATG as part of GVHD prophylaxis. RESULTS: The cumulative incidence of definite PJP was 3.52% at both 3 and 5 years (median follow up, 1648 days for survivors). PJP occurred in 13 non-GVHD patients between days 207 and 508, due in part to low CD4 T-cell counts (<200 CD4 T cells/µL). PJP occurred in eight GVHD patients between days 389 and 792, due in part to non-adherence to PJP prophylaxis guidelines (discontinuation of PJP prophylaxis at <3 months after discontinuation of IST). Breakthrough PJP infection was not observed in patients receiving prophylaxis with cotrimoxazole, dapsone or atovaquone, whereas three cases were observed with inhaled pentamidine. DISCUSSION: In conclusion, for non-GVHD patients receiving ATG-containing GVHD prophylaxis, 6 months of PJP prophylaxis is inadequate, particularly if the CD4 T-cell count is <200 cells/µL or if there is a high incidence of PJP in the community. For patients with GVHD receiving ATG-containing GVHD prophylaxis, continuing PJP prophylaxis until ≥3 months post-discontinuation of IST is important. Cotrimoxazole, dapsone and atovaquone are preferred over inhaled pentamidine.

Higher risk of urinary tract infections in renal transplant recipients receiving pentamidine versus trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis pneumonia prophylaxis.

Urinary tract infection (UTI) is one of the most common infectious complications among renal transplant patients. Trimethoprim-sulfamethoxazole (TMP-SMX) is routinely used as first-line prophylaxis against Pneumocystis pneumonia (PCP) and other opportunistic infections including UTI. Aerosolized pentamidine is an alternate agent used for PCP prophylaxis; however, it does not provide coverage against uropathogens. This is a retrospective study of 81 renal transplant recipients who received TMP-SMX or aerosolized pentamidine for PCP prophylaxis at our center over 1 year. Survival analysis demonstrated increased cumulative incidence of UTI among patients receiving pentamidine for PCP prophylaxis compared to those receiving TMP-SMX (log-rank test P < .001). Univariate and multivariate Cox proportional hazard regression model showed pentamidine prophylaxis (HR 3.740; 95% CI 1.745-8.016; P = .001) and female sex (HR 4.025; 95% CI 1.770-9.154; P = .001) to independently increase UTI risk. Age, induction agent, graft type, diabetes, and delayed graft function (DGF) were not associated with increased risk. This study concludes that the use of pentamidine for PCP prophylaxis compared to TMP-SMX is associated with increased risk of UTI. Secondary UTI prophylaxis may be considered for patients who are unable to tolerate TMP-SMX and who have other risk factors for UTI; however, the efficacy of this has not been studied.

Pentamidine sensitizes FDA-approved non-antibiotics for the inhibition of multidrug-resistant Gram-negative pathogens.

Pentamidine sensitizes FDA-approved antibiotics to combat Gram-negative pathogens. We screened 1374 FDA-approved non-antibiotics for their ability to be sensitized by pentamidine against Escherichia coli. We identified mitomycin C and mefloquine as potent hits effective against multiple drug-resistant, Gram-negative bacteria. Killing kinetics and an in vivo model with Caenorhabditis elegans (C. elegans) revealed that such combinations produced synergy against colistin-resistant Enterobacter cloacae (E. cloacae). These findings suggest combinations of FDA-approved non-antibiotics, and pentamidine can be repurposed into new antimicrobial agents.

Distribution, treatment outcome and genetic diversity of Leishmania species in military personnel from Colombia with cutaneous leishmaniasis.

