A retrospective study of intravenous pentamidine for Pneumocystis jirovecii pneumonia prophylaxis in adult patients with hematologic malignancies-its utility during respiratory virus pandemics.

OBJECTIVES: In hematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematologic malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent; however, its use is not straightforward. Inhaled pentamidine is the recommended second-line agent; however, aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic hematopoietic stem cell transplantation recipients and patients with hematologic malignancies during COVID-19. RESULTS: A total of 202 unique patients who received 239 courses of IV pentamidine, with a median of three doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The most common reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients developed an infusion reaction or experienced adverse effects from IV pentamidine. CONCLUSIONS: Pentamidine administered IV monthly is safe and effective.

Evaluation of pentamidine tolerability and efficacy between CYP2C19 phenotypes.

Intravenous pentamidine is used for prophylaxis against Pneumocystis jirovecii pneumonia, an infection seen in hematopoietic stem cell transplant recipients. Pentamidine is partially metabolized by CYP2C19, which is vulnerable to pharmacogenetic variation. This retrospective study evaluated allogeneic hematopoietic stem cell transplant patients who received intravenous pentamidine as P. jirovecii pneumonia prophylaxis. The primary objective was the association between CYP2C19 phenotype and discontinuation of pentamidine due to drug-related side effects based on univariate logistic regression (N = 81). Ten patients (12.3%) discontinued pentamidine because of side effects. There was no difference in discontinuation between phenotype groups (p = 0.18) or discontinuation due to side effects (p = 0.76). Overall, no association was seen between phenotypes and pentamidine-related side effects (p = 0.475). Drug discontinuation rates and P. jirovecii pneumonia infection rates were low.

Using pentamidine to treat cutaneous leishmaniasis in children: a 10-year study in French Guiana.

There are little data on pentamidine as a treatment for paediatric cutaneous leishmaniasis (CL). The objective of this study was to describe the effectiveness and safety of pentamidine over a 10-year period. Every child seen in French Guiana between 2010 and 2020 with proven CL and treated with pentamidine was included. In total, 55 children met the inclusion criteria - 23 girls and 32 boys. There were 38 patients (38/55, 69%) with a > 50% improvement at 1 month after pentamidine treatment and a complete cure at 3 months; 16 children had a < 50% improvement at 1 month and were given a second dose. Of these 16, 8 showed a complete cure at 3 months, 5 were lost to follow-up and 3 showed therapeutic failure at 3 months. The overall cure rate was 84% (46/55) after one or two doses. In terms of the safety of pentamidine, no severe adverse events (grade ≥ 3) were reported.

[Adequacy to diagnostic recommendations in patients with Pneumocystis jirovecii pneumonia treated with intravenous pentamidine]. / Adecuación a las recomendaciones diagnósticas en pacientes con neumonía por Pneumocystis jirovecii tratados con pentamidina intravenosa.

OBJECTIVE: To determine the rate of microbiological confirmation in the diagnosis of Pneumocystis jirovecii pneumonia in patients treated with intravenous pentamidine and the potential correlation with treatment effectiveness and safety. METHODS: Single-centre retrospective study (2010-2020), which included those patients who received intravenous pentamidine treatment for at least 48 hours. The sample collection procedure and the microbiological analysis performed were recorded. Efficacy was determined by 14-day mortality rate and admission to the Intensive Care Unit (ICU), and disease control was determined by length of hospital stay and time from completion of treatment to discharge. The safety profile was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: A total of 17 patients with P. jirovecii pneumonia were treated with pentamidine (76.5% male (n=13); mean age [standard deviation]: 58.6 [15.5]). Microbiological confirmation of the pathogen was established in 47.1% (n=8) of cases. Targeted use of pentamidine significantly reduced the time from treatment completion to hospital discharge (p=0.019). The safety profile was acceptable, with grade I toxicity occurring in one patient. CONCLUSIONS: The study shows that more than 50% of patients receive treatment based on a presumptive diagnosis and without adhering to the established recommendations, with repercussions on the duration of admission and recovery of the patient. Future studies with a larger sample size will be necessary to consolidate the results obtained.

