Course Of Pentamidine Research Articles

In Memoriam: Sandy Ford (1950–2015).

Sandra Lee Ford (Figure) died April 11, 2015, at 64 years of age. To her children, she was a loving mother; to her co-workers, she was a caring human being and dedicated public health worker; to the world, she was a herald of the AIDS epidemic, playing a major role in alerting the world to the onset of this epidemic. Figure Sandy Ford with vials of pentamidine for distribution to patients with Pneumocystis pneumonia. In January 1979, Sandy took a position in the Parasitic Diseases Division in the Centers for Disease Control, now the Centers for Disease Control and Prevention (CDC). Her job was to respond to requests for drugs that CDC provided through the Parasitic Diseases Drug Service (PDDS). These drugs had been unavailable in the United States. By complying with the Food and Drug Administration’s rigorous requirements for investigational new drugs, CDC was able to import and dispense these drugs and fill a therapeutic gap. One of the 10 drugs in the armamentarium of the PDDS was pentamidine isethionate, which was intended to treat rare, imported cases of African trypanosomiasis. An unanticipated need for pentamidine was its use in treating Pneumocystis carinii pneumonia, now known as Pneumocystis jiroveci pneumonia or Pneumocystis pneumonia (PCP). Pentamidine had replaced sulfa drugs as the treatment of choice for PCP, which had been occurring mainly in infants and children with primary and secondary immune deficiencies and in adults receiving immunosuppressive drugs. Demand for pentamidine was brisk. Sandy interacted skillfully with hundreds of clinicians across the United States to provide life-saving pentamidine to severely ill patients, and she kept very careful records. She relished the opportunity to help physicians, and she cared deeply about their ill patients. She wanted to be known as a drug technician, a title she coined for herself. On numerous occasions, she said how much she loved her job. In early 1981, Sandy noticed an increase in the number of requests for pentamidine to treat cases of PCP. The cases were unusual because they were in adult male patients, a departure from the usual cases in children. In one instance, a New York physician asked for a second course of pentamidine to treat a patient with PCP who had not responded to the first dose; these circumstances were unprecedented. Two weeks later, another New York physician told Sandy about 5 male patients who had both PCP and Kaposi sarcoma. Sandy learned that the sexual orientation for all these patients was homosexual. She knew that something unusual was occurring and informed her supervisor of this cluster of cases. In his bestselling book And the Band Played On, which chronicled the discovery of AIDS, Randy Shilts said, “That was how the thorough GS-7 drug technician in Room 161 of the Centers for Disease Control’s Building 6 alerted the federal government to the new epidemic” (1). Simultaneously, clinicians in major medical centers were seeing, for the first time, homosexual patients with Kaposi sarcoma, PCP, cytomegalovirus infection, and other opportunistic infections. On June 5, 1981, CDC’s Morbidity and Mortality Weekly Report described 5 severe pneumonia cases observed during October 1980–May 1981 in 3 Los Angeles hospitals (2). All 5 patients were young men with PCP, and the sexual orientation of all was homosexual. This publication was historic because it marked the beginning of awareness in the United States of a new, fearsome disease that was eventually given the name of acquired immunodeficiency syndrome (AIDS). The rest, as they say, is history. Louis Pasteur famously said, “Chance favors the prepared mind.” Chance placed Sandy as a drug technician in CDC’s PDDS at a critical juncture in medical history. Although she had no formal training in medical science, she had a prepared mind and thought like an epidemiologist. When she comprehended that something unusual was occurring, she took appropriate action. In addition to her seminal role in the book And the Band Played On, Sandy was also portrayed in the movie by the same name and was the subject of many magazine and newspaper articles. A heroine of the AIDS epidemic, she continued her career at CDC until retiring in 2008 after 34 years of service. She did not capitalize on her notoriety and conducted her work and her relationships with dignity. She personified the woman in King Solomon’s poem Eshet Chayil, which praises a woman of valor: “A woman of valor, who can find? Her worth is far above jewels…. She is robed in strength and dignity, and cheerfully faces whatever may come…. Wherever people gather, her deeds speak her praise” (Proverbs 31:10–31).

