Clinical Pharmacology, 11e

Viral, fungal, protozoal and helminthic infections

Sani Aliyu

Synopsis

• Viruses present a more difficult problem of chemotherapy than do higher organisms, e.g. bacteria, for they are intracellular parasites that use the metabolism of host cells.¹ Highly selective toxicity is, therefore, harder to achieve. In the past 15 years, identification of the molecular differences between viral and human metabolism has led to the development of many effective antiviral agents; four were available in 1990, now there are over 40.

• Fungal infections range from inconvenient skin conditions to life-threatening systemic diseases; the latter have become more frequent as opportunistic infections in patients immunocompromised by drugs or AIDS, or in those receiving intensive medical and surgical interventions in intensive care units.

• Protozoal infections. Malaria is the major transmissible parasitic disease in the world. Drug resistance is an increasing problem and differs with geographical location, and species of plasmodium.

• Helminthic infestations cause considerable morbidity. The drugs that are effective against these organisms are summarised.

Viral infections

Antiviral agents are most active when viruses are replicating. The earlier that treatment is given, therefore, the better the result. Apart from primary infection, viral illness is often the consequence of reactivation of latent virus in the body. Patients whose immune systems are compromised may suffer particularly severe illness. Viruses are capable of developing resistance to antimicrobial drugs, with similar implications for the individual patient, for the community and for drug development. An overview of drugs that have proved effective against virus diseases appears in Table 15.1.

Table 15.1 Drugs of choice for virus infections

Organism	Drug of choice	Alternative
Varicella zoster
chickenpox	Aciclovir	Valaciclovir or famciclovir
zoster	Aciclovir or famciclovir	Valaciclovir
Herpes simplex
keratitis	Aciclovir (topical)
labial	Aciclovir (topical and/or oral)	Valaciclovir or famciclovir
genital	Aciclovir (topical and/or oral)	Valaciclovir
	Famciclovir (oral)	Penciclovir
encephalitis	Aciclovir
disseminated	Aciclovir	Foscarnet
Human immunodeficiency virus (HIV)	Lamivudine/emtricitabine	Abacavir
	Tenofovir	Didanoside
	Zidovudine	Stavudine
	Lopinavir/ritonavir	Saquinavir
	Atazanavir	Darunavir
	Fosamprenavir	Tipranavir
	Efavirenz	Nevirapine
	Etravirine
	Raltegravir
	Enfuvirtide
	Maraviroc
Hepatitis B	Pegylated interferon α-2a and interferon 2b, lamivudine	Adefovir, tenofovir, entecavir, telbivudine
Hepatitis C	Pegylated interferon α-2a or interferon 2b plus ribavirin
Hepatitis D	Interferon-α	Pegylated interferon α-2a and interferon 2b
Influenza A	Zanamivir, oseltamivir	Amantadine
Cytomegalovirus (CMV)	Valganciclovir, ganciclovir	Foscarnet, cidofovir
Respiratory syncytial virus	Ribavirin	Palivizumab
Papillomavirus (genital warts)	Imiquimod
Molluscum contagiosum	Imiquimod	Cidofovir

Herpes simplex and varicella zoster

Aciclovir

Aciclovir (t_½ 3 h) is a nucleoside analogue that is selectively phosphorylated by virus-specific thymidine kinase. Phosphorylated aciclovir inhibits viral replication by acting as a substrate for viral DNA polymerase, thus accounting for its high therapeutic index. It is effective against susceptible herpes viruses if started early in the course of infection, but it does not eradicate persistent infection because viral DNA is integrated in the host genome. About 20% is absorbed from the gut, but this is sufficient for oral systemic treatment of some infections. It distributes widely in the body; the concentration in CSF is approximately half that of plasma, and the brain concentration may be even lower. These differences are taken into account in dosing for viral encephalitis (for which aciclovir must be given i.v.). Dose adjustment is required for patients with impaired renal function, as the drug is predominantly excreted in the urine. For oral and topical use the drug is given five times daily. It can be given twice daily orally for suppressive therapy.

Indications

for aciclovir include:

Herpes simplex virus:

• Skin infections, including initial and recurrent labial and genital herpes, most effective when new lesions are forming; skin and mucous membrane infections (as tablets or oral suspension).

• Ocular keratitis (topical treatment with ophthalmic ointment is standard, oral treatment is also effective).

• Prophylaxis and treatment in the immunocompromised (oral, as tablets or suspension).

• Encephalitis and disseminated disease (i.v.).

Aciclovir-resistant herpes simplex virus has been reported in patients with AIDS but remains rare in immunocompetent patients. Foscarnet (p. 221) and cidofovir (p. 221) have been used in these cases.

Varicella zoster virus:

• Chickenpox, particularly in the immunocompromised (i.v.) or in the immunocompetent with pneumonitis or hepatitis (i.v.).

• Shingles in immunocompetent persons (as tablets or suspension, and best started within 48 h of the appearance of the rash). Immunocompromised persons will often have more severe symptoms and require i.v. administration.

Adverse reactions

are remarkably few. The ophthalmic ointment causes a mild transient stinging sensation and a diffuse superficial punctate keratopathy which clears when the drug is stopped. Oral or i.v. use may cause gastrointestinal symptoms, headache and neuropsychiatric reactions. Extravasation with i.v. use causes severe local inflammation. Crystal-induced acute renal failure is an important complication of i.v. therapy that can be avoided by ensuring good hydration during treatment.

Valaciclovir

is a prodrug (ester) of aciclovir, i.e. after oral administration the parent aciclovir is released. It has an improved bio-availability (about 60%) due to the addition of an ester side chain, thus allowing for a less frequent, 8-hourly, dosing. It is used for treating herpes zoster infections and herpes simplex infections of the skin and mucous membranes.

Famciclovir

(t_½ 2 h) is a prodrug of penciclovir, which is similar to aciclovir; it is used for herpes zoster and genital herpes simplex infections, and a single dose is effective at reducing the time to healing of labial herpes simplex. It need be given only 8-hourly. Penciclovir is also available as a cream for treatment of labial herpes simplex.

Idoxuridine

was the first widely used antiviral drug; it is variably effective topically for ocular and cutaneous herpes simplex, with few adverse reactions. It has been superseded by aciclovir.

Human immunodeficiency virus (HIV)

According to World Health Organization data, 33 million people worldwide were living with human immunodeficiency virus (HIV) in 2008, with close to 3 million new infections yearly; almost 10 million were in need of antiretroviral therapy but more than half of these had no access to treatment.

General comments

• The aims of antiretroviral therapy are to delay disease progression and prolong survival by suppressing the replication of the virus. Optimal suppression also prevents the emergence of drug resistance and reduces the risks of onward transmission to sexual partners and the unborn children of HIV-infected mothers. Virological failure may be defined as primary where there is inability to reduce plasma HIV viral load to fewer than 50 copies per microlitre despite 6 months of antiretroviral therapy, or secondary if there is failure to maintain viral load suppression at less than 50 copies per microlitre.

• No current antiviral agents or combinations eliminate HIV infection, but the most effective combinations (so-called ‘highly active antiretroviral therapy’, HAART) produce profound suppression of viral replication in many patients and allow useful reconstitution of the immune system, measured by a fall in the plasma viral load and an increase in the numbers of cytotoxic T cells (CD4 count). Rates of opportunistic infections such as Pneumocystis cariniipneumonia and cytomegalovirus (CMV) retinitis are reduced when CD4 counts are restored, and life expectancy is markedly increased.

• Combination therapy reduces the risks of emergence of resistance to antiretroviral drugs, which is increasing in incidence even in patients newly diagnosed with HIV. Mutations in the viral genome either prevent binding of the drug to the active site of the protease or reverse transcriptase enzymes, or lead to removal of the drug from the reverse transcriptase active site. The potential for rapid development of resistance is immense because untreated HIV replicates rapidly (50% of circulating virus is replaced daily), the spontaneous mutation rate is high, the genome is small, the virus will develop single mutations at every codon every day, and for many antiretroviral agents a single mutation will render the virus fully resistant.

• The decision to begin antiretroviral therapy is based primarily on the CD4 cell count (most current recommendations are to start in patients with counts below 350 cells per microlitre). Early initiation of antiretroviral therapy should also be considered for patients with CD4 cell count above 350 cells per microlitre but a low CD4 percentage (e.g < 14%), those with an AIDS diagnosis (e.g. Kaposi sarcoma), hepatitis B and HIV co-infection where treatment is indicated, and in conditions where achieving a suppressed viral load is desired in order to prevent transmission (e.g. in pregnancy).

• There are currently more than 20 approved antiretroviral agents in four classes, plus various fixed drug combinations (Table 15.2).

• Current HAART regimens use a combination of drugs that act at different phases of the viral life cycle. The most frequently used combinations employ a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (rPI). The choice for the individual patient is best made after reference to contemporary, expert advice (see the websites listed in the Guide to further reading).

• Alternative combinations are used if these variables deteriorate or unwanted drug effects occur. Antiretroviral resistance testing, both genetic (by searching viral RNA for sequences coding for resistance) and phenotypic (by testing antiretroviral agents against the patient's virus in cell culture), also guide the choice of drug regimen, especially after virological failure.

• Pregnancy and breast feeding pose special problems. The objectives of therapy are to minimise drug toxicity to the fetus while reducing the maternal viral load and the catastrophic results of HIV transmission to the neonate. Prevention of maternal–fetal and maternal–infant spread is the most cost-effective way of using antiretroviral drugs in less developed countries. Maternal–fetal transmission rates are related to maternal viral load, with rates of 0.1% reported when maternal viral load is less than 50 copies per microlitre while on HAART. Where resources permit, access to safe alternatives to breast feeding should be provided to infected mothers.

• Combination antiretroviral therapy, especially the thymidine nucleoside analogue reverse transcriptase inhibitors zidovudine and stavudine, causes redistribution of body fat in some patients – the ‘lipodystrophy syndrome’. Protease inhibitors can disturb lipid and glucose metabolism to a degree that warrants a change to drugs with limited effects on lipid metabolism, e.g. ritonavir-boosted atazanavir, and the introduction of lipid-lowering agents.

• Impaired cell-mediated immunity leaves the host prey to opportunistic infections including: candidiasis, coccidioidomycosis, cryptosporidiosis, CMV disease, herpes simplex, histoplasmosis, Pneumocystis carinii pneumonia, toxoplasmosis and tuberculosis (often with multiply resistant organisms). Treatment of these conditions is referred to elsewhere in this text.²

• Improvement in immune function as a result of antiretroviral treatment may provoke an inflammatory reaction against residual opportunistic organisms (immune reconstitution inflammatory syndrome, IRIS). Although infrequent, this may present with development of new infections or worsening opportunistic infections, e.g. tuberculosis and cryptococcal disease.

• Antiretroviral drugs may also be used in combination to reduce the risks of infection with HIV from injuries, e.g. from HIV-contaminated needles and following sexual exposure to a high-risk partner. The decision to offer such post-exposure prophylaxis (PEP), and the optimal combination of drugs used, is a matter for experts; administration must begin within a few hours of exposure and continue for 28 days.

• Some drugs described here have found additional indications, or are used only, for therapy of non-HIV infections, e.g. adefovir for chronic hepatitis B infection.

Table 15.2 Classification and mechanism of antiretrovirals

Nucleoside and nucleotide reverse transcriptase inhibitors

The HIV replicates by converting its single-stranded RNA into double-stranded DNA, which is incorporated into host DNA; this crucial conversion, the reverse of the normal cellular transcription of nucleic acids, is accomplished by the enzyme reverse transcriptase. Nucleoside reverse transcriptase inhibitors have a high affinity for the reverse transcriptase enzyme and are integrated by it into the viral DNA chain, causing premature chain termination. While all nucleoside reverse transcriptase inhibitors require activation by host enzymes to triphosphates prior to incorporation into the DNA chain, tenofovir (as the only nucleotide analogue) is unique in requiring only two phosphorylations for activation.

Zidovudine (AZT, Retrovir)

Zidovudine, a thymidine analogue, is the first antiretroviral licensed for the treatment of HIV-1. Resistance develops rapidly when used as monotherapy through the sequential accumulation of thymidine analogue mutations (TAMs) at codon 41, 67, 70, 215 and 219; conversely, point mutations at codon 184 selected by lamivudine and emtricitabine therapy enhance susceptibility to zidovudine (and stavudine) by delaying the emergence of TAMs.

Pharmacokinetics

Zidovudine is well absorbed from the gastrointestinal tract (it is available as capsules and syrup) and is rapidly cleared from the plasma (t_½ 1 h); concentrations in cerebrospinal fluid (CSF) are approximately half of those in plasma. Zidovudine is also available i.v. for patients temporarily unable to take oral medications, for neonates and for intrapartum use. The drug is inactivated mainly by glucuronidation in the liver, but 20% is excreted unchanged by the kidney. Zidovudine competitively inhibits the intracellular phosphorylation of stavudine, therefore use in combination with stavudine should be avoided.

