STRUCTURE. These agents are active against anaerobic organisms, notably anaerobic bacteria and some pathogenic protozoa. The most widely used drug is metronidazole (Fig. 1.14). Minor modifications in the structure of nitroimidazole have produced other related compounds such as tinidazole and nimorazole.
MECHANISM OF ACTION. After reduction of their nitro group to a nitrosohydroxyl ammo group by microbial enzymes, nitroimidazoles cause strand breaks in microbial DNA.
INDICATIONS FOR USE. Metronidazole is of major importance in the treatment of anaerobic bacterial infection, particularly that due to Bacteroides. It is also used prophylactically in colonic surgery. It may be given orally, by suppository (entirely satisfactory blood levels can be obtained by this route) or intravenously (very expensive). It is also the treatment of choice for amoebiasis, giardiasis and infection with Trichomonas vaginalis.
INTERACTIONSN. itroimidazoles can produce a disulfiram like reaction with ethanol.
TOXICITY. Nitroimidazoles are tumorigenic in animals and mutagenic for bacteria, although carcinogenicity has not been described in humans. They cause a metallic taste, and peripheral neuropathy with prolonged use. They should be avoided in pregnancy.
Vancomycin is produced by Streptomyces orientalis. STRUCTURE. Vancomycin is a complex and unusual glycopeptide active against Gram-positive bacteria.
MECHANISM OF ACTION. Vancomycin inhibits cellwall synthesis and is bactericidal.
INDICATIONS FOR USE. Vancomycin is given orally for Clostridium difficile-related pseudomembranous enterocolitis and intravenously for methicillin-resistant Staph.
aureus and other multiresistant Gram-positive organisms. Also used for treatment and prophylaxis against Grampositive infections in penicillin-allergic patients.
TOXICITY. Vancomycin can cause ototoxicity and nephrotoxicity and thus serum levels should be monitored. Care must be taken to avoid extravasation at the injection site as this causes necrosis and thrombophlebitis.
This is another glycopeptide antibiotic which is less nephrotoxic. More favourable pharmacokinetic properties, allowing once daily dosing.
NATURALLY OCCURRING COMPOUNDS
The most potent of these is amphotericin B, which is used intravenously in severe systemic fungal infections. Nephrotoxicity is a major problem and dosage levels must take background renal function into account. Liposomal amphotericin B is less toxic but very expensive. Nystatin is not absorbed through mucous membranes and is therefore useful for the treatment of oral and enteric candidiasis and for vaginal infection. It can only be given orally or as pessaries. Polyenes react with the sterols in fungal membranes, increasing permeability and
thus damaging the organism.
This naturally occurring antifungal is concentrated in keratin and is therefore useful for chronic fungal infection of nails, although treatment may be required for many months. It is also widely used for the treatment of ringworm.
Imidazoles such as miconazole (Fig. 1.15), ketoconazole and clotrimazole are broad-spectrum antifungal drugs. CLOTRIMAZOLE is used topically for the treatment of ringworm.
MICONAZOLE is a potent systemic antifungal and is
active both orally and parenterally. It is not as effective as amphotericin B and has been superseded by the triazoles, fluconazole and itraconazole.
KETOCONAZOLE is active orally but can produce liver damage. It is effective in candidiasis and deep mycoses including histoplasmosis and blastomycosis but not in aspergillosis and cryptococcosis. FLUCONAZOLE is noted for its ability to enter CSF and is used for treatment of central nervous system (CNS) infection with Cryptococcus neoformans and candidiasis. hRACONAZOLE fails to penetrate CSF. The indications are as for ketoconazole but may also be effective in cryptococcosis and aspergillosis. Toxicity is mild.
The fluorinated pyridine derivative, flucytosine, is usually used in combination with amphotericin B for systemic fungal infection. Side-effects are uncommon, although it may cause bone marrow suppression. It is active when given both orally and parenterally.
This agent is active against herpes simplex virus (HSV) as a 5% solution with dimethyl sulphoxide (DMSO), but to be effective it must be applied to the skin before the appearance of vesicles. It is also effective as a 0.1% solution when instilled into the eye for HSV keratitis. Similar topical use in herpes zoster probably alters the clinical course of the illness if given early. Vidarabine (adenine arabinoside) This agent may be given intravenously and is active against HSV and varicella zoster virus (VZV). It is also used in severe varicella infection (chickenpox). Its major effects include bone marrow suppression and renal impairment.
This agent, which inhibits viral DNA synthesis, is relatively free from side-effects and is effective against many herpes virus infections. Oral and topical preparations are available for the treatment of herpes simplex and zoster viral infections. An intravenous preparation can be used for the treatment of systemic virus infection in the immunocompromised host, particularly VZV infections, and also for primary HSV infection, e.g. encephalitis. Ribavirin (Tribavirin) Given during the first week of Lassa fever this drug reduces mortality from about 50% to 5%. Oral prophylaxis for 10 days is indicated for contacts.
AZT (zidovudine) (Fig. 1.16), a thymidine analogue, inhibits HIV reverse transcriptase and thereby impairs viral replication. It is strongly recommended for HIV patients in Group IV (see p. 99), particularly those with opportunistic infection and neurological disease. Bone marrow toxicity is frequent (c. 30%) and serious.
Polymyositis and an encephalitis-like syndrome may also occur.
This guanine analogue is used for cytomegalovirus retinitis and gastrointestinal disease in patients with HIV. The major complication is neutropenia.
This is a simple phosphonate analogue. It inhibits both viral D A polymerase and reverse transcriptase but at different loci to acyclovir and AZT. It is active against herpes virus including cytomegalovirus and is used for this in patients with HIV infection. Side-effects are reduced renal function and anaemia.
This is a naturally occurring substance produced by T lymphocytes during virus infection. Interferon production occurs in response to many different viruses and production stimulated by one virus may confer protection against a second viral invader. It is currently being
used as a treatment for acute and chronic hepatitis Band C as well as in certain malignancies.