Aerodigestive adverse effects during intravenous pentamidine infusion for Pneumocystis jirovecii pneumonia prophylaxis.

Aerodigestive adverse effects (AD-AE) during intravenous pentamidine (IV-P) infusion for Pneumocystis jiroveci pneumonia prophylaxis are uncommon in retrospective chart review studies. We conducted a survey in patients on IV-P, which included 31 specific questions. Twenty-five patients were included in the analysis; AD-AE were observed in 22 (88%) with recurrence of symptoms in 88% participants with subsequent infusions. Five leading symptoms were congestion (48%), lip tingling (32%), nausea (28%), tongue tingling (24%), vomiting, and throat swelling (17%); multiple symptoms were reported in 72% of the patients. In conclusion, AD-AE of IV-P infusion are common, self-limited, and tend to be recurrent.

Safety and efficacy of reduced-dose pentamidine as second-line treatment for HIV-related pneumocystis pneumonia.

OBJECTIVES: Parenteral pentamidine isethionate (PM) 4 mg/kg/day is recommended as an alternative therapeutic regimen after failure of first-line treatment for pneumocystis pneumonia (PCP). However, the dose is often reduced to 3 mg/kg/day in clinical settings because of high rates of adverse events and drug toxicity. Although considered equally efficacious, this lower dose has not been well evaluated. METHODS: This was a single-center, retrospective cohort study that analyzed 75 patients with HIV-PCP who were treated with trimethoprim-sulfamethoxazole, but discontinued treatment because of treatment failure or adverse events; they were then administered 3 mg/kg/day of intravenous PM as a salvage therapy. The primary outcomes were the regimen completion rate with the reduced PM dose. RESULTS AND CONCLUSIONS: In total, 40 (53.3%) of the eligible patients completed PCP therapy with reduced-dose PM salvage treatment. The overall survival rate of PCP was 73 (97.3%). The median duration of second-line PM treatment was 8.0 days (interquartile range: 6.0-10.0). Although, the adverse events with reduced-dose PM were observed in 41 (54.7%), including 35 treatment-limiting adverse events, grade 3 or 4 adverse events occurred in only three patients (thrombocytopenia, one patient; neutropenia, two patients). Life-threating adverse events, such as hypoglycemia and arrhythmia, were not observed with reduced-dose PM. Salvage therapy with reduced-dose PM for patients with HIV-PCP is relatively safe and effective; moreover, life-threating adverse events did not occur. This therapy could be recommended for patients with HIV-PCP who fail to respond to first-line treatment with trimethoprim-sulfamethoxazole.

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.

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.

Comparative study on liposomal amphotericin B and other therapies in the treatment of mucosal leishmaniasis: A 15-year retrospective cohort study.

BACKGROUND: Liposomal amphotericin B (L-AMB) has been used for mucosal leishmaniasis (ML), but comparative studies on L-AMB and other drugs used for the treatment of ML have not been conducted. The present study aimed to evaluate the outcome of patients with ML who were treated with L-AMB. METHODS: This is a 15-year retrospective study of Brazilian patients with a confirmed diagnosis of ML. The therapeutic options for the treatment of ML consisted of L-AMB, amphotericin B lipid complex (ABLC), deoxycholate amphotericin B (d-AMB), itraconazole, antimonial pentavalent, or pentamidine. Healing, cure rate and adverse effects (AEs) associated with the drugs used to treat this condition were analyzed. RESULTS: In 71 patients, a total of 105 treatments were evaluated. The outcome of the treatment with each drug was compared, and results showed that L-AMB was superior to other therapeutic regimens (P = 0.001; odds ratio [OR] = 4.84; 95% confidence interval [CI] = 1.78-13.17). d-AMB had worse AEs than other treatment regimens (P = 0.001, OR = 0.09; 95% CI = 0.09-0.43). Approximately 66% of the patients presented with AEs during ML treatment. Although L-AMB was less nephrotoxic than d-AMB, it was associated with acute kidney injury compared with other drugs (P <0.05). CONCLUSION: L-AMB was more effective than other therapies for the treatment of ML. However, a high incidence of toxicity was associated with its use. Therapeutic choices should be reassessed, and the development of new drugs is necessary for the treatment of ML.