Uses

Zidovudine is indicated for the treatment of HIV infection as part of a combination regimen. It is an established choice for the prevention of maternal–fetal transmission, both as part of a combination regimen antenatally in the mother and as monotherapy in the newborn. The enhanced CNS penetration of zidovudine makes it an important option for the treatment of HIV-associated neurocognitive disease (HAND). The drug is available as part of a fixed drug combination with lamivudine (as Combivir), and with abacavir and lamivudine (as Trizivir).

Adverse reactions

early in treatment may include anorexia, nausea, vomiting, headache, dizziness, malaise and myalgia, but tolerance develops to these and usually the dose does not need to be altered. More serious are anaemia and neutropenia, which develop more commonly when the dose is high, with advanced disease, and in combination with ganciclovir, interferon-α and other marrow suppressive agents. A toxic myopathy (not easily distinguishable from HIV-associated myopathy) may develop with long-term use. Rarely, a syndrome of hepatic necrosis with lactic acidosis may occur with zidovudine (and with other reverse transcriptase inhibitors).

Didanosine

Didanosine (ddI) is a thymidine analogue with similar activity to zidovudine. It has a short plasma half-life (t_½ 1 h) but a much longer intracellular duration than zidovudine, and thus prolonged antiretroviral activity. Didanosine is rapidly but incompletely absorbed from the gastrointestinal tract (30–40%) and is widely distributed in body water; 30–65% is recovered unchanged in the urine. Drug absorption is affected by food and therefore it has to be taken on an empty stomach or at least 2 h after a meal. Didanosine may cause pancreatitis, lactic acidosis, hepatomegaly with steatosis and peripheral neuropathy. Other adverse effects include hyperuricaemia and diarrhoea, any of which may give reason to reduce the dose or discontinue the drug. Retinal changes and optic neuritis have also been reported. The combination of stavudine and didanosine is associated with a high risk of toxicity and should be avoided. Dose adjustment of didanosine is required when used in combination with tenofovir and in patients with renal insufficiency.

Lamivudine and emtricitabine

Lamivudine (3TC) is a reverse transcriptase inhibitor with a relatively long intracellular half-life (14 h; plasma t_½ 6 h). Lamivudine is the most common nucleoside analogue used in HAART regimens due to its excellent tolerance profile. A nucleoside backbone of lamivudine with zidovudine (Combivir), abacavir (Kivexa) or emtricitabine and tenofovir (Truvada) as fixed drug combinations, appears to reduce viral load effectively and to be well tolerated. The drug is well absorbed from the gastrointestinal tract (86%) and excreted mainly by the kidney with minimal metabolism; dose modification is necessary in renal impairment.

Lamivudine was the first nucleoside analogue to be licensed for therapy of chronic hepatitis B infection, for which it should be used in combination with tenofovir (as part of a HAART regimen) in HIV co-infected patients. Emergence of resistant mutants of hepatitis B is troublesome (due to mutations of the viral reverse transcriptase/DNA polymerase), occurring in up to about 30% of patients after 1 year and 70% after 5 years of therapy.

The most common unwanted effects include headache and gastrointestinal upset. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. A higher dose of lamivudine is required for the treatment of HIV than for hepatitis B infection; patients with co-infection should receive doses appropriate for treatment of HIV.

Emtricitabine

Emtricitabine has a similar structure, tolerability, efficacy and resistance profile. It should not be used in combination with lamivudine, as it contains the same active constituent.

Abacavir

Abacavir (t_½ 2 h) has high therapeutic efficacy; it is usually well tolerated, but adverse effects include hypersensitivity reactions especially during the first 6 weeks of therapy, affecting about 8% of patients; the drug must be stopped immediately and avoided in future if hypersensitivity is suspected. The presence of the HLA-B*5701 allele predicts increased risk of hypersensitivity reaction in the Caucasian population; patients should be tested for the presence of this allele prior to starting therapy.

Tenofovir

Tenofovir (t_½ 17 h), administered orally as the prodrug tenofovir disoproxil fumarate, is also effective against hepatitis B virus. Some 80% is excreted renally and dose adjustment is recommended in patients with a creatinine clearance of less than 50 mL/min. Monitor closely for signs of new onset or acute renal impairment, electrolyte and renal tubular disturbance (Fanconi syndrome); avoid concomitant nephrotoxic drugs while on tenofovir.

Tenofovir competes with didanosine for renal tubular excretion, raising didanosine plasma concentrations with associated risk of pancreatitis, peripheral neuropathy and lactic acidosis. Severe acute exacerbation of hepatitis has been described following cessation of therapy for hepatitis B infection.

Stavudine

Stavudine (d4T) inhibits reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate, and additionally is incorporated into viral DNA, causing termination of chain elongation (t_½ 1.5 h). Troublesome lipoatrophy has limited its use by most authorities outside the developing world. Hepatic toxicity and pancreatitis are reported, and a dose-related peripheral neuropathy may occur, all probably related to mitochondrial toxicity. Stavudine is more frequently associated with lactic acidosis than other nucleoside analogues.

Adefovir

Adefovir dipivoxil is a nucleoside analogue used for chronic hepatitis B infection, including against lamivudine-resistant strains. It is administered as the oral prodrug (plasma t_½ 8 h, intracellular t_½ of active metabolite 17 h). Adverse effects are uncommon, but include headache, abdominal pain and diarrhoea. Resistance emerges over time (30% after 5 years), but much less commonly than with lamivudine therapy, possibly due to the flexibility of the adefovir molecule, which allows it to conform to mutated binding sites. Dose adjustment is required for patients with renal impairment. Adefovir should not be co-prescribed with tenofovir. The recommended adefovir dose for hepatitis B therapy will not suppress HIV infection; HIV status should therefore be confirmed prior to commencing adefovir for hepatitis B infection, as unrecognised co-infection may lead to the emergence of HIV resistance.

Protease inhibitors

In its process of replication, HIV produces precursor proteins, which are subsequently cleaved by the protease enzyme into component parts and reassembled into virus particles; protease inhibitors disrupt this essential process.

Protease inhibitors reduce viral RNA concentration (‘viral load’), increase the CD4 count and improve survival when used in combination with other agents. They are metabolised extensively by isoenzymes of the cytochrome P450 system, notably by CYP 3A4, and most protease inhibitors inhibit these enzymes. They have a plasma t_½ of 2–4 h, except for fosamprenavir (8 h) and atazanavir (7 h with food). The drugs have broadly similar therapeutic effects. Members of the group include:

• amprenavir, atazanavir, fosamprenavir (a prodrug of amprenavir), lopinavir, ritonavir, saquinavir, tipranavir, indinavir and darunavir.

Adverse effects

include gastrointestinal disturbance, headache, dizziness, sleep disturbance, raised liver enzymes, neutropenia, pancreatitis and rashes. Unique side-effects include asymptomatic reversible unconjugated hyperbilirubinaemia with atazanavir and nephrolithiasis with indinavir.

Interactions

Involvement with the cytochrome P450 system provides scope for numerous drug–drug interactions. Agents that induce P450 enzymes, e.g. rifampicin, St John's wort, accelerate their metabolism, reducing plasma concentration and therapeutic efficacy; enzyme inhibitors, e.g. ketoconazole, cimetidine, raise their plasma concentration with risk of toxicity.

The powerful inhibiting effect of ritonavir on CYP 3A4 and CYP 2D6 is harnessed usefully by its combination in low (subtherapeutic) dose with other protease inhibitors; the result is to decrease the metabolism and increase the therapeutic efficacy of the concurrently administered protease inhibitors (called ritonavir ‘boosting’ or ‘potentiation’), i.e. a beneficial drug–drug interaction. Ritonavir boosting is particularly advantageous in patients infected with low-level resistant virus where the high drug levels help improve efficacy, but this may be at the detriment of increased gastrointestinal side-effects and metabolic disturbances. Ritonavir boosting is now a recommended treatment standard for all protease inhibitor containing regimens.

Non-nucleoside reverse transcriptase inhibitors

This group is structurally different from the reverse transcriptase inhibitors; members are active against the subtype HIV-1 but not HIV-2, a subtype encountered mainly in West Africa. Non-nucleoside reverse transcriptase inhibitors are metabolised by CYP 450 enzymes and hence the potential for significant drug–drug interactions. The drugs have considerably longer half-lives when compared to nucleoside reverse transcriptase inhibitors.

Efavirenz

is taken once per day (t_½ 52 h). Rash is relatively common during the first 2 weeks of therapy, but resolution usually occurs within a further 2 weeks; the drug should be stopped if the rash is severe or if there is blistering, desquamation, mucosal involvement or fever. Neurological adverse reactions occur in about 50% of patients, usually insomnia, depression and abnormal dreams; this may be reduced by taking the drug before retiring at night; gastrointestinal side-effects and occasional hepatitis and pancreatitis have also been reported. Efavirenz is teratogenic, so should be avoided in pregnancy. Resistance is associated with mutations at codon 103 and 181, which also confers cross-resistance to nevirapine.

Nevirapine

is used in combination with at least two other antiretroviral drugs. It is commonly prescribed in the developing world and is relatively safe in pregnancy. It penetrates the CSF well, and undergoes hepatic metabolism (t_½ 28 h); it induces its own metabolism and the dose should be increased gradually. Nevirapine is initially commenced as a once-daily regimen, with a 2-week lead-in period to twice daily if tolerated. Rash (including Stevens–Johnson syndrome) is seen in up to 20% of patients and, occasionally, fatal hepatitis. The risk of an adverse drug event is closely related to the CD4 count; nevirapine is contraindicated in females with CD4 counts above 250 per microlitre and males with CD4 counts above 400 per microlitre.

Etravirine

(t_½ 41 h) is administered twice daily after meals; rash is the commonest adverse effect, generally appearing within the first 6 weeks of therapy, and peripheral neuropathy. Etravirine has activity againt NNRTI-resistant HIV strains and should be used in combination with other antiretroviral agents. Due to potentially significant drug interactions, etravirine should not be co-administered with other NNRTIs, unboosted protease inhibitors and ritonavir-boosted tipranavir, fosamprenavir and atazanavir.

Entry inhibitors

Enfuvirtide

is the first antiretroviral agent to target the host cell attachment/entry stage in the HIV replication cycle; the linear 36-amino acid synthetic peptide inhibits fusion of the cellular and viral membranes. It is given by subcutaneous injection (t_½ 4 h). The drug seems most effective when combined with several antiretroviral agents to which the virus is susceptible and is licensed for use in treatment-experienced patients with extensive drug resistance. Enfuvirtide does not inhibit cytochrome P450 enzymes and therefore has limited drug interactions.

Adverse effects are usually limited to mild injection-site reactions, although hypersensitivity, peripheral neuropathy and other adverse reactions are reported rarely. HIV isolates with decreased susceptibility have been recovered from enfuvirtide-treated patients; these exhibit mutations in the gp41 outer envelope glycoprotein of the virus (which plays a key role in infection of CD4 cells by fusing the HIV envelope with the host cell membrane).

Maraviroc

is an entry inhibitor that specifically targets and blocks the chemokine co-receptor CCR5, which is used by HIV for fusion and cell entry. Maraviroc has no activity against HIV virions that preferentially bind to another surface chemokine co-receptor (CXCR4), found in about 60% of antiretroviral experienced patients. Hence a ‘Trofile assay’ is required to determine if a susceptible (CCR5 tropic) strain is present as the dominant quasispecies in a patient prior to commencing maraviroc therapy. It is recommended as part of a combination regimen in treatment-experienced patients with multidrug-resistant strains.

Integrase inhibitors

Raltegravir

(t_½ 41 h) targets the HIV integrase enzyme, which is essential in integrating viral genetic material into the DNA of the host target cell. It is generally well tolerated and metabolised by glucuronidation. It has a low genetic barrier to resistance (arising from mutations in the integrase gene) and should be used with caution in patients at increased risk of myopathy or rhabdomyolysis.

Fixed-dose combinations of antiretroviral drugs

are convenient, help to lessen pill burden and may improve compliance, but the components of the combination may differ in their dependence on metabolic inactivation or renal excretion; particular attention to these is necessary when use in patients with renal or hepatic impairment is proposed.

Fixed-dose combination antiretrovirals

Combivir	zidovudine and lamivudine
Kivexa (Europe), Epzicom (USA)	abacavir and lamivudine
Truvada	tenofovir and emtricitabine
Trizivir	zidovudine and lamivudine and abacavir
Atripla	tenofovir and emtricitabine and efavirenz
Kaletra	lopinavir and ritonavir

Influenza A

Neuraminidase inhibitors are highlighted by the emergence of avian influenza viruses with the potential for mutation to cause pandemic spread in the human population, although their clinical effectiveness is not high. The two antiviral drugs oseltamivir and zanamivir were widely used for the public health control of the 2009 influenza A (H1N1) pandemic.