BACKGROUND: Leishmaniasis is one of the most important infectious diseases affecting the Colombian National Army due to the high number of reported cases and exposure throughout military operations in endemic areas. The main aim of this study was to estimate the geographical distribution along with the genetic diversity and treatment outcome of Leishmania species in Colombian military personnel. METHODS: Skin lesion samples by smear and aspirate were collected in 136 patients having parasitological cutaneous leishmaniasis (CL) diagnosis. DNA was extracted, the nuclear marker heat shock protein 70 (HSP70) was amplified by PCR and sequenced. Leishmania species were identified by BLASTn. The geo-spatial distribution of the identified parasites was determined according to the possible site of infection. Gene tree was constructed by maximum likelihood (ML), diversity indices (π, h) were estimated and haplotype network was constructed under the Templeton-Crandall-Sing algorithm in order to determine the geographic relationships of the genetic variants of Leishmania species circulating in Colombian military population. RESULTS: The species were identified in 77.94% of the samples, with a predominance of L. braziliensis (65.09%), followed by L. panamensis (31.13%), L. naiffi by the first time reported in Colombia in two patients (1.89%) as well as L. lindenbergi in a single patient (0.945%) with possible infection in the municipality of Miraflores, Guaviare and L. infantum in a single patient (0.945%) notified with CL in the municipality of Tumaco, Nariño. The phylogenetic analysis was consistent according to bootstrap, showing four strongly differentiated clades. CONCLUSIONS: The geo-spatial distribution suggested that L. braziliensis has a greater abundance, while L. panamensis has a greater dispersion. The phylogenetic relationships of Leishmania species in Colombian military personnel was estimated with the confirmation of two new species circulating without prior report in the country and a species with no background for CL in the Colombian army. A substantial genetic diversity of Leishmania braziliensis was defined. This study contributes through the understanding of the molecular epidemiology to the CL transmission in Colombia.

Effectiveness and tolerability of intravenous pentamidine for Pneumocystis carinii pneumonia prophylaxis in adult hematopoietic stem cell transplant patients: a retrospective study.

BACKGROUND: Pneumocystis carinii pneumonia (PCP) prophylaxis is recommended after hematopoietic stem cell transplantation (HSCT). In patients who are unable to take first-line prophylaxis, trimethoprim/sulfamethoxazole, aerosolized pentamidine is recommended. This drug may not, however, be available at all institutions, and its administration requires special techniques. Therefore, intravenous pentamidine (IVP) has been used in adult patients as an alternative, despite limited data. We evaluated the effectiveness and tolerability of IVP for PCP prophylaxis in adult patients who had undergone HSCT. METHODS: A single-center retrospective study was conducted of adult patients who had undergone allogenic or autologous HSCT between January 2014 and September 2018 and had received at least three doses of IVP for PCP prophylaxis. The IVP dose was 4 mg/kg administered monthly. Data on PCP infection and adverse reactions were collected from both patients' electronic medical records and the pharmacy adverse drug reactions documentation system. Patients were followed from the start of IVP up to 6 months after discontinuation of therapy. A confirmed PCP infection was defined as radiographic evidence of PCP and positive staining of a respiratory specimen. Descriptive statistics were used to analyze the study outcomes. RESULTS: During the study period, 187 patients were included. The median age was 36.4 years (range, 18-64), 58% were male, and 122 (65%) had received allogeneic HSCT while the remainder autologous HSCT. The median number of IVP doses administered per patient was 5 (range, 3-29). During the study period, none of the patients had evidence of confirmed PCP infection. However; there were two cases with high clinical suspicion of PCP infection (i.e. required anti-pneumocystis therapy) and one reported case of central nervous system toxoplasmosis while receiving IVP for PCP prophylaxis. Only one case of nausea associated with IVP administration was reported. CONCLUSIONS: In a cohort of adult patients with HSCT who received IVP for PCP prophylaxis, there was no evidence of confirmed PCP infection, and the treatment appeared to be well tolerated. Prospective studies should be conducted to confirm the efficacy and tolerability of IVP.

Safety profile of the concomitant use of foscarnet and aerosolized pentamidine in allogeneic hematopoietic stem cell transplantation recipients.