First report of treatment failure in a patient with cutaneous leishmaniasis infected by Leishmania (Viannia) naiffi carrying Leishmania RNA virus: a fortuitous combination?

We report the case of a 32-year-old man from Rio de Janeiro, who was infected in the Amazon region of Brazil by Leishmania (Viannia) naiffi. Generally, patients with L. naiffi cutaneous leishmaniasis exhibit a good therapeutic response to either pentavalent antimonials or pentamidine. However, after pentamidine treatment, this patient's infection evolved to therapeutic failure. To understand this clinical outcome, we investigated the presence of the Leishmania RNA virus (LRV) in parasites isolated from the cutaneous lesion; herein, we discuss the possible association between a poor response to pentamidine therapy and the presence of the LRV.

Electrophysiological evaluation of pentamidine and 17-AAG in human stem cell-derived cardiomyocytes for safety assessment.

Human ether-a-go-go-related gene (hERG) trafficking inhibition is known to be one of the mechanisms of indirect hERG inhibition, resulting in QT prolongation and lethal arrhythmia. Pentamidine, an antiprotozoal drug, causes QT prolongation/Torsades de Pointes (TdP) via hERG trafficking inhibition, but 17-AAG, a geldanamycin derivative heat shock protein 90 (Hsp90) inhibitor, has not shown torsadogenic potential clinically, despite Hsp90 inhibitors generally being hypothesized to cause TdP by hERG trafficking inhibition. In the present study, we investigated the underlying mechanisms of both drugs' actions on hERG channels using hERG-overexpressing CHO cells (hERG-CHOs) and human embryonic stem cell-derived cardiomyocytes (hES-CMs). The effects on hERG tail current and protein levels were evaluated using population patch clamp and Western blotting in hERG-CHOs. The effects on field potential duration (FPD) were recorded by a multi-electrode array (MEA) in hES-CMs. Neither drug affected hERG tail current acutely. Chronic treatment with each drug inhibited hERG tail current and decreased the mature form of hERG protein in hERG-CHOs, whereas the immature form of hERG protein was increased by pentamidine but decreased by 17-AAG. In MEA assays using hES-CMs, pentamidine time-dependently prolonged FPD, but 17-AAG shortened it. The FPD prolongation in hES-CMs upon chronic pentamidine exposure is relevant to its clinically reported arrhythmic risk. Cav1.2 or Nav1.5 current were not reduced by chronic application of either drug at a relevant concentration to hERG trafficking inhibition in human embryonic kidney (HEK293) cells. Therefore, the reason why chronic 17-AAG shortened the FPD despite the hERG trafficking inhibition occur is still unknown.

Consecutive hypoglycemia attacks induced by co-trimoxazole followed by pentamidine in a patient with acquired immunodeficiency syndrome.

Both co-trimoxazole and pentamidine are used for the treatment of pneumocystis pneumonia (PCP) and are known to cause hypoglycemia as an adverse drug reaction. Here, we describe a rare case of a late-diagnosed female patient with acquired immunodeficiency syndrome (AIDS) who developed the first hypoglycemic attack as an adverse effect of co-trimoxazole, followed by a second hypoglycemic attack as an adverse effect of pentamidine. Physicians caring for patients with AIDS and PCP should be aware of possible hypoglycemia in patients with many risk factors.

First report of treatment failure in a patient with cutaneous leishmaniasis infected by Leishmania (Viannia) naiffi carrying Leishmania RNA virus: a fortuitous combination?

Abstract We report the case of a 32-year-old man from Rio de Janeiro, who was infected in the Amazon region of Brazil by Leishmania (Viannia) naiffi. Generally, patients with L. naiffi cutaneous leishmaniasis exhibit a good therapeutic response to either pentavalent antimonials or pentamidine. However, after pentamidine treatment, this patient's infection evolved to therapeutic failure. To understand this clinical outcome, we investigated the presence of the Leishmania RNA virus (LRV) in parasites isolated from the cutaneous lesion; herein, we discuss the possible association between a poor response to pentamidine therapy and the presence of the LRV.