Amantadine

Amantadine is effective only against influenza A; it acts by interfering with the uncoating and release of viral genome into the host cell. It is well absorbed from the gastrointestinal tract and is eliminated in the urine (t_½ 3 h). Following the emergence of the 2009 influenza A (H1N1) virus as the predominant circulating strain, resistance to amantadine is now almost universal; for this reason amantidine is no longer recommended for the treatment of influenza.

Adverse reactions

include dizziness, nervousness, lightheadedness and insomnia. Drowsiness, hallucinations, delirium and coma may occur in patients with impaired renal function. Convulsions may be induced, and amantadine should be avoided in epileptic patients.

Amantadine for Parkinson's disease: see page 365.

Zanamivir (Relenza)

Zanamivir is a viral neuraminidase inhibitor that blocks both entry of influenza A and B viruses to target cells and the release of their progeny. It is administered as a dry powder twice daily in a 5-day course by a special inhaler. The limited bio-availability (2%) of zanamivir has made it the preferred antiviral in pregnancy. The duration of symptoms is reduced from about 6 to 5 days, with a smaller reduction in the mean time taken to return to normal activities. In high-risk groups the reduction in duration of symptoms is a little greater, and fewer patients need antibiotics. It is also effective for prophylaxis given as a once-daily inhalation.

The UK National Institute for Health and Clinical Excellence (NICE) recommends that zanamivir be reserved for:

• At-risk patients (those with chronic respiratory or cardiovascular disease, immunosuppression or diabetes mellitus, or over the age of 65 years).

• When virological surveillance in the community indicates that influenza virus is circulating.

• Only those presenting within 48 h of the onset of influenza-like symptoms.

Zanamivir retains activity against amantadine-resistant and some oseltamivir-resistant strains.

Unwanted effects

are uncommon, but bronchospasm may be precipitated in asthmatics, and gastrointestinal disturbance and rash are occasionally seen.

Oseltamivir (Tamiflu)

Oseltamivir is an oral prodrug of a viral neuraminidase inhibitor. It reduces the severity and duration of symptoms caused by influenza A or B in adults and children if commenced within 36 h of the onset of symptoms. More specifically, the risk of respiratory complications such as secondary pneumonia, antibiotic use and hospital admission are reduced. It is effective for post-exposure prophylaxis, where it should be started within 48 h of contact with the index case and continued daily for 10 days, a usage that might be appropriate for health-care workers and those especially likely to suffer serious complications from pre-existing illness. Prophylaxis may be given for 2 weeks after influenza immunisation while protective antibodies are being produced.

Oseltamivir is one option for treatment and prophylaxis of avian H5N1 and 2009 influenza A (H1N1) virus. In the event of a pandemic, treatment for 5 days and prophylactic use for up to 6 weeks (or until 48 h after last exposure) are suggested.

Unwanted effects

are uncommon; some people experience gastrointestinal symptoms that are reduced by taking the drug with food.

Resistance to oseltamivir emerged in late 2007 among seasonal influenza A H1N1 viruses as a result of a spontaneous mutation at position 274 (His274Tyr) in the neuraminidase enzyme. So far, this mutation appears to be confined mostly to seasonal influenza A H1N1 strains, with the majority of 2009 influenza A (H1N1) viruses still susceptible to oseltamivir; the mutation also does not appear to confer resistance to zanamivir.

Peramivir

is an experimental neuraminidase inhibitor formulated for intravenous use and currently undergoing phase III trials. The drug was granted temporary emergency use authorisation by the US Food and Drug Administration (FDA) during the 2009 influenza A (H1N1) pandemic for hospitalised patients with severe suspected or confirmed influenza A (H1N1) infection where oseltamivir or zanamivir therapy has failed or the inhalational or oral routes are considered unreliable.

Cytomegalovirus

Ganciclovir

Ganciclovir resembles aciclovir in its mode of action, but is much more toxic. An acyclic analogue of guanosine, the drug is converted to a triphosphate form which competitively inhibits virion DNA polymerase, leading to chain termination. It is given i.v. and is eliminated in the urine, mainly unchanged (t_½ 4 h). Ganciclovir is active against several types of virus but toxicity limits its i.v. use to life- and sight-threatening CMV infection in immunocompromised patients, including CMV retinitis, pneumonitis, colitis and disseminated disease.

Valganciclovir

is an oral prodrug of ganciclovir that provides systemic concentrations almost as high as those following i.v. therapy. It is used for treatment of CMV retinitis (acute treatment of peripheral retinal lesions and maintenance suppressive therapy) in patients with AIDS, and to prevent CMV disease in patients receiving immunosuppressive therapy following organ transplantation (especially liver transplants). A combined approach of ganciclovir-releasing intraocular implant plus oral valganciclovir is sometimes considered in patients with immediate sight-threatening CMV retinitis.

Ganciclovir-resistant CMV isolates have been reported, and require treatment with foscarnet or cidofovir.

Adverse reactions

include neutropenia and thrombocytopenia, which are usually but not always reversible. Concomitant use of potential marrow-depressant drugs, e.g. co-trimoxazole, amphotericin B, azathioprine, zidovudine, should be avoided, and co-administration of granulocyte colony-stimulating factor may ameliorate the myelosuppressive effects. Other reactions are fever, rash, gastrointestinal symptoms, confusion and seizure (the last especially when imipenem is co-administered).

Foscarnet

Foscarnet finds use i.v. for CMV retinitis in patients with HIV infection when ganciclovir is contraindicated, and for aciclovir-resistant herpes simplex virus infection (see p. 213). It is generally less well tolerated than ganciclovir; adverse effects include renal toxicity (usually reversible), nausea and vomiting, neurological reactions and marrow suppression. Hypocalcaemia is seen especially when foscarnet is given with pentamidine, e.g. during treatment of multiple infections in patients with AIDS. Renal toxicity can be minimised with good hydration and dose modification. Foscarnet causes a contact dermatitis which can lead to unpleasant genital ulcerations due to high urine drug concentrations; this is potentially preventable with good urinary hygiene.

Cidofovir

Cidofovir

is given by i.v. infusion (usually every 1–2 weeks) for CMV retinitis in patients with AIDS when other drugs are unsuitable or resistance is a problem. It has also been used i.v. and topically to produce resolution of molluscum contagiosum skin lesions in immunosuppressed patients, and it may be effective in other poxvirus infections. Nephrotoxicity is common with i.v. use, but is reduced by hydration with i.v. fluids before each dose and co-administration with probenecid. Other unwanted effects include bone marrow suppression, nausea and vomiting, and iritis and uveitis, and cause about 25% of patients to discontinue therapy.

Fomivirsen

Fomivirsen, an antisense oligonucleotide, is available in some countries as an intravitreal injection for CMV retinitis in HIV-infected patients who cannot tolerate or who have failed treatment with other drugs.

Respiratory syncytial virus (RSV)

Ribavirin

is a synthetic nucleoside used for RSV bronchiolitis in infants and children, inhaled by a special ventilator. As therapeutic efficacy for this indication is controversial, it is usually reserved for the most severe cases and those with coexisting illnesses, such as immunosuppression. Systemic absorption by the inhalational route is negligible.

Ribavirin is effective by mouth (t_½ 45 h) for reducing mortality from Lassa fever and hantavirus infection (possibly also other viral haemorrhagic fevers and West Nile virus) and, when combined with interferon α-2b or peg-interferon, for chronic hepatitis C infection (see below). It does not cross the blood–brain barrier, so is unlikely to be effective in viral encephalitides. Systemic ribavirin is an important teratogen, and it may cause cardiac, gastrointestinal and neurological adverse effects. It may also cause haemolytic anaemia, for which close monitoring is required.

Palivizumab

is a humanised monoclonal antibody directed against the F glycoprotein on the surface of RSV. It is given by monthly i.m. injection in the winter and early spring to infants and children less than 2 years old at high risk of RSV infection. Transient fever and local injection site reactions are seen and rarely, gastrointestinal disturbance, rash, leucopenia or disturbed liver function occur. Anaphylaxis has occurred rarely (1 in 10 000).

Drugs that modulate the host immune system

Interferons

Virus infection stimulates the production of protective glycoproteins (interferons) which act:

• directly on uninfected cells to induce enzymes that degrade viral RNA

• indirectly by stimulating the immune system

• to modify cell regulatory mechanisms and inhibit neoplastic growth.

Interferons are classified as α, β or γ according to their antigenic and physical properties. α-Interferons (subclassified -2a, -2b and -N1) are effective against conditions that include hairy cell leukaemia, chronic myelogenous leukaemia, recurrent or metastatic renal cell carcinoma, Kaposi's sarcoma in patients with AIDS (an effect that may be due partly to its activity against HIV) and condylomata acuminata (genital warts).

Interferon α-2a and -2b also improve the manifestations of viral hepatitis, but responses differ according to the infecting agent. Therapy with interferon α-2b leads in about a third of patients with chronic hepatitis B to loss of circulating ‘e’ antigen, a return to normal liver enzyme levels, histological improvement in liver architecture, and a lowered rate of progression of liver disease. It is contraindicated in patients with decompensated liver disease.

Pegylated (bound to polyethylene glycol) interferon α-2a is more effective than standard interferon α and is now the standard of care for patients with chronic hepatitis C infection. Over 50% of patients with hepatitis C respond to the combination of pegylated interferon plus ribavirin, and 30–40% to peg-interferon alone. Successful treatment results in the serum concentration of viral RNA becoming undetectable by polymerase chain reaction (PCR). Hepatitis D (δ agent co-infection with hepatitis B) requires a much larger dose of interferon to obtain a response, and relapse may yet occur when the drug is withdrawn. Interferon α-2b may be effective in West Nile virus encephalitis.

See also p. 553 for lamivudine and adefovir, use in chronic hepatitis B infection.

Adverse reactions

are common and include an influenza-like syndrome (naturally produced interferon may be responsible for symptoms in natural influenza infection), fatigue and depression, which respond to lowering the dose but tend to improve after the first week. Other effects are anorexia (sufficient to induce weight loss), alopecia, convulsions, hypotension, hypertension, cardiac arrhythmias and bone marrow depression (which may respond to granulocyte colony-stimulating factors and erythropoietin). Interferons inhibit the metabolism of theophylline, increasing its effect, and autoimmune diseases such as thyroiditis may be induced or exacerbated.

Imiquimod

is used topically for genital warts (caused by papillomaviruses). Treatment for 2–3 months results in gradual clearance of warts in about 50% of patients, and recurrence is less common than after physical removal, e.g. with liquid nitrogen.

Inosine pranobex

is reported to stimulate the host immune response to virus infection and has been used for mucocutaneous herpes simplex, genital warts and subacute sclerosing panencephalitis. It is administered by mouth and metabolised to uric acid, so should be used with caution in patients with hyperuricaemia or gout.

Fungal infections

Widespread use of immunosuppressive chemotherapy and the emergence of AIDS have contributed to a rise in the incidence of opportunistic infection ranging from comparatively trivial cutaneous infections to systemic diseases that demand prolonged treatment with potentially toxic agents.

Superficial mycoses

Dermatophyte infections (ringworm, tinea)

Longstanding remedies such as Compound Benzoic Acid Ointment (Whitfield's ointment) are still acceptable for mild infections, but a topical imidazole (clotrimazole, econazole, miconazole, sulconazole), which is also effective against candida, is now usually preferred. Tioconazole is effective topically for nail infections. When multiple areas are affected, especially if the scalp or nails are included, and when topical therapy fails, oral itraconazole or terbinafine are used.

Candida infections

Cutaneous infection is generally treated with topical amphotericin, clotrimazole, econazole, miconazole or nystatin. Local hygiene is also important. An underlying explanation should be sought when a patient fails to respond to these measures, e.g. diabetes, the use of a broad-spectrum antibiotic or of immunosuppressive drugs.

Candidiasis of the alimentary tract mucosa responds to amphotericin, fluconazole, ketoconazole, miconazole or nystatin as lozenges (to suck, for oral infection), gel (held in the mouth before swallowing), suspension or tablets.

Vaginal candidiasis is treated by clotrimazole, econazole, isoconazole, ketoconazole, miconazole or nystatin as pessaries or vaginal tablets or cream inserted once or twice a day with cream or ointment on surrounding skin. Failure may be due to a concurrent intestinal infection causing re-infection, and nystatin tablets may be given by mouth 8-hourly with the local treatment. Alternatively, oral fluconazole may be used, now available without prescription (‘over the counter’) in the UK. The male sexual partner may use a similar antifungal ointment for his benefit and for the patient's (re-infection).

