The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance

Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance

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Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria

The oral azole drugs--ketoconazole, fluconazole, and itraconazole--represent a major advance in systemic antifungal therapy. Among the three, fluconazole has the most attractive pharmacologic profile, including the capacity to produce high concentrations of active drug in cerebrospinal fluid and urine. Ketoconazole, the first oral azole to be introduced, is less well tolerated than either fluconazole or itraconazole and is associated with more clinically important toxic effects, including hepatitis and inhibition of steroid hormone synthesis. However, ketoconazole is less expensive than fluconazole and itraconazole--an especially important consideration for patients receiving long-term therapy. All three drugs are effective alternatives to amphotericin B and flucytosine as therapy for selected systemic mycoses. Ketoconazole and itraconazole are effective in patients with the chronic, indolent forms of the endemic mycoses, including blastomycosis, coccidioidomycosis, and histoplasmosis; itraconazole is also effective in patients with sporotrichosis. Fluconazole is useful in the common forms of fungal meningitis--namely, coccidioidal and cryptococcal meningitis. In addition, fluconazole is effective for selected patients with serious candida syndromes such as candidemia, and itraconazole is the most effective of the azoles for the treatment of aspergillosis.

Oral Azole Drugs as Systemic Antifungal Therapy

Publisher Summary This chapter reviews the role of mathematical models in the investigations of the population or transmission dynamics of human helminths. It focuses on the biological assumptions employed in model construction, the insights that emerge from model analysis, the comparison of predictions with observed trends, and the estimation of parameter values from epidemiological data. The chapter provides a brief description of observed epidemiological patterns, concentrating on age-prevalence and age-intensity trends and a historical review of the development of the mathematical models of helminth infections. The chapter also discusses mathematical models for schistosome flukes, for intestinal nematodes, and for the filarial infections and the essential features of the models for specific infections to provide a general framework for the description of helminth transmission dynamics. The general framework is presented to consider the design of control policies for helminth infections in human communities.

Helminth infections of humans: mathematical models, population dynamics, and control.

Modes of action of anthelmintic drugs are described. Some anthelmintic drugs act rapidly and selectively on neuromuscular transmission of nematodes. Levamisole, pyrantel and morantel are agonists at nicotinic acetylcholine receptors of nematode muscle and cause spastic paralysis. Dichlorvos and haloxon are organophosphorus cholinesterase antagonists. Piperazine is a GABA (gamma-amino-butyric acid) agonist at receptors on nematode muscles and causes flaccid paralysis. The avermectins increase the opening of glutamate-gated chloride (GluCl) channels and produce paralysis of pharyngeal pumping. Praziquantel has a selective effect on the tegument of trematodes and increases permeability of calcium. Other anthelmintics have a biochemical mode of action. The benzimidazole drugs bind selectively to beta-tubulin of nematodes, cestodes and fluke, and inhibit microtubule formation. The salicylanilides: rafoxanide, oxyclozanide, brotianide and closantel and the substituted phenol, nitroxynil, are proton ionophores. Clorsulon is a selective antagonist of fluke phosphoglycerate kinase and mutase. Diethylcarbamazine blocks host, and possibly parasite, enzymes involved in arachidonic acid metabolism, and enhances the innate, nonspecific immune system.

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Modes of Action of Anthelmintic Drugs

Biochemical effects of miconazole on fungi. II. Inhibition of ergosterol biosynthesis in Candida albicans

Ketoconazole, an orally active antimycotic drug, is a potent inhibitor of ergosterol biosynthesis in Candida albicans when added to culture media which support yeast or mycelial growth or to cultures containing outgrown mycelium. This inhibition coincides with accumulation of sterols with a methyl group at C-14 and can thus be attributed to an interference with one of the reactions involved in the removal of the 14 alpha-methyl group of lanosterol. When administered to rats infected with C. albicans, ketocanazole also inhibits fungal synthesis of ergosterol. A six-times-higher dose is required to effect cholesterol synthesis by rat liver.

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis.

Mebendazole, its fluorine analogue flubendazole, and other benzimidazole derivatives are active against many gastrointestinal and tissue-stage helminths. This article reviews the published literature and proceedings of a workshop on the use of benzimidazoles against larval echinococcosis (hydatid disease). Orally administered high doses (30–50 mg/kg body weight) of mebendazole given daily for 20–90 days to rodents or sheep infected with larvalEchinococcus granulosus cause damage or destruction of the cyst wall, loss of cyst fluid, and death of protoscolices. Similar treatment of rodents infected withE. multilocularis with mebendazole, flubendazole, fenbendazole, and albendazole for 60–300 days leads to reduction of weight, inhibition of growth and of metastases formation ofE. multilocularis tissue, and to prolonged host survival time although the metacestodes are not killed. Mebendazole or flubendazole treatment of human patients infected withE. granulosus is followed by subjective improvement in most, and evidence of regression of cysts in some; in other patients, cysts continue to grow or have been proven viable even after several months of high-dose mebendazole therapy. In patients infected withE. multilocularis, the progressive course of the disease appeared to be arrested, but treatment apparently did not kill the parasite. Side effects in some patients have included allergic reactions, alopecia, and reversible neutropenia. Some possible reasons for differnet responses to treatment include inadequate plasma drug absorption from the gut and age, condition, and location of cysts. Many remaining questions concerning the risk versus benefits of mebendazole therapy can be answered only through controlled clinical trials.

Chemotherapy for larval echinococcosis in animals and humans: report of a workshop

Although several good antiparasitic agents are available, new drugs are needed for the treatment of diseases such as chloroquine-resistant malaria, Chagas' disease, leishmaniasis and filariasis. The ‘semirational approach’ should be the basis for their synthesis.

H. Van Den Bossche

Papers

Biochemical effects of miconazole on fungi. II. Inhibition of ergosterol biosynthesis in Candida albicans

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis.

Chemotherapy for larval echinococcosis in animals and humans: report of a workshop

Chemotherapy of parasitic infections

The Host-Invader Interplay