BACKGROUND: Concomitant use of foscarnet and intravenous pentamidine can very frequently cause severe hypocalcemia. However, it is unknown whether aerosolized pentamidine has a similar adverse interaction with foscarnet. The present study was aimed at examining the safety profile of concomitantly used foscarnet and aerosolized pentamidine in patients receiving allogeneic hematopoietic stem cell transplantation. METHODS: Data from allogeneic hematopoietic stem cell recipients who had been administered foscarnet therapy for over 7 days were analyzed. We compared electrolyte abnormalities and serum creatinine level between patients who received aerosolized pentamidine concomitantly and those who did not. RESULTS: A total of 84 consecutive patients and 135 episodes of foscarnet therapy between May 2011 and April 2016 were evaluable. Of these 135 episodes, 25 episodes of therapy included concurrent therapy with 300 mg dose of aerosolized pentamidine once a month (pentamidine group) and 110 episodes did not (non-pentamidine group). The incident rates of grade 3/4 hypocalcemia did not significantly differ between the pentamidine and non-pentamidine groups (P = .207; 0/25 [0%] vs 10/110 [9.1%], respectively). In addition, we observed no significant difference in the incident rates of grade 3/4 serum creatinine increase between the two groups (P = 1.00; 0/25 [0%] vs 4/110 [3.6%], respectively). CONCLUSION: Our results suggest that the drug interactions between foscarnet and aerosolized pentamidine may not be clinically significant.

Topical 15% Paromomycin-Aquaphilic for Bolivian Leishmania braziliensis Cutaneous Leishmaniasis: A Randomized, Placebo-controlled Trial.

BACKGROUND: Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% paromomycin topical formulations have been in clinical experimentation. Recently, 15% paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS: We performed a randomized trial of 15% paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS: Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS: Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION: NCT03096457.

Pentamidine protects mice from cecal ligation and puncture-induced brain damage via inhibiting S100B/RAGE/NF-κB.

The brain is one of the earliest organs to be influenced during sepsis. Sepsis-associated encephalopathy (SAE) is frequent, but seldomly recognized and has no testified pharmacological therapy. In this study, we demonstrated that pentamidine, an antiprotozoal drug, is a good candidate since it blocks S100B/RAGE/NF-κB signaling pathway. Pentamidine ameliorated cecal ligation and puncture (CLP)-induced brain damage assessed by crystal violet staining and hematoxylin and eosin (H&E) staining. Moreover, pentamidine reduced neuroinflammation in mouse hippocampi. Immunofluorescence and Western blot analysis also showed that pentamidine inhibited CLP-induced gliosis and S100B/RAGE/NF-κB pathway activation. Interestingly, it could also attenuate oxidative stress indicated by decreased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and attenuation of malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) consumption. Thus the S100B/RAGE/NF-κB pathway may be crucial in the pathogenesis of SAE and may be a promising pharmacological target to prevent SAE.

Efficacies of atovaquone, pentamidine, and trimethoprim/sulfamethoxazole for the prevention of Pneumocystis jirovecii pneumonia in patients with connective tissue diseases.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection in patients on steroid therapy for connective tissue diseases. The standard agent for primary PCP prophylaxis is trimethoprim/sulfamethoxazole (TMP-SMX), although this agent can cause common adverse reactions, including myelosuppression and renal toxicity, that result in cessation. Aerosolized pentamidine and oral atovaquone are alternatives for PCP prophylaxis. The efficacies of atovaquone, pentamidine, and TMP-SMX to prevent PCP in patients with connective tissue diseases have never been compared. METHODS: Hospitalized patients with connective tissue diseases who started steroid therapy and PCP prophylaxis were enrolled. PCP prophylaxis regimens were oral TMP-SMX, aerosolized pentamidine, or oral atovaquone. Information was retrospectively collected from medical records about laboratory findings, duration of PCP prophylaxis, and reasons for terminating PCP prophylaxis. RESULTS: Ninety-six patients received PCP prophylaxis. All of them were initially treated with TMP-SMX, but this was replaced during the study period with pentamidine in 33 patients and with atovaquone in 7. Forty-one (43%) patients discontinued TMP-SMX because of adverse events, and 5 (15%) also discontinued pentamidine. None of the patients discontinued atovaquone. The most frequent causes of TMP-SMX and pentamidine cessation were cytopenia (N = 15) and asthma (N = 2). The rates of continuing treatment with TMP-SMX, pentamidine, and atovaquone at one year after starting PCP prophylaxis were 55.3%, 68.6%, and 100%, respectively (P = 0.01). None of the patients developed PCP. CONCLUSION: Although TMP-SMX for PCP prophylaxis had to be discontinued in 43% of patients with connective tissue diseases, pentamidine and atovaquone were well tolerated.