Fluconazole is often given orally or i.v. to heavily immunocompromised patients, e.g. during periods of profound granulocytopenia, and to severely ill patients on intensive care units to reduce the incidence of systemic candidiasis. Candida albicans is rarely (1% of clinical isolates) resistant to fluconazole, but other Candida species may be, more commonly in hospitals where prophylactic fluconazole use is extensive.

Isolation of candida from the bloodstream or intravenous catheter tips of patients with predisposing factors for systemic candidasis, e.g. prolonged intravenous access, neutropenia, is associated with a significant risk of serious sequelae, e.g. retinal or renal deposits, and should be treated with an effective antifungal for at least 3 weeks; fluconazole, amphotericin or any of the echinocandins will be appropriate.

Systemic mycoses

The principal treatment options are summarised in Table 15.3.

Table 15.3 Drugs of choice for some fungal infections

Infection	Drug of first choice	Alternative
Aspergillosis	Amphotericin or voriconazole	Caspofungin, itraconazole, posaconazole
Blastomycosisa	Itraconazole or amphotericin	Fluconazole
Candidiasis
mucosal	Fluconazole or amphotericin	Caspofungin, voriconazole or fluconazole
systemic	Fluconazole or amphotericin ± flucytosine	Caspofungin, micafungin, anidulafungin, voriconazole
Coccidioidomycosisa	Fluconazole, amphotericin or itraconazole
Cryptococcosis	Amphotericin + flucytosine (followed by fluconazole)	Fluconazole
Fusariosis	Voriconazole	Amphotericin
Histoplasmosis	Itraconazole or amphotericin	Fluconazole
chronic suppressionb	Itraconazole	Amphotericin
Mucormycosis	Amphotericin	Posaconazole
Paracoccidioidomycosis	Itraconazole or amphotericin	Ketoconazolec
Pseudallescheriasis	Voriconazole, ketoconazole or itraconazole
Sporotrichosis
cutaneous	Itraconazole	Potassium iodide
deep	Amphotericin	Itraconazole or fluconazole
Tinea pedis	Terbinafine cream or topical azole (miconazole, clotrimazole, econazole)	Fluconazole

This table was drawn substantially from The Medical Letter on Drugs and Therapeutics (2005, USA).

The authors are grateful to the Chairman of the Editorial Board for permission to publish the material.

a Patients with severe illness, meningitis, AIDS or some other causes of immunosuppression should receive amphotericin.

b For patients with AIDS.

c Continue treatment for 6–12 months.

Classification of antifungal agents

• Drugs that disrupt the fungal cell membrane:

   polyenes, e.g. amphotericin

   azoles: imidazoles, e.g. ketoconazole, triazoles, e.g. fluconazole

   allylamine: terbinafine.

• Drugs that disrupt the fungal cell wall:

   echinocandins, e.g. caspofungin, anidulafungin, micafungin.

• Drugs that inhibit mitosis: griseofulvin.

• Drugs that inhibit DNA synthesis: flucytosine.

Pneumocystosis,

caused by Pneumocystis jirovecii, is an important cause of potentially fatal pneumonia in the immunosuppressed, especially HIV-positive patients. It is treated with high dose co-trimoxazole at 120 mg/kg daily in two to four divided doses for 21 days by mouth or i.v. infusion; monitoring of plasma concentrations is recommended. Patients with more severe illness should also receive corticosteroid. Although co-trimoxazole resistance is rare, patients who fail to respond or are intolerant may benefit from pentamidine or primaquine plus clindamycin. Other options include atovaquone for mild disease. Co-trimoxazole, dapsone (with pyrimethamine if toxoplasma prophylaxis is indicated) or atovaquone by mouth, or intermittent inhaled pentamidine, are used for primary and secondary prophylaxis in patients with AIDS.

Drugs that disrupt the fungal cell membrane

Polyenes

These act by binding tightly to sterols present in cell membranes. The resulting deformity of the membrane allows leakage of intracellular ions and enzymes, causing cell death. Those polyenes that have useful antifungal activity bind selectively to ergosterol, the most important sterol in fungal (but not mammalian) cell walls.

Amphotericin (amphotericin B)

Amphotericin is absorbed negligibly from the gut and must be given by i.v. infusion for systemic infection; about 10% remains in the blood and the fate of the remainder is not known but is probably bound to tissues. The t_½ is 15 days and, after stopping treatment, drug persists in the body for several weeks.

Amphotericin is at present the drug of choice for most systemic fungal infections (but see Table 15.3). The diagnosis of systemic infection should, whenever possible, be firmly established; tissue biopsy and culture may be necessary, and methods using the PCR to detect aspergillus DNA may revolutionise management of invasive infection.

A conventional course of treatment for filamentous fungal infection lasts 6–12 weeks, during which at least 2 g amphotericin is given (usually 0.7–1 mg/kg daily, and up to 10 mg/kg daily of lipid-associated formulations for the most severe, invasive infections), but lower total and daily doses (e.g. 0.6 mg/kg daily) are used for candida infections, with correspondingly better tolerance. Antifungal drugs may be combined with immune-stimulating agents, e.g. granulocyte colony-stimulating factor, and clinical response in neutropenic episodes is closely related to return of normal neutrophil counts.

Lipid-associated formulations of amphotericin offer the prospect of reduced risk of toxicity while retaining therapeutic efficacy. In an aqueous medium, a lipid with hydrophilic and hydrophobic properties will form vesicles (liposomes) comprising an outer lipid bilayer surrounding an aqueous centre. The AmBisome formulation incorporates amphotericin in a lipid bilayer (55–75 nm diameter) from which the drug is released. Other lipid-associated complexes include Abelcet (‘amphotericin B lipid complex’) and Amphocil (‘amphotericin B colloidal dispersion’). Lipid-associated formulations may be more effective for some indications because higher doses (3 mg/kg daily) may be given rapidly and safely. They are the first choice when renal function is impaired. Treatment often begins with the conventional formulation in those with normal kidneys, resorting to lipid-associated formulations if the patient's renal function deteriorates.

Adverse reactions

Gradual escalation of the dose limits toxic effects, which may be deemed justifiable in life-threatening infection if conventional amphotericin is used. A strategy of continuous i.v. infusion appears to combine therapeutic efficacy with tolerability. Renal impairment is invariable, although reduced by adequate hydration; nephrotoxicity is reversible, at least in its early stages. Hypokalaemia and hypomagnesaemia (due to distal renal tubular acidosis) may necessitate replacement therapy. Other adverse effects include anorexia, nausea, vomiting, malaise, abdominal, muscle and joint pains, loss of weight, anaemia, and fever. Aspirin, an antihistamine (H₁-receptor) or an antiemetic may alleviate symptoms. Severe febrile reactions are mitigated by hydrocortisone 25–50 mg before each infusion. Lipid-formulated preparations are associated with adverse reactions much less often, but fever, chills, nausea, vomiting, nephrotoxicity, electrolyte disturbance and occasional nephrotoxicity and hepatotoxicity are reported.

Nystatin

(named after New York State Health Laboratory)

Nystatin is too toxic for systemic use. It is not absorbed from the alimentary canal and is used to prevent or treat superficial candidiasis of the mouth, oesophagus or intestinal tract (as suspension, tablets or pastilles), for vaginal candidiasis (pessaries) and cutaneous infection (cream, ointment or powder).

Azoles

The antibacterial, antiprotozoal and anthelminthic members of this group are described in the appropriate sections. Antifungal azoles comprise the following:

• Imidazoles (ketoconazole, miconazole, fenticonazole, clotrimazole, isoconazole, tioconazole) interfere with fungal oxidative enzymes to cause lethal accumulation of hydrogen peroxide; they also reduce the formation of ergosterol, an important constituent of the fungal cell wall which thus becomes permeable to intracellular constituents. Lack of selectivity in these actions results in important adverse effects.

• Triazoles (fluconazole, itraconazole, voriconazole, posaconazole) damage the fungal cell membrane by inhibiting lanosterol 14-α-demethylase, an enzyme crucial to ergosterol synthesis, resulting in accumulation of toxic sterol precursors. Triazoles have greater selectivity against fungi, better penetration of the CNS, resistance to degradation and cause less endocrine disturbance than do the imidazoles.

Ketoconazole

Ketoconazole is well absorbed from the gut (poorly where there is gastric hypoacidity; see below); it is widely distributed in tissues but concentrations in CSF and urine are low; its action is terminated by metabolism by cytochrome P450 3A (t_½ 8 h). For systemic mycoses, ketoconazole (see Table 15.3) has been superseded by fluconazole and itraconazole on grounds of improved pharmacokinetics, tolerability and efficacy. Impairment of steroid synthesis by ketoconazole has been put to other uses, e.g. inhibition of testosterone synthesis lessens bone pain in patients with advanced androgen-dependent prostatic cancer.

Adverse reactions

include nausea, giddiness, headache, pruritus and photophobia. Impairment of testosterone synthesis may cause gynaecomastia and decreased libido in men. Of particular concern is impairment of liver function, ranging from a transient increase in levels of hepatic transaminases and alkaline phosphatase to severe injury and death.

Interactions

Drugs that lower gastric acidity, e.g. antacids, histamine H₂-receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes, inhibiting their action and thereby increasing effects of oral anticoagulants, phenytoin and ciclosporin, and increasing the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole.

Other imidazoles

Miconazole is an alternative. Clotrimazole is widely used as an effective topical agent for dermatophyte, yeast and other fungal infections (intertrigo, athlete's foot, ringworm, pityriasis versicolor, fungal nappy rash). Econazole and sulconazole are similar. Tioconazole is used for fungal nail infections, and isoconazole and fenticonazole for vaginal candidiasis.

Fluconazole

Fluconazole is absorbed from the gastrointestinal tract and is excreted largely unchanged by the kidney (t_½ 30 h). It is effective by mouth for oropharyngeal and oesophageal candidiasis, and i.v. for systemic candidiasis and cryptococcosis (including cryptococcal meningitis; it penetrates the CSF well). It is used prophylactically in a variety of conditions predisposing to systemic candida infections, including at times of profound neutropenia after bone marrow transplantation, and in patients in intensive care units who have intravenous lines in situ, are receiving antibiotic therapy and have undergone bowel surgery. It may cause gastrointestinal discomfort, headaches, reversible alopecia, increased levels of liver enzymes and allergic rash, but is generally well tolerated. Animal studies demonstrate embryotoxicity and there have been reports of multiple congenital abnormalities in women treated with long-term high-dose fluconazole, therefore fluconazole should be avoided in pregnant women. High doses increase the effects of phenytoin, ciclosporin, zidovudine and warfarin.

Itraconazole

Itraconazole is available for oral (suspension and capsule) and i.v. administration (t_½ 25 h, increasing to 40 h with continuous treatment). The intravenous preparation is not available in many countries. Absorption from the gut is about 55%, but variable. It is improved by ingestion with food, but decreased by fatty meals and therapies that reduce gastric acidity. Plasma concentrations should be monitored during prolonged use for critical indications. The oral suspension formulation has significantly improved bio-availability compared to the capsule formulation and is much less affected by gastric hypoacidity. Itraconazole is heavily protein bound and virtually none is found within the CSF. It is almost completely oxidised in the liver (by CYP 3A) and excreted in the bile; little unchanged drug enters the urine.

Itraconazole is used for a variety of superficial mycoses, as a prophylactic agent for aspergillosis and candidiasis in the immunocompromised, and i.v. for treatment of histoplasmosis. It is licensed in the UK as a second-line agent for Candida, Aspergillus and Cryptococcus infections, and it may be convenient as ‘follow-on’ therapy after systemic aspergillosis has been brought under control by an amphotericin preparation. It appears to be an effective adjunct treatment for allergic bronchopulmonary aspergillosis.

Adverse effects

are uncommon, but include transient hepatitis and hypokalaemia. Prolonged use may lead to cardiac failure, especially in those with pre-existing cardiac disease. Co-administration of a calcium channel blocker adds to the risk. Cyclodextrin (used as a vehicle for the i.v. formulation) accumulates and causes sodium overload in renally impaired patients, but the oral formulation avoids this problem.

Interactions

Enzyme induction of CYP 3A, e.g. by rifampicin, reduces the plasma concentration of itraconazole. Additionally, its affinity for several P450 isoforms, notably CYP 3A4, causes it to inhibit the oxidation of a number of drugs, including phenytoin, warfarin, ciclosporin, tacrolimus, midazolam, triazolam, cisapride and terfenadine (see above), increasing their intensity and/or duration of effect.

Voriconazole

Voriconazole (t_½ 7 h) is more active in vitro than itraconazole against Aspergillus because of more avid binding of the sterol synthetic enzymes of filamentous fungi; it also appears to have synergistic activity against Aspergillus in combination with amphotericin. It is as active as the other triazoles against yeasts and is more reliably and rapidly absorbed than itraconazole by mouth, but cross-resistance between these agents is usual. It is more effective than conventional amphotericin in invasive aspergillosis, and probably equivalent to lipid-associated formulations. Oral absorption is not significantly reduced by gastric hypoacidity. CSF and brain tissue concentrations are at least 50% of those in the plasma, and are sufficient for effective therapy of fungal infections of the eye and CNS.

