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Host Defense and Parasite Evasion
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
In 1979 Sandy Ford joined the CDC in Atlanta. Her job as a drug technician included responding to requests for drugs that were unavailable in the United States, except through the CDC’s parasitic diseases drug service. One such drug was pentamidine, used to treat pneumonia caused by Pneumocystis jirovecii (then called P. carinii). At the time, P. jirovecii was considered to be a protozoan. It has since been recognized as a fungus (see Chapter 2). In 1979 pneumonia caused by this organism was rare and seen almost exclusively in infants or those with compromised immune defenses, such as those undergoing cancer chemotherapy. So when Ford noticed a spike in requests for pentamidine in 1981 and that the patients were all adult male homosexuals, she knew that something was very wrong. She reported the cluster of cases to her supervisor, the first alarm that a new disease, later recognized as AIDS, had reared its head. At about the same time, clinicians were first noticing patients with unusual opportunistic diseases, including pneumocystis pneumonia, and on June 5, 1981, this worrisome new situation was first reported in the CDC’s Morbidity and Mortality Weekly Report (Figure 4.1). This historic publication marked the initial awareness of a new, fearsome immunosuppressive virus, later named HIV, thanks in large measure to Ford’s alertness and attention to detail.
Diagnosing Invasive Fungal Infections
Published in Firza Alexander Gronthoud, Practical Clinical Microbiology and Infectious Diseases, 2020
The following questions can help determine the presence of an IFI: Is the patient persistently febrile despite ≥36 hours of antibiotic treatment?Does the patient belong to a population at risk for IFI?Is the patient on any antifungal prophylaxis?Fluconazole reduces likelihood of invasive candidiasisVoriconazole or posaconazole reduces likelihood of invasive candidiasis and aspergillosis if prophylactic levels have been attainedTrimethoprim/sulfamethoxazole significantly reduces the risk of Pneumocystis jirovecii pneumonia. Alternatively pentamidine inhalation, dapsone or atovaquone can be used, but there is less evidence regarding their effectiveness
Pneumocystis carinii
Published in Peter D. Walzer, Robert M. Genta, Parasitic Infections in the Compromised Host, 2020
Peter D. Walzer, C. Kurtis Kim, Melanie T. Cushion
Prophylactic TMP-SMX is well tolerated in non-AIDS patients but has found little application in persons with AIDS. The fixed combination of pyrimethamine and sulfadoxine (Fansidar), which was first used in prophylaxis in the epidemic form of pneumocystosis (504), has been used in limited numbers of AIDS patients with mixed results (448-452). Toxicity considerations with this drug and other sulfonamides or sulfones are the same as those discussed under treatment. Pentamidine, administered intravenously or via aerosol, is currently receiving a lot of attention, but controlled studies have not yet been performed. Immunological approaches to P. carinii prophylaxis have attracted little interest. The results of active immunization in the rat model or the administration of immune plasma or serum globulin preparations in small numbers of humans have been discouraging (27,505,506).
Early infectious risk in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis according to remission-induction therapy
Published in Scandinavian Journal of Rheumatology, 2023
M Gérard, H de Boysson, R Morello, N Martin-Silva, A-C Leroux, A Dumont, G Maigné, J Boutemy, K Khoy, D Mariotte, T Lobbedez, A Aouba, S Deshayes
In our cohort, the median infection-free survival was 3 months in the RTX group, which is concordant with previous studies (26–29). This highlights the highly immunosuppressed status of AAV patients and the importance of implementing prophylactic measures as early as possible. Among these, vaccination against pneumococcal disease is recommended in AAV patients but also prior to RTX use (6, 39). As previously reported, the absence of prophylactic use of trimethoprim–sulfamethoxazole was a strong risk factor for both severe infection and infections of any severity in univariate and multivariate analyses (27). In contrast, patients treated with aerosolized pentamidine were at increased risk of infections in univariate analysis. This fact highlights the dual benefit of trimethoprim–sulfamethoxazole, which prevents both Pneumocystis and usual bacterial infections and should be associated with induction treatment in AAV patients (6, 40). Severe infections were predominantly bacterial, confirming the clear role of trimethoprim–sulfamethoxazole in the prevention of these infections.
The advantages of nanomedicine in the treatment of visceral leishmaniasis: between sound arguments and wishful thinking
Published in Expert Opinion on Drug Delivery, 2021
Kevin Matha, Brice Calvignac, Jean-Pierre Gangneux, Jean-Pierre Benoit
Pentamidine is used in its isethionate salt form under the trade name Pentacarinat®. Pentamidine mechanism is still not well elucidated, it enters the parasite through the polyamine and arginine transporters and inhibits DNA replication [14], by inhibition of mitochondrial topoisomerase II leading to Leishmania death [15]. This drug is used either IV or IM at a dose of 3 to 4 mg/kg, every 48 h for a total of 10 injections. The most serious reactions observed come from gastrointestinal and cardiac toxicity [16], other adverse effects observed are hypoglycemia, hypotension, diabetes, and renal dysfunction. Due to the side effects, the pentamidine is a second-line drug. Moreover a drop in efficacy from 99% to 70% in two decades has been observed in India [17–19]. Pentamidine resistance protein 1 (PRP1) is a member of the ATP-binding cassette (ABC) transporter superfamily that has been discovered in L. major and could be the source of potential resistance [20].
Comparative in vitro transportation of pentamidine across the blood-brain barrier using polycaprolactone nanoparticles and phosphatidylcholine liposomes
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Geofrey Omarch, Yunus Kippie, Shireen Mentor, Naushaad Ebrahim, David Fisher, Grace Murilla, Hulda Swai, Admire Dube
The major problems and challenges in treatment of HAT are the level of toxicities exhibited by the drugs [1,10]. Pentamidine isethionate (see chemical structure in Figure 1) is an aromatic dicationic diamidine molecule [11,12] which is a white crystalline powder soluble in water and glycerine and insoluble in acetone, ether and chloroform. It is chemically designated as 4, 4′ diamidino-dephenoxypentane di (β hydroxyethanesulfonate) [13]. It is administered daily by deep intramuscular administration at a dose of 4 mg/kg for 7–10 days [8,12,14]. Patients treated with pentamidine are reported to experience undesirable side effects including abdominal pain, diarrhoea, nausea, vomiting [15] cardiac arrhythmias, very high or low blood sugar, pancreas, kidney and liver problems [11,16]. Furthermore, pentamidine treatment is complicated by the mode of drug administration which requires hospitalization of a patient for more than 7 days and therefore, creates significant logistical and societal problems in the remote rural areas of Africa, where HAT is endemic. This makes it difficult to implement with consistency because of poor health facilities and few healthcare personnel [5,12,16,17]. Pentamidine is not well absorbed through gastrointestinal tract (GIT) which leads to poor oral bioavailability and has a very slow rate of diffusion across the biological membranes and thus, making the concentrations not sufficient enough to affect the trypanosomes which advance to the central nervous system (CNS) [11].