Urban Transmission of Human African Trypanosomiasis, Gabon

To the Editor: We describe a confirmed case of human African trypanosomiasis (HAT) in an expatriate returning to France from Gabon after a probable tsetse fly bite in the urban setting of Libreville. This case indicates a possible urban transmission of HAT in Gabon and stresses the need for entomologic studies in Libreville. HAT is endemic to sub-Saharan Africa. Trypanosoma brucei rhodesiense (eastern Africa) and T.b. gambiense (western Africa) parasites are transmitted to humans by tsetse flies of the Glossina morsitans group (T.b. rhodesiense) and of the G. palpalis group (T.b. gambiense), which are found only in Africa. T.b. gambiense represents >90% of all reported cases of HAT worldwide. HAT has always been a travel-associated disease. It is a rare cause of fever, cutaneous lesions, and neurologic signs in travelers returning from disease-endemic areas and involves T.b. rhodesiense in 70% of the cases, resulting mostly from an exposure during safari in game parks (1,2). A 58-year-old previously healthy Portuguese man who worked in Gabon for 13 years for a French company was admitted to the tropical and infectious diseases ward because of a 2-month history of intermittent fever, fatigue, and a 10-kg weight loss. The patient recalled a painful unidentified insect bite on his right thigh 2 months before in his garden in Libreville (Lalala quarter). A 8-cm, indurated, erythematous, and painful plaque (chancre) progressively developed (Figure) in the following weeks after the assumed insect bite. When admitted to the hospital, the patient had a temperature of 39°C, anorexia, insomnia, pruritus of the left arm, and paresthesia of the hands and feet. Two additional large annular erythematous macules, centrally pale (trypanids), were found on his back (Figure). A subclavicular 0.5-cm lymph node was observed. There was no hepatosplenomegaly. Figure Thigh chancre (1) and back trypanids (2 and 3) in a patient with human African trypanosomiasis infection, Gabon. His laboratory results showed moderate anemia (hemoglobin 11.8 g/dL) and thrombopenia (134,000 platelets/mm3) and elevated levels of C-reactive protein (30.6 mg/L) and gammaglobulins (23.9 g/L). A thick-blood smear showed no malaria parasites but a few trypomastigotes of Trypanosoma spp. PCR of blood identified T.b. gambiense. A cerebrospinal fluid sample showed moderate elevation of total proteins (0.43 g/L) and albumin (291 mg/L), 11 leukocytes, and no IgM elevation. Direct examination and PCR showed no trypanosome in the cerebrospinal fluid. Specific antibodies were found in the blood by indirect immunofluorescence (titer 200). Biopsies of 2 skin lesions (thigh, back) showed a lymphoplasmocytic vasculitis consistent with cutaneous locations of HAT; no parasite was observed in situ. The patient was treated successfully with a 7-day course of pentamidine. The case was reported to World Health Organization Control of Neglected Tropical Diseases Department. A total of 328 HAT cases were reported to the World Health Organization in Gabon during 2000–2009; most infections were acquired in the mangrove swamp Atlantic coast focus in Noya (Estuaire Province) and some in the focus of Bendje (Ogooue-Maritime Province) (3). Four of 6 cases of T.b. gambiense imported to Europe during 2005–2009 were in expatriates with a travel history to Gabon (1). In the 4 case-patients infected in Gabon, an exposure in rural forest areas was assessed (4–6; D. Malvy, pers. comm.). In the fifth case reported here, the tsetse bite likely occurred in the urban setting of Libreville. The patient did not report occupational exposure to tsetse bites outside Libreville during the previous year. He occasionally went in Pointe Denis during weekends but did not remember having been bitten by a tsetse fly. Although the patient did not identify the insect in his garden, the chronology of his clinical history and the presence of a typical chancre at the place of the insect bite that occurred before symptoms provide strong arguments in favor of this hypothesis. The bite occurred during the morning hours, in the patient’s home garden in the Lalala area of Libreville (0.357568N, 9.475365E) near the Ogombie River. This area is located 125 km and 75 km from the Bendje and Noya HAT foci, respectively. Two studies provided evidence for urban transmission of HAT in Kinshasa (Democratic Republic of Congo) and in Bonon (Cote d’Ivoire) (7,8). Concurrently, some tsetse species, such as G. palpalis, adapt to high human densities and are found in the largest urban centers of western Africa (9). Entomologic studies in Libreville should prompt further investigation into a possible urban transmission of HAT in Gabon, as we suspect in the case reported.

Traitement des leishmanioses en France : proposition d’un référentiel consensuel

Because it relies on potentially toxic, difficult-to-handle, or expensive compounds the therapy of leishmaniasis is still a complex issue in 2010, especially for visceral leishmaniasis in immuno-suppressed subjects, or in patients with cutaneous and mucosal involvement. This induces a wide diversity of observed therapeutic practices, some being sub-optimal. The Société de Pathologie Exotique organised a meeting dedicated to the therapy of leishmaniasis in France that led to the first consensus on therapeutic guidelines. Liposomal amphotericin B is the first-line option for visceral leishmaniasis both in immunocompetent, and immunosuppressed patients (cumulated doses of 20 mg/kg and 30-40 mg/kg, respectively). Secondary prophylaxis with either liposomal amphotericin B, pentamidine or meglumine antimoniate is proposed to patients with heavy immunosuppression until immunity has been restored for at least 6 months. While the efficacy of new topical formulations of paromomycin is being tested, patients with Old World cutaneous leishmaniasis may be left untreated, or be administered a combination of superficial cryotherapy plus intralesional antimony, or even--in complex situations--receive systemic therapy. The efficacy of a short course of pentamidine (L. guyanensis/L. panamensis) and a 20-day schedule of meglumine antimoniate (L. braziliensis) is solidly established. However, in well-defined situations, local therapy of New World cutaneous leishmaniasis is now considered acceptable.