Adverse effects

Administration i.v. gives rise rapidly to transient visual disturbance in 30% of patients (blurring, alerted visual perception such as reversal of light and dark, visual hallucinations and photophobia). These often resolve after the first week of therapy, and almost all of those affected are able to continue with the course of treatment.

Accumulation of the cyclodextrin vehicle (see above) may cause sodium retention in renally impaired patients with i.v. use. Patients with hepatic cirrhosis should receive a standard loading, but only half of the daily maintenance dose. Transiently raised liver enzyme levels are seen in up to 20% of patients, but serious liver impairment is rare. Rashes and photosensitivity appear to be more common than with the other triazoles.

Extensive metabolism of voriconazole by the cytochrome P450 system (predominantly CYP 2C19) may lead to unwanted interaction with patients receiving rifampicin, ciclosporin or tacrolimus.

Posaconazole

Posaconazole (t_½ 20 h) is structurally related to itraconazole and has similar in vitro antifungal activity to voriconazole. It is fungistatic against Candida spp. but fungicidal against Aspergillus spp., and is also active against a range of other filamentous fungi. It provides effective prophylaxis against invasive fungal infection in leukaemia and bone marrow transplant patients. The oral bio-availabilty is high (90%), especially when taken with a fatty meal. More than 75% of the dose is excreted in the faeces.

Adverse effects

are uncommon, but include gastrointestinal disturbance, dizziness and fatigue, neutropenia (7% of patients) and transient disturbance of liver function. Dose adjustment is not required for renal or hepatic impairment.

Allylamine

Terbinafine

Terbinafine interferes with ergosterol biosynthesis, and thereby with the formation of the fungal cell membrane. It is absorbed from the gastrointestinal tract and undergoes extensive metabolism in the liver (t_½ 14 h). Terbinafine is used topically for dermatophyte infections of the skin and orally for infections of hair and nails where the site, e.g. hair, severity or extent of the infection renders topical use inappropriate (see pp. 270–271). Treatment may need to continue for several weeks. Terbinafine may cause nausea, diarrhoea, dyspepsia, abdominal pain, headaches and cutaneous reactions.

Drugs that disrupt the fungal cell wall

Echinocandins

The echinocandins are large lipopeptide molecules that inhibit synthesis of β-(1,3)-d-glucan, a vital component of the cell walls of many fungi (excepting Cryptococcus neoformans, against which they have no useful activity). In vitro and in vivo, the echinocandins are rapidly fungicidal against most Candida spp. and fungistatic against Aspergillus spp. Echinocandins have no activity against emerging pathogens such as Fusarium sp., Scedosporium sp. and zygomycetes. They are available as i.v. preparations only.

Caspofungin

(t_½ 10 h) is the first member of this group. It is licensed for i.v. treatment of invasive candidiasis, suspected fungal infections in febrile neutropenic patients, and Aspergillus infections in patients who have not responded to amphotericin or itraconazole. Caspofungin retains activity against most triazole- and polyene-resistant yeasts, and is also active against Pneumocystis jirovecii. It is widely distributed through body tissues and highly protein bound. It penetrates the CSF poorly, but clinical responses in fungal CNS infection have been reported.

Caspofungin is generally well tolerated, but headache, fever, raised liver function tests and hypokalaemia occur. Patients with significant liver impairment should receive a reduced dose. Patients might experience histamine-induced reactions when the drug is infused too rapidly.

Micafungin

has similar activity to caspofungin and is licensed for the treatment of invasive candida infections (oesophagitis, peritonitis and candidaemia) and for prophylaxis of Candida spp. and Aspergillus infection in patients undergoing haemopoetic stem cell transplantation. It is highly protein bound and, unlike caspofungin and anidulafungin, does not require a loading dose. Micafungin was found to induce the development of liver tumours in rats after treatment for 3 months and longer; close monitoring of patients for liver damage is advised.

Anidulafungin

is a semi-synthetic echinocandin derived from Aspergillus nidulans. It has a much longer elimination half-life than the other echinocandins (27 h) and is not metabolised by the liver, but undergoes slow chemical degradation to inactive metabolites. It has no significant drug–drug interactions, with no dose adjustment required in renal or hepatic impairment. Anidulafungin is approved for the treatment of invasive candidiasis in adult non-neutropenic patients.

Other antifungal drugs

Griseofulvin

Griseofulvin prevents fungal growth by binding to microtubular proteins and inhibiting mitosis. The therapeutic efficacy of griseofulvin depends on its capacity to bind to keratin as it is being formed in the cells of the nail bed, hair follicles and skin, for dermatophytes specifically infect keratinous tissues. Griseofulvin does not kill fungus already established; it merely prevents infection of new keratin so that the duration of treatment is governed by the time that it takes for infected keratin to be shed. On average, hair and skin infection should be treated for 4–6 weeks, although toenails may need a year or more. Treatment must continue for a few weeks after both visual and microscopic evidence has disappeared. Fat in a meal enhances absorption of griseofulvin; it is metabolised in the liver and induces hepatic enzymes (t_½ 15 h).

Griseofulvin is effective against all superficial ringworm (dermatophyte) infections, but ineffective against pityriasis versicolor, superficial candidiasis and all systemic mycoses.

Adverse reactions

include gastrointestinal upset, rashes, photosensitivity, headache and various CNS disturbances.

Flucytosine

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil, which inhibits nucleic acid synthesis. It is well absorbed from the gut, penetrates effectively into tissues, and almost all is excreted unchanged in the urine (t_½ 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine, which ought not to be used alone; it may be combined with amphotericin (see Table 15.3), but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk:benefit balance is favourable, e.g. Cryptococcus neoformans meningitis.

Protozoal infections

Malaria

About half of the world's population is exposed to malaria, with an estimated 250 million cases and 1 million deaths annually, mainly in sub-Saharan African children (where a child dies from malaria on average every 30 seconds). In terms of socioeconomic impact, malaria is the most important of the transmissible parasitic diseases.

Quinine as cinchona bark was introduced into Europe from South America in 1631 (by Agostino Salumbrino, a Jesuit priest and trained apothecary, who sent a small quantity of bark to Rome where much of the terrain was swampy and fevers were common – hence the term ‘Jesuit's bark’). It was used for all fevers, among them malaria, the occurrence of which was associated with damp places with bad air (‘mal aria’).

Life cycle of the malaria parasite and sites of drug action

The incubation period of malaria is 10–35 days. The principal features of the life cycle (Fig. 15.1) of the malaria parasite must be known in order to understand its therapy.

Fig. 15.1 Life cycle of the malaria parasite. (The numbers are referred to in the text.)

Female anopheles mosquitoes require a blood meal for egg production, and in the process of feeding they inject salivary fluid containing sporozoites into humans. As no drugs are effective against sporozoites, infection with the malaria parasite cannot be prevented.

Hepatic cycle

(site 1 in Fig. 15.1)

Sporozoites enter liver cells where they develop into schizonts, which form large numbers of merozoites which, after 5–16 days, but sometimes after months or years, are released into the circulation. Plasmodium falciparumdiffers in that it has no persistent hepatic cycle.

Primaquine, proguanil and tetracyclines (tissue schizontocides) act at this site and are used for:

• Radical cure, i.e. an attack on persisting hepatic forms (hypnozoites, i.e. sleeping) once the parasite has been cleared from the blood; this is most effectively accomplished with primaquine; proguanil is only weakly effective.

• Preventing the initial hepatic cycle. This is also called causal prophylaxis. Primaquine was long regarded as too toxic for prolonged use but evidence now suggests it may be used safely, and it is inexpensive; proguanil is weakly effective. Doxycycline may be used short term.

Vaccine development against both falciparum and vivax malaria concentrates mostly on surface antigens (e.g. circumsporozoite protein) involved in the pre-erythrocytic stages, before invasion of liver cells (stage 1).

Erythrocyte cycle

(site 2 in Fig. 15.1)

Merozoites enter red cells, where they develop into schizonts, which form more merozoites that are released when the cells burst, giving rise to the features of the clinical attack. The merozoites re-enter red cells and the cycle is repeated.

Chloroquine, quinine, mefloquine, halofantrine, proguanil, pyrimethamine and tetracyclines (blood schizontocides) kill these asexual forms. Drugs that act at this stage in the cycle of the parasite may be used for:

• Treatment of acute attacks of malaria.

• Prevention of attacks by early destruction of the erythrocytic forms. This is called suppressive prophylaxis as it does not cure the hepatic cycle (above).

Sexual forms

(site 3 in Fig. 15.1)

Some merozoites differentiate into male and female gametocytes in the erythrocytes and can develop further only if they are ingested by a mosquito, where they form sporozoites (site 4 in Fig. 15.1) and complete the transmission cycle.

Quinine, mefloquine, chloroquine, artesunate, artemether and primaquine (gametocytocides) act on sexual forms and prevent transmission of the infection because the patient becomes non-infective and the parasite fails to develop in the mosquito (site 4).

In summary,

drugs may be selected for:

• treatment of clinical attacks

• prevention of clinical attacks

• radical cure.

Drugs used for malaria, and their principal actions, are classified in Table 15.4.

Table 15.4 Antimalarial drugs and their sites of action

Drug	Biological activity
	Blood schizontocide	Tissue schizontocide
4-Aminoquinolone
chloroquine	++	0
Arylaminoakohols
quinine	++	0
mefloquine	++	0
Phenanthrene methanol
halofantrine	++	0
lumefantrine	++	0
Antimetabolites
proguanil	+	+
pyrimethamine	+	0
sulfadoxine	+	0
dapsone	+	0
Antibiotics
tetracycline	+	+
doxycycline	+	+
minocycline	+	+
8-Aminoquinolone
primaquine	0	+
Sesquiterpenes
artesunate	+	0
artemether	+	0

Drug-resistant malaria

Drug-resistant parasites constitute a persistent problem. Plasmodium falciparum is now resistant to chloroquine and sulfadoxine-pyrimethamine in many parts of the world. Areas of high risk for resistant parasites include sub-Saharan Africa, Latin America, Oceania (Papua New Guinea, Solomon Islands, Vanuatu) and some parts of South-East Asia. Mefloquine resistance is rare outside South-East Asia. There are concerns with emerging artesunate resistance in western Cambodia due to monotherapy. Chloroquine-resistant Plasmodium vivax is also reported. Hyperparasitaemia and inappropriate or low dosing of antimalarials are important drivers of resistance.

Resistance can be reduced by combining antimalarials with different mechanisms of action, usually in the form of artemisinin-based combination therapies (ACTs). ACTs are often more effective than single-agent therapy or non-artemisinin-based combinations and are now recommended by the World Health Organization for the treatment of Plasmodium falciparum malaria globally.

Any physician who is unfamiliar with the resistance pattern in the locality from which patients have come, or to which they are going, is well advised to check the current position. Because prevalence and resistance rates are so variable, advice on therapy and prophylaxis in this section is given for general guidance only and readers are referred to specialist sources for up-to-date information.

Chemotherapy of an acute attack of malaria³

Successful management demands attention to the following points of principle:

• Whenever possible, the diagnosis should be confirmed before treatment by examination of blood smears; this is not often possible in the developing world, where clinically diagnosed illnesses may receive unnecessary courses of antimalarials, thus increasing the risks of plasmodial resistance.

• When the infecting organism is not known or infection is mixed, treatment should begin as for Plasmodium falciparum (below).

• Drugs used to treat Plasmodium falciparum malaria must always be selected with regard to the prevalence of local patterns of drug resistance.

• Patients not at risk of re-infection should be re-examined several weeks after treatment for signs of recrudescence, which may result from inadequate chemotherapy or survival of persistent hepatic forms.

Falciparum (‘malignant’) malaria

Falciparum malaria in the non-immune is a medical emergency, and malaria of unknown infecting species should be treated as though it were falciparum. The regimen depends on the condition of the patient; the doses quoted are for adults. Chloroquine resistance is now widespread; therefore this drug should not be used for the treatment of falciparum malaria.

If the patient can swallow

and there are no serious complications such as impairment of consciousness, treatment options are as follows:

• A quinine salt:⁴ 600 mg 8-hourly by mouth for 5–7 days, followed by doxycycline 200 mg daily for at least 7 days. This additional therapy is necessary as quinine alone tends to be associated with a higher rate of relapse. Clindamycin (450 mg four times daily for 7 days) may be given as an alternative follow-on therapy instead of doxycycline, and is particularly suitable for pregnant women. If the parasite is likely to be sensitive, Fansidar (pyrimethamine plus sulfadoxine) 3 tablets as a single dose is an alternative.

• Malarone (atovaquone and proguanil hydrochloride): 4 tablets once daily for 3 days.

