Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

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Drug Resistance in Leishmaniasis

The current interest in leishmaniasis stems from the importance of this disease with respect to travel medicine, veterans of Operation Desert Storm, humanitarian concerns, and infection with human immunodeficiency virus. Herein, I review aspects of leishmaniasis that are of practical value to practitioners, including presentation, diagnosis, and chemotherapy; I will emphasize advances in chemotherapy over the last 10 years. Amphotericin B and its new lipid formulations are now competitive with pentavalent antimony as primary therapy for visceral leishmaniasis. Pentamidine, paromomycin, and adjunctive therapy with interferon-gamma are secondary regimens for the treatment of this condition. High-dose long-term regimens of antimony have been shown to be highly effective for the treatment of cutaneous leishmaniasis. Preliminary evidence of efficacy has been observed with short courses of pentamidine for the treatment of Leishmania braziliensis complex disease and topical paromomycin/methylbenzethonium chloride for the treatment of Leishmania major disease.

Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years.

Over 850 Leishmania-human immunodeficiency virus (HIV) coinfection cases have been recorded, the majority in Europe, where 7 to 17% of HIV-positive individuals with fever have amastigotes, suggesting that Leishmania-infected individuals without symptoms will express symptoms of leishmaniasis if they become immunosuppressed. However, there are indirect reasons and statistical data demonstrating that intravenous drug addiction plays a specific role in Leishmania infantum transmission: an anthroponotic cycle complementary to the zoonotic one has been suggested. Due to anergy in patients with coinfection, L. infantum dermotropic zymodemes are isolated from patient viscera and a higher L. infantum phenotypic variability is seen. Moreover, insect trypanosomatids that are currently considered nonpathogenic have been isolated from coinfected patients. HIV infection and Leishmania infection each induce important analogous immunological changes whose effects are multiplied if they occur concomitantly, such as a Th1-to-Th2 response switch; however, the consequences of the viral infection predominate. In fact, a large proportion of coinfected patients have no detectable anti-Leishmania antibodies. The microorganisms share target cells, and it has been demonstrated in vitro how L. infantum induces the expression of latent HIV-1. Bone marrow culture is the most useful diagnostic technique, but it is invasive. Blood smears and culture are good alternatives. PCR, xenodiagnosis, and circulating-antigen detection are available only in specialized laboratories. The relationship with low levels of CD4+ cells conditions the clinical presentation and evolution of disease. Most patients have visceral leishmaniasis, but asymptomatic, cutaneous, mucocutaneous, diffuse cutaneous, and post-kala-azar dermal leishmaniasis can be produced by L. infantum. The digestive and respiratory tracts are frequently parasitized. The course of coinfection is marked by a high relapse rate. There is a lack of randomized prospective treatment trials; therefore, coinfected patients are treated by conventional regimens. Prophylactic therapy is suggested to be helpful in preventing relapses.

Leishmania and human immunodeficiency virus coinfection: the first 10 years.

Enterococci, leading causes of nosocomial bacteremia, surgical wound infection, and urinary tract infection, are becoming resistant to many and sometimes all standard therapies. New rapid surveillance methods are highlighting the importance of examining enterococcal isolates at the species level. Most enterococcal infections are caused by Enterococcus faecalis, which are more likely to express traits related to overt virulence but--for the moment--also more likely to retain sensitivity to at least one effective antibiotic. The remaining infections are mostly caused by E. faecium, a species virtually devoid of known overt pathogenic traits but more likely to be resistant to even antibiotics of last resort. Effective control of multiple-drug resistant enterococci will require 1) better understanding of the interaction between enterococci, the hospital environment, and humans, 2) prudent antibiotic use, 3) better contact isolation in hospitals and other patient care environments, and 4) improved surveillance. Equally important is renewed vigor in the search for additional drugs, accompanied by the evolution of new therapeutic paradigms less vulnerable to the cycle of drug introduction and drug resistance.

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Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future.

Context.—Gulf War (GW) veterans report nonspecific symptoms significantly more
often than their nondeployed peers. However, no specific disorder has been
identified, and the etiologic basis and clinical significance of their symptoms
remain unclear.Objectives.—To organize symptoms reported by US Air Force GW veterans into a case
definition, to characterize clinical features, and to evaluate risk factors.Design.—Cross-sectional population survey of individual characteristics and
symptoms and clinical evaluation (including a structured interview, the Medical
Outcomes Study Short Form 36, psychiatric screening, physical examination,
clinical laboratory tests, and serologic assays for antibodies against viruses,
rickettsia, parasites, and bacteria) conducted in 1995.Participants and Setting.—The cross-sectional questionnaire survey included 3723 currently active
volunteers, irrespective of health status or GW participation, from 4 air
force populations.The cross-sectional clinical evaluation included 158 GW
veterans from one unit, irrespective of health status.Main Outcome Measures.—Symptom-based case definition; case prevalence rate for GW veterans
and nondeployed personnel; clinical and laboratory findings among veterans
who met the case definition.Results.—We defined a case as having 1 or more chronic symptoms from at least
2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence
of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155
GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness
was not associated with time or place of deployment or with duties during
the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases,
86 (54%) mild-to-moderate cases, and 13 (8%) severe cases. Although no physical
examination, laboratory, or serologic findings identified cases, veterans
who met the case definition had significantly diminished functioning and well-being.Conclusions.—Among currently active members of 4 Air Force populations, a chronic
multisymptom condition was significantly associated with deployment to the
GW. The condition was not associated with specific GW exposures and also affected
nondeployed personnel.