An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region.

BACKGROUND: American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil. OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose. MATERIALS AND METHODS: This study was conducted as a controlled, randomized, open-label clinical trial for a total number of 159 patients with CL. Individuals aged 16-64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment. RESULTS: From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred. CONCLUSION: The present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg. TRIAL REGISTRATION: ClinicalTrials.gov NCT02919605.

Miltefosine Combined with Intralesional Pentamidine for Leishmania braziliensis Cutaneous Leishmaniasis in Bolivia.

Bolivian cutaneous leishmaniasis due to Leishmania braziliensis was treated with the combination of miltefosine (150 mg/day for 28 days) plus intralesional pentamidine (120 µg/mm2 lesion area on days 1, 3, and 5). Ninety-two per cent of 50 patients cured. Comparison to historic controls at our site suggests that the efficacy of the two drugs was additive. Adverse effects and cost were also additive. This combination may be attractive when a prime consideration is efficacy (e.g., in rescue therapy), avoidance of parenteral therapy, or the desire to treat locally and also provide systemic protection against parasite dissemination.

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.

Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for Pneumocystis jirovecii pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough Pneumocystis jirovecii pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven Pneumocystis pneumonia, and 4 cases (0.5%) of possible Pneumocystis pneumonia. The incidence of possible breakthrough Pneumocystis pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], P = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], P = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], P = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, P = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against Pneumocystis jirovecii pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.

Use of the intramuscular route to administer pentamidine isethionate in Leishmania guyanensis cutaneous leishmaniasis increases the risk of treatment failure.

BACKGROUND: New world cutaneous leishmaniasis (NWCL) can be found in French Guiana as well as in several other parts of Central and South America. Leishmania guyanensis accounts for nearly 90% of cases in French Guiana and is treated with pentamidine isethionate, given by either intramuscular or intravenous injection. The military population is particularly exposed due to repeated missions in the rainforest. The purpose of the present study was to identify the factors associated with pentamidine isethionate treatment failure in a series of service members with L. guyanensis NWCL acquired in French Guiana. METHOD: All the French service members reported as having acquired leishmaniasis in French Guiana from December 2013 to June 2016 were included. RESULTS: Seventy-three patients infected with L. guyanensis were included in the final analysis. Patients treated with IV pentamidine isethionate had better response rates than those treated with IM pentamidine isethionate (p = 0.002, adjusted odds ratio (AOR) = 0.15, 95% CI [0.04-0.50]). The rate of treatment success was 85.3% (95% CI [68.9-95.0]) for IV pentamidine isethionate and 51.3% (95% CI [34.8-67.6]) for IM pentamidine isethionate. CONCLUSIONS: The use of intramuscular pentamidine isethionate in the treatment of Leishmania guyanensis cutaneous leishmaniasis is associated with more treatment failures than intravenous pentamidine isethionate.

A prospective study of intravenous pentamidine for PJP prophylaxis in adult patients undergoing intensive chemotherapy or hematopoietic stem cell transplant.

Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is recommended for patients undergoing hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy. Trimethoprim-sulfamethoxazole and inhaled pentamidine are used frequently, but are limited, by their tolerability and therefore compliance. Intravenous (IV) pentamidine is a potential alternative agent. Here we conducted the first prospective study of the safety and efficacy of IV pentamidine for PJP prophylaxis in adult patients undergoing HSCT or intensive chemotherapy (clinicaltrials.gov NCT02669706). Fifty patients requiring PJP prophylaxis were enrolled and received monthly IV pentamidine at 4 mg/kg (maximum 300 mg) while undergoing intensive chemotherapy or HSCT. Patients were followed for the occurrence of PJP pneumonia and for adverse events. Satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4) survey. Seventeen (34%) patients experienced a grade 1 or 2 adverse event. There were no grade 3/4 events. The TSQM questionnaire indicated that the majority of patients were satisfied with the administration of IV pentamidine (n = 43, 86%, p = 0.01). There were no cases of PJP during the 24 month follow-up period. Our study illustrates the safety, feasibility, and high degree of patient satisfaction when using IV pentamidine for PJP prophylaxis.