• Riamet (artemether plus lumefantrine): if weight > 35 kg, 4 tablets initially, followed by five further doses of 4 tablets given at 8, 24, 36, 48 and 60 h.

• Mefloquine is also effective, but resistance has been reported in several regions, including South-East Asia. It is not necessary to use follow-on therapy after Riamet, mefloquine or Malarone.

Seriously ill patients

should be treated with:

• A quinine salt:⁴ 20 mg/kg as a loading dose⁵ (maximum 1.4 g) infused i.v. over 4 h, followed 8 h later by a maintenance infusion of 10 mg/kg (maximum 700 mg) infused over 4 h, repeated every 8 h⁶ until the patient can swallow tablets to complete the 7-day course. Patients at increased risk of arrhythmias and the elderly should have ECG monitoring while on the infusion.

• Doxycycline or clindamycin should be given subsequently, as above (mefloquine is an alternative, but this must begin at least 12 h after parenteral quinine has ceased).

• Intravenous artesunate showed a clear benefit when compared to quinine in patients with severe falciparum malaria.⁷ A large randomised trial showed a 34% reduction in mortality with intravenous artesunate when compared to quinine; the number needed to treat to prevent one death was 13.⁸ Intravenous artesunate is not licensed in the European Union, but should be considered on a ‘named patient’ basis for severe cases not responsive to quinine or if quinine resistance is suspected, or there is a high parasite count (> 20%). Intravenous artesunate should be accompanied by a 7-day course of doxycycline.

Treatment in pregnancy should always be based on expert advice.

Non-falciparum (‘benign’) malarias

These are usually due to Plasmodium vivax or less commonly to Plasmodium ovale or Plasmodium malariae.

The drug of choice is chloroquine, which should be given by mouth as follows:

• Initial dose: 620 mg (base),⁹ then 310 mg as a single dose 6–8 h later.

• Second day: 310 mg as a single dose.

• Third day: 310 mg as a single dose.

The total dose of chloroquine base over 3 days should be approximately 25 mg/kg base. This is sufficient for Plasmodium malariae infection, but for Plasmodium vivax and Plasmodium ovale eradication of the hepatic parasites is necessary to prevent relapse, by giving:

• Primaquine, 15 mg/day for 14 days started after the chloroquine course has been completed. Plasmodium vivax infections require 30 mg/day for 14 days. Primaquine can lead to haemolysis in patients with G6PD deficiency (if mild G6PD deficiency, lower dosing of 45 mg once-weekly for 8 weeks may suffice without undue risk of haemolysis).

Chemoprophylaxis of malaria

Geographically variable plasmodial drug resistance has become a major factor. The World Health Organization gives advice in its annually revised booklet Vaccination Certificate Requirements and Health Advice for International Travel, and national bodies publish recommendations, e.g. British National Formulary, that apply particularly to their own residents.

General principles

• Chemoprophylaxis aims to prevent deaths from falciparum malaria, but only ever gives relative protection; travellers should guard against bites by using mosquito nets and repellents, and wearing well-covering clothing especially during high-risk times of day (after dusk).

• Mefloquine, doxycycline and atovaquone-proguanil (Malarone) are the most commonly advised prophylactic regimens, and are particularly recommended for areas of chloroquine-resistant falciparum malaria. Chloroquine, alone or in combination with proguanil, may be considered in areas of the world where the risk of acquiring chloroquine resistant falciparum malaria is low, although there is considerable concern regarding the protective efficacy of this regimen. Due to widespread P. falciparum resistance to proguanil, single-agent prophylaxis with this agent is rarely appropriate for most regions of the world.

• Effective chemoprophylaxis requires that there be a plasmodicidal concentration of drug in the blood when the first infected mosquito bites, and that it be sustained safely for long periods.

• The progressive rise in plasma concentration to steady state (after t_½ × 5), sometimes attained only after weeks (consider mefloquine t_½ 21 days, chloroquine t_½ 50 days), allows unwanted effects (which can impair compliance or be unsafe) to be delayed, in some instances until after a subject has entered a malarial area. Thus, it is advised that prophylaxis begin long enough before travel to reveal acute intolerance and to impress on the subject the importance of compliance (to relate drug-taking to a specific daily or weekly event).

• Prompt achievement of efficacy and safety, i.e. plasmodicidal concentrations, by one (or two) doses is plainly important for travellers who cannot wait on dosage schedules to deliver both only when steady-state blood concentrations are attained; the schedules must reflect this need.

• Prophylaxis should continue for at least 4 weeks after leaving an endemic area to kill parasites that are acquired about the time of departure, are still incubating in the liver and will develop into the erythrocyte phase. Malarone, however, only needs to be taken for a week after return. The traveller should be aware that any illness occurring within a year, and especially within 3 months, of return, may be malaria.

• Chloroquine and proguanil may be used for periods of up to 5 years, and mefloquine for up to 1–2 years; expert advice should be taken by long-term travellers, especially those going to areas for which other prophylactic drugs are recommended.

• Naturally acquired immunity offers the most reliable protection for people living permanently in endemic areas (below). Repeated attacks of malaria confer partial immunity and the disease often becomes no more than an occasional inconvenience. Vaccines to confer active immunity are under development.

• A short course of prophylaxis (4–6 weeks) may be considered for pregnant women and young children returning to their permanent homes in malarious areas after a prolonged period of stay in a non-endemic area, pending suitable arrangements for health care.

• As a rule, the partially immune should not take a prophylactic. The reasoning is that immunity is sustained by the red cell cycle, loss of which through prophylaxis diminishes their resistance and leaves them highly vulnerable to the disease. There are, however, exceptions to this general advice, and the partially immune may or should use a prophylactic:

   if it is virtually certain that they will never abandon its use

   if they go to another malarial area where the strains of parasite may differ

   during the last few months of pregnancy in areas where Plasmodium falciparum is prevalent (to avert the risk of miscarriage).

Examples of standard prophylactic regimens

• Chloroquine: 300 mg (base) once weekly (start 1 week before travel).

• Proguanil: 200 mg once daily (start 1 week before travel).

• Chloroquine plus proguanil in the above doses.

• Malarone: 1 tablet daily (start 1–2 days before travel).

• Mefloquine: 250 mg once weekly (start 1 week, preferably 2–3 weeks, before travel).

• Doxycycline: 100 mg once daily (start 1–2 days before travel).

For ‘last minute’ travellers

The standard regimens normally provide immediate protection, but it will be sensible to avoid mefloquine (if an alternative antimalarial is available) in the last minute traveller with no history of previous mefloquine exposure or who is intolerant of the drug. Current UK national guidelines do not recommend giving a loading dose of prophylactic antimalarials for the purpose of rapidly achieving steady-state plasma concentration.

Drug interactions

Where subjects are already taking other drugs, e.g. antiepileptics and cardiovascular drugs, it is desirable to start prophylaxis as much as 2–3 weeks in advance to establish safety.

Antimalarial drugs and pregnancy

Women living in endemic areas in which Plasmodium falciparum remains sensitive to chloroquine should take chloroquine prophylactically throughout pregnancy. Proguanil (an ‘antifol’, see below) may be taken for prophylaxis provided it is accompanied by folic acid 5 mg/day. Chloroquine may be used in full dose to treat chloroquine-sensitive infections. Quinine is the only widely available drug that is acceptable as suitable for treating chloroquine-resistant infections during pregnancy. Mefloquine is teratogenic in animals and a woman should avoid pregnancy while taking it, and for 3 months afterwards (although evidence is accruing that it may be safe for use in chloroquine-resistant areas). Doxycycline is contraindicated throughout pregnancy, and Malarone (proguanil plus atovaquone) should be avoided unless there is no suitable alternative.

Individual antimalarial drugs

Chloroquine

Chloroquine (t_½ 50 days) is concentrated within parasitised red cells and forms complexes with plasmodial DNA. It is active against the blood forms and also the gametocytes (formed in the mosquito) of Plasmodium vivax, Plasmodium ovale and Plasmodium malariae; it is ineffective against many strains of Plasmodium falciparum and also its immature gametocytes. Chloroquine is readily absorbed from the gastrointestinal tract and is concentrated several-fold in various tissues, e.g. erythrocytes, liver, spleen, heart, kidney, cornea and retina; the long t_½ reflects slow release from these sites. A priming dose is used in order to achieve adequate free plasma concentration (see acute attack, above). Chloroquine is partly inactivated by metabolism and the remainder is excreted unchanged in the urine.

Adverse effects

are infrequent at doses normally used for malaria prophylaxis and treatment, but are more common with the higher or prolonged doses given for resistant malaria or for rheumatoid arthritis or lupus erythematosus (see p. 251).

Corneal deposits of chloroquine may be asymptomatic or may cause halos around lights or photophobia. These are not a threat to vision and reverse when the drug is stopped. Retinal toxicity is more serious, and may be irreversible. In the early stage it takes the form of visual field defects; late retinopathy classically gives the picture of macular pigmentation surrounded by a ring of pigment (the ‘bull's-eye’ macula). The functional defect can take the form of scotomas, photophobia, defective colour vision and decreased visual acuity resulting, in the extreme case, in blindness.

Other reactions include pruritus, which may be intolerable and is common in Africans, headaches, gastrointestinal disturbance, precipitation of acute intermittent porphyria in susceptible individuals, mental disturbances and interference with cardiac rhythm, the latter especially if the drug is given i.v. in high dose (it has a quinidine-like action). Long-term use is associated with reversible bleaching of the hair and pigmentation of the hard palate.

Acute overdose

may be rapidly fatal without treatment, and indeed has even been described as a means of suicide.¹⁰ Pulmonary oedema is followed by convulsions, cardiac arrhythmias and coma; as little as 50 mg/kg can be fatal. These effects are principally due to the profound negative inotropic action of chloroquine. Diazepam was found fortuitously to protect the heart and adrenaline/epinephrine reduces intraventricular conduction time; this combination of drugs, given by separate i.v. infusions, improves survival.

Halofantrine

Halofantrine (t_½ 2.5 days) is active against the erythrocytic forms of all four Plasmodium species, especially Plasmodium falciparum and Plasmodium vivax, and at the schizont stage. Its mechanism of action is not fully understood. Absorption of halofantrine from the gastrointestinal tract is variable, incomplete and substantially increased (6–10-fold) by taking the drug with food (see below). It is converted to an active metabolite and no unchanged drug is recovered in the urine. Due to cardiotoxicity concerns, halofantrine is not included in any of the WHO-approved artemisinin combination therapy (ACT) options for treatment of uncomplicated Plasmodium falciparum malaria. It is no longer recommended for the treatment of drug-resistant Plasmodium vivax malaria and should also not be used for prophylaxis.

Lumefantrine

Lumefantrine (t_½ 3 days) has a similar structure and mechanism of action to halofantrine. It is only available as a fixed drug combination with artemether (Riamet or Co-artem). It has variable bio-availability; absorption is substantially increased by fatty meals, with plasma levels peaking about 10 h after oral intake. Unlike halofantrine, there are no cardiotoxicity concerns and it is well tolerated.

Mefloquine

Mefloquine (t_½ 21 days) is similar in several respects to quinine although it does not intercalate with plasmodial DNA. It is used for malaria chemoprophylaxis, and occasionally to treat uncomplicated Plasmodium falciparum (both chloroquine-sensitive and chloroquine-resistant) and chloroquine-resistant Plasmodium vivax malaria. Mefloquine is rapidly absorbed from the gastrointestinal tract and its action is terminated by metabolism. When used for prophylaxis, 250 mg (base)/week should be taken, commencing 1–3 weeks before entering and continued for 4 weeks after leaving a malarious area. It should not be given to patients with hepatic or renal impairment.

Adverse effects

include nausea, dizziness, disturbance of balance, vomiting, abdominal pain, diarrhoea and loss of appetite. More rarely, hallucinations, seizures and psychoses occur. Mefloquine should be avoided in patients taking β-adrenoceptor and calcium channel antagonists, because it causes sinus bradycardia; quinine can potentiate these and other dose-related effects of mefloquine.

Neuropsychiatric events, including seizures and psychoses, occur after high-dose therapy in about 1 in 10 000 of those using the drug for prophylaxis. Less severe reactions including headache, dizziness, depression and insomnia have been reported but there is uncertainty as to whether these can be ascribed to mefloquine. The drug should not be used in travellers with a history of neuropsychiatric disease including convulsions and depression, and in those whose activities require fine coordination or spatial performance, e.g. airline flight-deck crews.

Primaquine

Primaquine (t_½ 6 h) acts at several stages in the development of the plasmodial parasite, possibly by interfering with its mitochondrial function. Its unique effect is to eliminate the hepatic forms of Plasmodium vivax and Plasmodium ovale after standard chloroquine therapy, but only when the risk of re-infection is absent or slight. Primaquine also has weak activity against blood forms of the parasite. Due to its antigametocidal effect, single-dose primaquine is now recommended at the end of an ACT course of therapy for falciparum malaria in areas where malaria elimination is a priority. Primaquine is well absorbed from the gastrointestinal tract, is only moderately concentrated in the tissues, and is rapidly metabolised.