Semicarbazone derivatives as promising therapeutic alternatives in leishmaniasis.

In the present study, we investigated the in vitro and in vivo leishmanicidal activity of synthetic compounds, containing a semicarbazone scaffold as a peptide mimetic framework. The leishmanicidal effect against amastigotes of Leishmania amazonensis was also evaluated at concentration of 100 µM-0.01 nM. The derivatives 2e, 2f, 2g and 1g, beyond the standards miltefosine and pentamidine, significantly diminished the number of L. amazonensis amastigotes in macrophages. These derivatives were also active against amastigotes of L. braziliensis. As 2g presented potent leishmanicidal activity against the amastigotes of L. amazonensis in macrophages, we also investigated the in vivo leishmanicidal activity of this compound against L. amazonensis. Approximately 105L. amazonensis promastigotes were subcutaneously inoculated into the dermis of the right ear of BALB/c mice, which were subsequently treated with 2g (p.o. or i.p.), miltefosine (p.o.) or glucantime (i.p.) at 30 µmol/kg/day x 28 days. Thus, a similar reduction in the lesion size was observed after the administration of 2g through oral (63.7 ±â€¯10.1%) and intraperitoneal (61.8 ±â€¯3.7%) routes. A larger effect was observed after treatment with miltefosine (97.7 ±â€¯0.4%), and glucantime did not exhibit activity at the dose administered. With respect to the ear parasite load, 2g diminished the number of parasites by p.o. (30.5 ±â€¯5.1%) and i.p. (33.3 ±â€¯4.3%) administration. In addition, 2g induced in vitro apoptosis, autophagy and cell cycle alterations on L. amazonensis promastigotes. In summary, the derivative 2g might represent a lead candidate for antileishmanial drugs, as this compound displayed pronounced leishmanicidal activity.

Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial.

Background: We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation. Methods: The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/µL at month 12; and (3) 12-month follow-up after stopping PSP. The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis. Results: For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up. The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count. Forty-five patients were relapse-free and in follow-up at month 12 of PSP. This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation. Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period. During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up. No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period. Conclusions: It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL. The management of those failing to reach this level remains to be defined. Clinical Trials Registration: NCT01360762.

In vitro and in vivo efficacy of diamidines against Trypanosoma equiperdum strains.

Trypanosoma equiperdum is a protozoan parasite responsible for causing Dourine, a debilitating neglected veterinary disease, found worldwide affecting equids. It is the only pathogenic trypanosome species that does not require an invertebrate vector for transmission, thus being passed from animal to animal via coitus. At present, there is no officially recognized form of chemotherapeutic treatment and therefore all confirmed (or suspected) cases of infected animals must be slaughtered immediately. For many global communities and farming populations, which rely heavily on their animals for their livelihood, such stringent regulations can seriously enhance the socio-economic problems attributing to poverty. Two reference drugs, together with 37 novel diamidine compounds were tested in vitro using a 72 h drug sensitivity assay to determine their efficacy against two axenically adapted T. equiperdum strains. Further in vivo investigations in mouse models of infection against 4 'true' T. equiperdum strains were performed using the 17 most active diamidines. Single bolus doses of 10 mg kg-1, given i.p. were administered to NMRI mice infected with one of the 4 T. equiperdum strains. The results obtained from this study show that experimentally T. equiperdum can indeed be effectively treated with chemotherapy using in vivo mouse models of infection.

The use of intravenous pentamidine for the prophylaxis of Pneumocystis pneumonia in pediatric patients.

Pneumocystis jiroveci pneumonia was common in the immunocompromised host before the widespread use of prophylaxis. When trimethoprim-sulfamethoxazole is not tolerated, prophylaxis with intravenous pentamidine (IVP) may be initiated. We performed a retrospective analysis of all pediatric patients who received IVP regarding efficacy, safety, and reason for initiation. Of 106 patients included in our analysis, one patient tested positive for Pneumocystis DNA. Adverse events were reported in 18% of IVP courses, and main reason for initiation was cytopenia (59%). We found IVP to be effective and safe, and recommend the use of IVP in pediatric patients in whom first-line prophylaxis is contraindicated.