https://jamanetwork.com/journals/jama/articlepdf/187978/joc71162.pdf

Chronic Multisymptom Illness Affecting Air Force Veterans of the Gulf War

Background Visceral leishmaniasis, usually caused by Leishmania donovani, has rarely been reported from eastern Saudi Arabia, so it was not expected to affect the soldiers of Operation Desert Storm. Methods We evaluated eight soldiers with visceral leishmanial infection, examining their serum with an immunofluorescent-antibody assay, examining their marrow or biopsy tissue for amastigotes with an indirect immunofluorescent-monoclonal-antibody assay, and culturing the parasites. Cultured promastigotes were isolated and characterized by isoenzyme analysis. Results None of the eight soldiers had classic signs or symptoms of visceral leishmaniasis (kala-azar). Seven soldiers had unexplained fever, chronic fatigue, malaise, cough, intermittent diarrhea, or abdominal pain that began up to seven months after they returned to the United States; one had no symptoms. Five had adenopathy or mild, transient hepatosplenomegaly. None had cutaneous manifestations. Diagnoses were made by bone marrow aspiration (seven pat...

https://www.nejm.org/doi/pdf/10.1056/NEJM199305133281904

Visceral Infection Caused by Leishmania tropica in Veterans of Operation Desert Storm

We report an adult autologous stem cell transplant (ASCT) patient who developed transplant-associated thrombotic microangiopathy (TMA) due to human herpesvirus-6 (HHV-6) reactivation. A 58-year-old female with Stage IIIA IgGkappa multiple myeloma received a melphalan (200 mg/m2) ASCT with discharge home after resolution of ASCT-related toxicities. She presented on D+20 with dyspnea, rash, and fever to 105 degrees F, followed by worsening dyspnea, hypotension, and capillary leak. Mental status (MS) changes were noted on D+23, but head CT and EEG were unremarkable. On D+29, a generalized seizure occurred with decline in platelet count and haptoglobin. TMA was noted on peripheral blood smear and therapeutic plasma exchange (TPE) was initiated on D+31. Lumbar puncture (LP) revealed CSF protein 74 mg/dL and white blood count 7,000/mm3 with 74% lymphocytosis. TPE was continued without improvement in her MS or thrombocytopenia despite improvement in microangiopathy. An MRI of the brain showed a left hippocampus abnormality, and an EEG was consistent with encephalopathy. Serum polymerase chain regimen (PCR) was negative for CMV, HSV1, and HSV2 but was strongly positive for HHV-6. Repeat LP protein was 597 mg/dL. Foscarnet was initiated, and cerebrospinal fluid (CSF) PCR for HHV-6 revealed 1,400 DNA copies/mL. Her MS greatly improved within 48 hr of antiviral therapy, serum HHV-6 became negative, and TPE was tapered without recurrence of her TMA. TMA with HHV-6 reactivation is likely an underdiagnosed entity. Given its fulminant course and favorable response to therapy, HHV-6 reactivation should be considered a potential etiology in patients with TMA after ASCT.

Thrombotic microangiopathy (TMA) and stroke due to human herpesvirus-6 (HHV-6) reactivation in an adult receiving high-dose melphalan with autologous peripheral stem cell transplantation.

The Four Horsemen of the Apocalypse -- War, Famine, Pestilence, and Death -- ride the arid plains of Somalia. Despite the protection offered by modern chemoprophylaxis, immunization, and preventive medicine, military personnel safeguarding food delivery in Operation Restore Hope are threatened by exotic infectious diseases rarely seen by U.S. physicians. Some require prompt treatment to prevent death (Table 1). Many other infections acquired in Somalia will appear soon after exposure, some will become evident after the troops return home, and others will remain latent unless host immunity is compromised. Physicians caring for Somalis, particularly displaced persons in refugee camps, are . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199304083281430

A. J. Magill

Papers

Visceral Infection Caused by Leishmania tropica in Veterans of Operation Desert Storm

Thrombotic microangiopathy (TMA) and stroke due to human herpesvirus-6 (HHV-6) reactivation in an adult receiving high-dose melphalan with autologous peripheral stem cell transplantation.

The Threat of Infectious Diseases in Somalia

Visceral leishmaniasis in desert storm veterans. authors' reply