Adverse effects

include anorexia, nausea, abdominal cramps, methaemoglobinaemia, granulocytopenia and haemolytic anaemia, especially in patients with genetic deficiency of erythrocyte glucose-6-phosphate dehydrogenase (G6PD). Subjects should be tested for G6PD and, in those who are mildly deficient, the risk of haemolytic anaemia is greatly reduced by giving primaquine in reduced dose. Primaquine is not recommended during pregnancy, severe G6PD deficiency and conditions that predispose to granulocytopenia, e.g. rheumatoid arthritis and systemic lupus erythematosus.

Proguanil (chloroguanide)

Proguanil (t_½ 17 h) inhibits dihydrofolate reductase, which converts folic to folinic acid, deficiency of which inhibits plasmodial cell division. Plasmodia, like most bacteria but unlike humans, cannot make use of preformed folic acid. Pyrimethamine and trimethoprim, which share this mode of action, are collectively known as the ‘antifols’. Their plasmodicidal action is markedly enhanced by combination with sulfonamides or sulfones because there is inhibition of sequential steps in folate synthesis. It is used alone (usually with chloroquine) for malaria prophylaxis, and is also available with atovaquone (as Malarone: proguanil hydrochloride 100 mg plus atovaquone 250 mg) for prophylaxis and treatment.

Proguanil is moderately well absorbed from the gut and is excreted in the urine either unchanged or as an active metabolite. Being little stored in the tissues, proguanil must be used daily when given for prophylaxis. It is rarely recommended alone (as a single agent) for prophylaxis.

Adverse effects

In prophylactic doses, proguanil is well tolerated. Mouth ulcers and stomatitis have been reported. The drug should be avoided or used in reduced dose for patients with impaired renal function.

Pyrimethamine

Pyrimethamine (t_½ 4 days) inhibits plasmodial dihydrofolate reductase, for which it has a high affinity. It is well absorbed from the gastrointestinal tract and is extensively metabolised. It is seldom used alone (see below). Pregnant women should receive supplementary folic acid when taking pyrimethamine.

Adverse effects

reported include anorexia, abdominal cramps, vomiting, ataxia, tremor, seizures and megaloblastic anaemia.

Pyrimethamine with sulfadoxine

Pyrimethamine acts synergistically with sulfadoxine (as Fansidar) to inhibit folic acid metabolism (see ‘antifols’, above); sulfadoxine is excreted in the urine. In the past, this combination was used with quinine to treat acute attacks of malaria caused by susceptible strains of Plasmodium falciparum; the widespread emergence of pyrimethamine-sulfadoxine resistant falciparum and vivax malaria has led to changes in the use of this drug. An ACT regimen of artesunate and pyrimethamine-sulfadoxine is now available as separate scored tablets for the treatment of uncomplicated falciparum malaria in Africa, but should not be used in areas of multi-drug resistance, such as South-East Asia. Pyrimethamine-sulfadoxine, either as a single agent or combined with artesunate, is no longer considered an appropriate choice for the treatment of Plasmodium vivax malaria.

Adverse effects

Any sulphonamide-induced allergic reactions can be severe, e.g. erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis. Because of its ‘antifol’ action the combination should not be used by pregnant women unless they take a folate supplement.

Pyrimethamine with dapsone

This fixed drug combination (Maloprim or Deltaprim) of 12.5 mg pyrimethamine and 100 mg of dapsone was used for many years as prophylaxis against Plasmodium falciparum malaria. Due to toxicity concerns (agranulocytosis) and increasing resistance to pyrimethamine, this regimen is no longer recommended for prophylaxis, although it continues to be available in parts of Africa, in particular Zimbabwe and neighbouring countries.

Quinine

Quinine (t_½ 9 h; 18 h in severe malaria) is obtained from the bark of the South American cinchona tree. It binds to plasmodial DNA to prevent protein synthesis but its exact mode of action remains uncertain. It is used to treat Plasmodium falciparum malaria in areas of multiple drug resistance. Apart from its antiplasmodial effect, quinine is used for myotonia and muscle cramps because it prolongs the muscle refractory period. Quinine is included in dilute concentration in tonics and aperitifs for its desired bitter taste.

Quinine is well absorbed from the gastrointestinal tract and is almost completely metabolised in the liver.

Adverse effects

include tinnitus, diminished auditory acuity, headache, blurred vision, nausea and diarrhoea (common to quinine, quinidine, salicylates and called ‘cinchonism’). Idiosyncratic reactions include pruritus, urticaria and rashes. Hypoglycaemia may be significant when quinine is given by i.v. infusion, and supplementary glucose may be required.

When large amounts are taken, e.g. (unreliably) to induce abortion or in attempted suicide, ocular disturbances, notably constriction of the visual fields, may occur and even complete blindness, the onset of which may be very sudden. Vomiting, abdominal pain and diarrhoea result from local irritation of the gastrointestinal tract. Quinidine-like effects include hypotension, disturbance of atrioventricular conduction and cardiac arrest. Activated charcoal should be given. Supportive measures are employed thereafter as no specific therapy has proven benefit.

Quinidine,

the dextrorotatory isomer of quinine, has antimalarial activity, but is used mainly as a cardiac antiarrhythmic (see p. 430).

Artesunate and artemether

are soluble derivatives of artemisinin, which is isolated from the leaves of the Chinese herb qinghao (Artemisia annua); they act against the blood, including sexual, forms of plasmodia and may also reduce transmissibility. Artesunate is water soluble, while artemether is lipid soluble; both are available for oral, intramuscular and rectal administration. Artesunate is also available as an i.v. formulation. They are rapidly effective in severe and multidrug-resistant malaria, are well tolerated but should be used with caution in patients with chronic cardiac disorders as they prolong the PR and QTc interval in some experimental animals. Intravenous artesunate is restricted in the West because of concerns with manufacturing standards; rectal and intramuscular artemisinin preparations are widely used in the developing world as pre-referral treatment for patients with severe falciparum malaria who are unable to reach the nearest health facility without risking clinical deterioration. Artemisinins are not appropriate for prophylaxis (because of their short half-life) and should never be used as monotherapy for uncomplicated falciparum malaria.

Artemisinin-based combination therapies (ACTs)

Riamet,

a combination of artemether 20 mg and lumefantrine 120 mg, is licensed for acute uncomplicated falciparum malaria. Lumefantrine has the advantage of not being available as a single agent (unlike other ACTs), and hence less likely to generate resistance as a result of selection pressure due to inappropriate monotherapy. Riamet is highly effective, with cure rates exceeding 96%, even in areas with drug-resistant falciparum malaria. It is the first fixed dose ACT to satisfy stringent international quality and efficacy criteria and is now widely used as the standard of care for the treatment of uncomplicated falciparum malaria. The drug is given as a complex 6-dose regimen over a 60-hour period. Adverse effects are uncommon but irreversible hearing loss is reported.

Other WHO approved ACTs include:

• Artesunate plus mefloquine.

• Artesunate plus amodiaquine.

• Artesunate plus sulfadoxine-pyrimethamine.

• Dihydroartemisinin plus piperaquine.

Although the combination of artesunate and mefloquine shows similar efficacy to Riamet, there are concerns with tolerability of mefloquine, particularly among African children. ACTs containing amodiaquine and pyrimethamine-sulfadoxine should be avoided in areas where resistance to these agents exceeds 20%, e.g. parts of South-East Asia.

Amoebiasis

Infection occurs when mature cysts are ingested and pass into the colon, where they divide into trophozoites; these forms either enter the tissues or form cysts. Amoebiasis occurs in two forms, both of which need treatment:

• Bowel lumen amoebiasis is asymptomatic, and trophozoites (non-infective) and cysts (infective) are passed into the faeces. Treatment is directed at eradicating cysts with a luminal amoebicide; diloxanide furoate is the drug of choice; iodoquinol or paromomycin are alternatives.

• Tissue-invading amoebiasis gives rise to dysentery, hepatic amoebiasis and liver abscess. A systemically active drug (tissue amoebicide) effective against trophozoites must be used, e.g. metronidazole, tinidazole, ornidazole. Parenteral forms of these are available for patients too ill to take drugs by mouth. In severe cases of amoebic dysentery with suspected or confirmed peritonitis, broad-spectrum antibiotics should be administered and surgical intervention considered.

Treatment with tissue amoebicides should always be followed by a course of a luminal amoebicide to eradicate the source of the infection.

Dehydroemetine

(from ipecacuanha), less toxic than the parent emetine, is claimed by some authorities to be the most effective tissue amoebicide. It is reserved for the treatment of metronidazole-resistant amoebiasis and in dangerously ill patients, but these are more likely to be vulnerable to its cardiotoxic effects. When dehydroemetine is used to treat amoebic liver abscess, chloroquine should also be given.

The drug treatment of other protozoal infections is summarised in Table 15.5.

Table 15.5 Drugs for some protozoal infections

Infection	Drug and comment
Giardiasis	Metronidazole, tinidazole or mepacrine
Leishmaniasis
visceral	Sodium stibogluconate or meglumine antimoniate; resistant cases may benefit from combining antimonials with paromomycin, miltefosine or amphotericin (including AmBisome). Pentamidine is rarely used now due to toxicity concerns
cutaneous	Mild lesions heal spontaneously, fluconazole; antimonials or paromomycin may be injected intralesionally
Toxoplasmosis	Most infections are self-limiting in the immunologically normal patient. Pyrimethamine with sulfadiazine for chorioretinitis, and active toxoplasmosis in immunodeficient patients; folinic acid is used to counteract the inevitable megaloblastic anaemia. Alternatives include pyrimethamine with clindamycin or azithromycin or atovaquone. Spiramycin for primary toxoplasmosis in pregnant women. Expert advice is essential
Trichomoniasis	Metronidazole or tinidazole is effective
Trypanosomiasis
African (sleeping sickness)	Suramin or pentamidine is effective during the early stages but not for the later neurological manifestations for which melarsoprol should be used. Eflornithine is effective for both early and late stages. Expert advice is recommended
American (Chagas' disease)	Prolonged (1–3 months) treatment with benznidazole or nifurtimox may be effective

Notes on drugs for protozoal infections

Atovaquone is a quinone; it may cause gastrointestinal and mild neurological side-effects, and rare hepatotoxicity and blood dyscrasias.

Benznidazole is a nitroimidazole that may occasionally cause peripheral neuritis but is generally well tolerated, including by infants.

Dehydroemetine inhibits protein synthesis; it may cause pain at the site of injection, weakness and muscular pain, hypotension, precordial pain and cardiac arrhythmias.

Diloxanide furoate may cause troublesome flatulence, and pruritus and urticaria may occur.

Eflornithine inhibits protozoal DNA synthesis; it may cause anaemia, leucopenia and thrombocytopenia, and seizures.

Iodoquinol may cause abdominal cramps, nausea and diarrhoea. Skin eruptions, pruritus ani and thyroid gland enlargement have been attributed to its iodine content. The recognition of severe neurotoxicity with the related drug, clioquinol, in Japan in the 1960s must give cause for caution in its use.

Meglumine antimonate is a pentavalent antimony compound, similar to sodium stibogluconate (below).

Melarsoprol, a trivalent organic arsenical, acts through its high affinity for sulphydryl groups of enzymes. Adverse effects include encephalopathy, myocardial damage, proteinuria and hypertension.

Mepacrine (quinacrine) was formerly used as an antimalarial but is now an alternative to metronidazole or tinidazole for giardiasis. It may cause gastrointestinal upset, occasional acute toxic psychosis, hepatitis and aplastic anaemia.

Nifurtimox is a nitrofuran derivative. Adverse effects include anorexia, nausea, vomiting, gastric pain, insomnia, headache, vertigo, excitability, myalgia, arthralgia and convulsions. Peripheral neuropathy may necessitate stopping treatment.

Paromomycin, an aminoglycoside, is not absorbed from the gut; it is similar to neomycin.

Pentamidine is a synthetic aromatic amidine; it must be administered parenterally or by inhalation as it is absorbed unreliably from the gastrointestinal tract; it does not enter the CSF. Given systemically it frequently causes nephrotoxicity, which is reversible; acute hypotension and syncope are common especially after rapid i.v. injection. Pancreatic damage may cause hypoglycaemia due to insulin release.

Sodium stibogluconate (Pentostam) is an organic pentavalent antimony compound; it may cause anorexia, vomiting, coughing and substernal pain. Used in mucocutaneous leishmaniasis, it may lead to severe inflammation around pharyngeal or tracheal lesions which may require control with corticosteroid. Meglumine antimoniate is similar.