DISSEMINATED CUTANEOUS LEISHMANIASIS DUE TO LEISHMANIA GUYANENSIS: CASE OF A PATIENT WITH 425 LESIONS

Disseminated cutaneous leishmaniasis is characterized by the presence of a large (> or =10) number of lesions at several anatomic sites (head, limbs, and trunk). Most of the lesions are small, papular, and appear simultaneously with or secondarily to one or several ulcerated lesions of localized cutaneous leishmaniasis. We report the first case of disseminated cutaneous leishmaniasis in French Guiana. It concerns a 24-year-old woman who tested negative for human immunodeficiency virus (HIV). The disease began with three lesions that became ulcerated. One week later, multiple papulo-nodular lesions appeared. We counted a total of 425 lesions. Leishmania were observed in the lesions. The species involved was L. guyanensis, which has never been described in a case of disseminated cutaneous leishmaniasis. The patient was rapidly cured by a single course of pentamidine. Disseminated cutaneous leishmaniasis should be distinguished from other types of leishmaniasis with multiple lesions. These include anergic diffuse cutaneous leishmaniasis, post-kala-azar leishmaniasis, and leishmaniasis associated with HIV infection.

Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana.

The cure 'rates' achieved using intramuscular pentamidine isethionate (two injections of 4 mg/kg separated by an interval of 48 h) were investigated in French Guiana, in 198 consecutive patients with cutaneous leishmaniasis caused by Leishmania braziliensis guyanensis. One aim was to see if initial clinical presentation could be used to predict treatment failure. The cure rate after one course of pentamidine isethionate was 87% and almost all (80%) of the treatment failures responded to an identical second course. Although many of the patients complained of adverse effects, most commonly of pain at the injection site (54%), none of these effects was severe. Although frequently associated with discomfort, the two-injection course, giving a total of 8 mg pentamidine isethionate/kg, appears to be an effective treatment for cutaneous leishmaniasis in French Guiana. The observation of satellite papules on presentation was associated with a significantly increased risk of failure of the first course of treatment (P = 0.01), with an odds ratio (and 95% confidence interval) estimated at 3.5 (1.3-11.1), after adjusting for other clinical presentations and lesion size and number. The presence of satellite papules perhaps indicates that the patient's immune system is unable to control the progression of the parasite. Patients with more than three lesions were also less likely to be cured after one course of pentamidine than those with fewer lesions (P = 0.01).

Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana

Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana

Treatment of New World cutaneous and mucosal leishmaniases

The most extensive investigations of treatment of New World cutaneous leishmaniasis have been performed against L. panamensis disease in Colombia, and the relative value of regimens shown there may be instructive for disease from other areas. In Colombia, a 90–95% cure rate was achieved with three different drug regimens: The standard regimen of pentavalent antimony (20 mg/ kg/day for 20 days parenterally) A short course of pentamidine (3 mg/kg every other day for four injections intramuscularly The marketed combination of topical paromomycin (15%)-MBCI (12%) for 10 days, plus antimony (20 mg/kg/day parenterally) for 7 days. My view is that all these regimens could be chosen as first-line therapy for cutaneous disease in Colombia. The antimony regimen has the advantage of established use; the disadvantages are cost, requirement for injections each day for 20 days, and considerable morbidity in the last two weeks of therapy. The pentamidine regimen has the advantage of a short time course; the disadvantages are lack of experience with this new regimen and frequent, although moderate, morbidity. The combined topical-parenteral regimen has the advantage of requiring few and nontoxic injections; the primary disadvantage is that the regimen is novel and its efficacy has not been confirmed. It would be expected that cases of lesions in other areas caused by L. braziliensis complex would respond in a similar manner to these regimens. To date, however, only the efficacy of the standard antimonial regimen has been confirmed. In certain regions of Central America, other regimens may be effective. Thus, ketoconazole appears to be effective for the more rapidly self-curing forms of disease (cutaneous disease caused by L. mexicana and L. panamensis from Central America), and a short course of antimony may be effective against L. braziliensis in Guatemala.