Suramin forms stable complexes with plasma protein and is detectable in urine for up to 3 months after the last injection; it does not cross the blood–brain barrier. It may cause tiredness, anorexia, malaise, polyuria, thirst, and tenderness of the palms and soles.

Miltefosine is a phosphocholine analogue that was originally developed as an oral antineoplastic. It is the only effective oral treatment for cutaneous and visceral leishmaniasis. The main adverse effects are vomiting, diarrhoea and raised transaminases. The drug is teratogenic in animals, and therefore should be avoided in pregnancy and used with caution in women of reproductive age.

Helminthic infections

Helminths have complex life cycles, special knowledge of which is required by those who treat infections. Table 15.6 will suffice here. Drug resistance has not so far proved to be a clinical problem, though it has occurred in animals on continuous chemoprophylaxis.

Table 15.6 Drugs for helminthic infections

Infection	Drug	Comment
Cestodes (tapeworms)
Beef tapeworm Taenia saginata	Niclosamide or praziquantel	Praziquantel cures with single dose
Pork tapeworm Taenia solium	Niclosamide or praziquantel	Praziquantel cures with single dose
Cysticercosis Taenia solium	Albendazole or praziquantel	Treat in hospital as dying and disintegrating cysts may cause cerebral oedema
Fish tapeworm Diphyllobothrium latum	Niclosamide or praziquantel
Hydatid disease Echinococcus granulosus	Albendazole	Surgery for operable cyst disease
Nematodes (intestinal)
Ascariasis Ascaris lumbricoides	Levamisole, mebendazole, pyrantel pamoate, piperazine or albendazole
Hookworm Ancylostoma duodenale	Mebendazole, pyrantel pamoate, or	Anaemic patients require iron or blood transfusion
Necator americanus	Albendazole
Strongyloidiasis Strongyloides stercoralis	Thiabendazole or ivermectin	Alternatively, albendazole is better tolerated
Threadworm (pinworm) Enterobius vermicularis	Pyrantel pamoate, mebendazole, albendazole or piperazine salts
Whipworm Trichuris trichiuria	Mebendazole or albendazole
Nematodes (tissue)
Cutaneous larva migrans Ancylostoma braziliense; Ancylostoma caninum	Thiabendazole (topical for single tracks); ivermectin, albendazole or oral thiabendazole (for multiple tracks)	Calamine lotion for symptom relief
Guinea worm Dracunculus medinensis	Metronidazole, mebendazole	Rapid symptom relief
Trichinellosis Trichinella spiralis	Mebendazole	Prednisolone may be needed to suppress allergic and inflammatory symptoms
Visceral larva migrans Toxocara canis; Toxocara cati	Diethylcarbamazine, albendazole or mebendazole	Progressive escalation of dose lessens allergic reactions to dying larvae; prednisolone suppresses inflammatory response in ophthalmic disease
Lymphatic filariasis Wuchereria bancrofti; Brugia malayi; Brugia timori	Diethylcarbamazine	Destruction of microfilia may cause an immunological reaction (see below)
Onchocerciasis (river blindness) Onchocerca volvulus	Ivermectin	Cures with single dose. Suppressive treatment; a single annual dose prevents significant complications
Nematodes (tissue)—cont'd
Schistosomiasis (intestinal)
Schistosoma mansoni; Schistosoma japonicum	Praziquantel	Oxamniquine only for Schistosoma mansoni
Schistosomiasis (urinary)
Schistosoma haematobium	Praziquantel	Metriphonate only for Schistosoma haematobium
Flukes (intestinal, lung, liver)	Praziquantel	Alternatives: niclosamide for intestinal fluke, bithionol for lung fluke

Drugs for helminthic infections

Albendazole is similar to mebendazole (below).

Diethylcarbamazine kills both microfilariae and adult worms. Fever, headache, anorexia, malaise, urticaria, vomiting and asthmatic attacks following the first dose are due to products of destruction of the parasite, and reactions are minimised by slow increase in dosage over the first 3 days.

Ivermectin may cause immediate reactions due to the death of the microfilaria (see diethylcarbamazine). It can be effective in a single dose, but is best repeated at intervals of 6–12 months.

Levamisole paralyses the musculature of sensitive nematodes which, unable to maintain their anchorage, are expelled by normal peristalsis. It is well tolerated, but may cause abdominal pain, nausea, vomiting, headache and dizziness.

Mebendazole blocks glucose uptake by nematodes. Mild gastrointestinal discomfort may be caused, and it should not be used in pregnancy or in children under the age of 2 years.

Metriphonate is an organophosphorus anticholinesterase compound that was originally used as an insecticide. Adverse effects include abdominal pain, nausea, vomiting, diarrhoea, headache and vertigo.

Niclosamide blocks glucose uptake by intestinal tapeworms. It may cause some mild gastrointestinal symptoms.

Piperazine may cause hypersensitivity reactions, neurological symptoms (including ‘worm wobble’) and may precipitate epilepsy.

Praziquantel paralyses both adult worms and larvae. It is metabolised extensively. Praziquantel may cause nausea, headache, dizziness and drowsiness; it cures with a single dose (or divided doses in 1 day).

Pyrantel depolarises neuromuscular junctions of susceptible nematodes, which are expelled in the faeces. It cures with a single dose. It may induce gastrointestinal disturbance, headache, dizziness, drowsiness and insomnia.

Tiabendazole inhibits cellular enzymes of susceptible helminths. Gastrointestinal, neurological and hypersensitivity reactions, liver damage and crystalluria may be induced.

Guide to further reading

American Centers for Disease Control and Prevention (CDC-P). Their website includes a comprehensive travel section that contains high-quality and up-to-date information about prophylaxis, avoidance, diagnosis and treatment of infectious diseases of travel. Available online at http://www.cdc.gov/travel/ (accessed November 2011)

Baird J.K. Effectiveness of antimalarial drugs. N. Engl. J. Med.. 2005;352(15):1565–1577.

Beigel J.H., Farrar J., Han A.M., et alWriting Committee of WHO Consultation on Human Influenza A/H5, Avian influenza A (H5N1) infection in humans. of the. N. Engl. J. Med.. 2005;353:1374–1385.

Bethony J., Brooker S., Albonico M., et al. Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet. 2006;367:1521–1532.

Bouchaud O., Imbert P., Touze J.E., et al. Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base. Malar. J.. 2009;8:289.

British HIV Association. The Association provides a wealth of information on best practice management of HIV infection and opportunistic infections. See their website, available online at http://www.bhiva.org/ClinicalGuidelines.aspx (accessed November 2011)

Bruce-Chwatt L.J. Three hundred and fifty years of the Peruvian fever bark. Br. Med. J.. 1988;296:1486–1487.

Chiodini P., Hill D., Lalloo D., et al. Guidelines for Malaria Prevention in Travellers to the United Kingdom. London.: Health Protection Agency; 2007. January 2007

Deeks S.G. Antiretroviral treatment of HIV infected adults. Br. Med. J.. 2006;332:1489–1493.

Edwards G., Biagini G.A. Resisting resistance: dealing with the irrepressible problem of malaria. Br. J. Clin. Pharmacol.. 2006;61(6):690–693.

Esté J.A., Telenti A. HIV entry inhibitors. Lancet. 2007;370:81–88.

European Group for Blood and Bone Marrow Transplantation. Their website has an Infectious Diseases Working Party section containing recent evidence-based recommendations for managing fungal and viral infections. See European Conference on Infection in Leukaemia (ECIL-3) Working Party Guidelines. Available online at: http://www.ebmt.org (accessed November 2011)

Fit for Travel. Another useful contemporary source is ‘Fit for Travel’, the NHS public access website providing travel health information for people travelling abroad from the UK. Available online at: http://www.fitfortravel.scot.nhs.uk/ (accessed November 2011)

Franco-Paredes C., Santos-Preciado J.I. Problem pathogens: prevention of malaria in travellers. Lancet Infect. Dis.. 2006;6(3):139–149.

Gazzard B.G., Anderson J., Babiker A., et al. British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med.. 2008;9(8):563–608.

Geisbert T.W., Jahrling P.B., Exotic emerging viral diseases: progress and challenges. (supplement review). Nat Med., 2004;10(12):S110–S121.

Greenwood B.M., Bojang K., Whitty C.J., Targett G.A. Malaria. Lancet. 2005;365:1487–1498.

Gryseels B., Polman K., Clerinx J., Kestens L. Human schistosomiasis. Lancet. 2006;368:1106–1118.

Health Protection Agency. The Agency website has detailed information and links to common travel associated infections. Available online at: www.hpa.org.uk/ (accessed November 2011)

Jefferson T., Demicheli V., Rivetti D., et al. Antivirals for influenza in healthy adults: systematic review. Lancet. 2006;367:303–313.

Kremsner P.G., Krishna S. Antimalarial combinations. Lancet. 2004;364:285–294.

Lalloo D.G., Shingadia D., Pasvol G., et al. UK malaria treatment guidelines. J. Infect.. 2007;54:111–121.

HIV and AIDS. Lever A.M.L., Aliyu S.H., eds., Medicine Journal. 2009;37(7):313–390.

McManus D.P., Zhang W., Li J., Bartley P.B. Echinococcosis. Lancet. 2003;362:1295–1304.

Merson M.H. The HIV-AIDS pandemic at 25 – the global response. N. Engl. J. Med.. 2006;354(23):2414–2417.

Montoya J.G., Liesenfeld O. Toxoplasmosis. Lancet. 2004;363:1965–1976.

Moscona A. Neuraminidase inhibitors for influenza. N. Engl. J. Med.. 2005;353(13):1361–1373.

Murray H.W., Berman J.D., Davies C.R., Saravia N.G. Advances in leishmaniasis. Lancet. 2005;366:1561–1577.

Patterson T.F. Advances and challenges in management of invasive mycoses. Lancet. 2005;366:1013–1025.

Sepkowitz K.A. One disease, two epidemics – AIDS at 25. N. Engl. J. Med.. 2006;354(23):2411–2414.

Snow R.W., Marsh K. Malaria in Africa: progress and prospects in the decade since the Abuja Declaration. Lancet. 2010;376(9735):137–139.

University of Liverpool. interactive charts on antiretroviral drug interactions, information about advances in therapeutic drug monitoring and other resources. Available online at: http://www.hiv-druginteractions.org (accessed November 2011)

US Department of Health and Human Services. guidelines on use of antiretroviral agents in adults and adolescents, and children, which are updated several times per year. Available online at: http://www.aidsinfo.nih.gov (accessed November 2011)

World Health Organization. data on HIV infection. Available online at: http://www.who.int/topics/hiv_infections/en/ (accessed November 2011)

World Health Organization. guidelines for the treatment of malaria http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html, 2010. (accessed November 2011)

¹ The large-scale screening for natural compounds able to kill bacteria in vitro, which was the basis for the boom of antibiotics in the 1950s, was not successful for antivirals … The driving force for the boom of antivirals in this period has been the pressure to contain the HIV pandemic, combined with the increased understanding of the molecular mechanisms … which has allowed the identification of new targets for therapeutic intervention.' (Rappuoli R 2004 From Pasteur to genomics: progress and challenges in infectious diseases. Nature Medicine 10:1177–1185.)

² For a comprehensive review, see Kaplan J E, Benson C, Holmes K H et al 2009 Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recommendations and Reports 58(RR-4):1–207.

³ Treatment regimens vary in detail; those quoted here accord with the recommendations in the British National Formulary 2010 and national UK specialist guidelines; the BNF is a good source of contact numbers, addresses and websites to obtain expert advice on therapy and prophylaxis of malaria.

⁴ Acceptable as quinine hydrochloride, dihydrochloride or sulfate, but not quinine bisulfate, which contains less quinine.

⁵ The loading dose should not be given if the patient has received quinine, quinidine or mefloquine in the previous 24 h; see also warnings about halofantrine (below).

⁶ Reduced to 5–7 mg/kg of quinine salt if the infusion lasts for more than 48 h.

⁷ A Cochrane Review of six clinical trials showed a significantly reduced risk of death, reduced parasite clearance time and hypoglycaemia when artesunate was compared with quinine for the treatment of severe malaria. Jones K L, Donegan S, Lalloo D G 2007 Artesunate versus quinine for treating severe malaria. Cochrane Database Systematic Review Oct 17;(4):CD005967.

⁸ Dondorp A, Nosten F, Stepniewska K, et al 2005 Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366:717–725.

⁹ The active component of many drugs, whether acid or base, is relatively insoluble and may present a problem in formulation. This is overcome by adding an acid to a base or vice versa; the weight of the salt differs according to the acid or base component, i.e. chloroquine base 150 mg = chloroquine sulfate 200 mg = chloroquine phosphate 250 mg (approximately). Where there may be variation, therefore, the amount of drug prescribed is expressed as the weight of the active component, in the case of chloroquine, the base.

¹⁰ Report 1993 Chloroquine poisoning. Lancet 307:49.