A. DOXYCYCLINE

Formulations

Capsules and tablets containing 100 mg of doxycycline salt as hydrochloride.

Efficacy

Doxycycline is derived from and related to oxytetracycline, and has an identical spectrum of activity. It differs from tetracyclines (see below) in that it is more completely absorbed and more lipid-soluble; it also has a longer plasma half-life.

Use

Doxycycline, like tetracyclines, can be used for therapy in combination with quinine in areas where reduced susceptibility to quinine has been reported. Since the costs of tetracycline and doxycycline are equivalent, the once daily regimen of doxycycline offers a considerable operational advantage over tetracycline, which is given four times daily. Doxycycline should not be used alone for the treatment of malaria because of its slow action.

Doxycycline 200 mg of salt given as a daily dose for 5 days in combination with mefloquine or artesunate has been used successfully in Thailand to treat multiresistant uncomplicated falciparum malaria (297).

In contrast to tetracycline, doxycycline can also be used for chemoprophylaxis. Experience with this indication is limited but increasing. Doxycycline prophylaxis is recommended in areas of mefloquine-resistant falciparum malaria and for those visiting high-risk areas who are unable to take mefloquine (294, 295). It has been used successfully for this purpose by United Nations forces in Cambodia and Somalia (296).

As with tetracycline, oesophageal ulceration can be prevented if the oral dose is washed down with copious amounts of water. Other gastrointestinal symptoms can be reduced if doxycycline is taken with a meal. Milk products must be avoided since they reduce absorption.

Recommended treatment

(see also section on quinine)

In areas with high levels of resistance to quinine:

Quinine 8 mg of base per kg three times daily for 7 days

     plus

Doxycycline 100 mg of salt daily for 7 days (not in children under 8 years of age and not during pregnancy); a pharmacologically superior regimen would include a loading dose of 200 mg of doxycycline followed by 100 mg daily for 6 days.

In areas where parasites are sensitive to quinine and adherence to treatment may be a problem:

Quinine 8 mg base per kg three times daily for 3 days

     plus

Doxycycline 100 mg of salt daily for 7 days (not in children under 8 years of age and not during pregnancy); a pharmacologically superior regimen would include a loading dose of 200 mg of doxycycline followed by 100 mg daily for 6 days.

This dosage schedule should significantly improve adherence compared to that for quinine plus tetracycline, in which the latter is given four times daily.

Recommended chemoprophylaxis

Doxycyline100 mg of salt daily.

The prophylactic adult dose of 100 mg of salt daily is equivalent to 1.5 mg of salt per kg daily. It is not practical to give fractions of the capsule formulation to children. If tablets are available, those aged 8-13 years can be given fractions of tablets as shown in Table 16. Doxycycline is contraindicated in children under 8 years of age.

Use in pregnancy

Doxycycline is contraindicated in pregnancy and in nursing mothers since the risks of its use are similar to those with tetracycline (see below).

Drug disposition

Doxycycline is readily and almost completely absorbed from the gastrointestinal tract and absorption is not significantly affected by the presence of food in the stomach or duodenum. Peak plasma concentrations are reached around 2 h after oral administration. Doxycycline is bound to plasma proteins (80-90%) and has a biological half-life of 15-25 h. It is mainly excreted in the faeces. The drug is more lipid soluble than tetracycline and is widely distributed in tissues and body fluids. It is not thought to be accumulated in patients with renal dysfunction although there are some reports of accumulation in renal failure.

Adverse effects

Adverse effects include gastrointestinal irritation, phototoxic reactions (increased vulnerability to sunburn), transient depression of bone growth (largely reversible) and discoloration of teeth and enamel hypoplasia (permanent). Aggravation of renal impairment may occur but is less likely than with tetracyclines.

Contraindications

Doxycycline is contrainidicated in:

• persons with known hypersensitivity to tetracyclines,
• children under 8 years of age,
• pregnant and nursing mothers,
• persons with hepatic dysfunction.

B. TETRACYCLINE

Formulations

Capsules and tablets containing 250 mg of tetracycline hydrochloride, equivalent to

231 mg of tetracycline base.

Efficacy

Tetracycline is a broad-spectrum antimicrobial drug that has potent but slow action against the asexual blood stages of all Plasmodium species. It is also active against the primary intrahepatic stages of P. falciparum. The combination of quinine plus tetracycline given over 5-7 days is still highly effective for treatment in areas of multidrug resistance in Thailand if adherence with the regimen can be assured (298).

Use

Tetracycline can be used in combination with quinine in the treatment of falciparum malaria to decrease the risk of recrudescence. It should not be used alone for therapy because of its slow action. It is not used for chemoprophylaxis.

Recommended treatment

(see also section on quinine)

In areas with high levels of resistance to quinine:

Quinine 8 mg of base per kg three times daily for 7 days

     plus

Tetracycline 250 mg four times daily for 7 days (not in children under 8 years of age and not in pregnancy)

In areas where parasites are sensitive to quinine and adherence may be a problem

Quinine 8 mg of base per kg three times daily for 3 days

     plus

Tetracycline 250 mg four times daily for 5 days (not in children under 8 years of age and not in pregnancy)

Oesophageal ulceration is rare and can be prevented if tetracycline is taken with ample water. Other gastrointestinal symptoms can be reduced if this drug is taken with a meal. Milk products must be avoided since they reduce the absorption of tetracycline.

Use in pregnancy

Tetracycline is contraindicated in pregnancy. It impairs skeletal calcification in the fetus and can result in abnormal osteogenesis and hypoplasia of dental enamel. Tetracyclines cross the placenta and are found in breast milk and, therefore, should not generally be used in nursing mothers. However, in areas where falciparum infections have reduced susceptibility to quinine and are resistant to mefloquine, and more suitable alternatives are not available, the benefits of therapy with quinine and concomitant tetracycline may outweigh the risks.

Drug disposition

Absorption of tetracycline from the gut is always incomplete and can be further impaired by alkaline substances, chelating agents and, particularly, by milk and milk products, as well as aluminium, calcium, magnesium and iron salts. Peak plasma concentrations occur within 4 h with an elimination half-life of about 8 h. Excretion is primarily in the urine, and enterohepatic circulation gives rise to high concentrations in the bile and liver.

Adverse effects

Gastrointestinal effects include epigastric distress, abdominal discomfort, nausea, vomiting and diarrhoea. These are dose-related and can be alleviated by giving smaller doses more often. Long-term administration may result in alteration of the normal intestinal and vaginal bacterial flora and overgrowth of Candida and other bacteria in the bowel and vagina, although this is rare at the doses used for malaria treatment. Ossification disorders, transient depression of bone growth (largely reversible), discoloration of teeth and enamel dysplasia, which may be permanent in children, have been reported. Skin changes may include phototoxic reactions and increased vulnerability to sunburn. Morbilliform rashes, urticaria, fixed drug eruptions, exfoliative dermatitis, cheliosis, glossitis and vaginitis have also been recorded. Pre-existing renal insufficiency may be aggravated. Hypersensitivity reactions occur rarely. Other adverse effects include angioedema, anaphylaxis and pseudo-tumor cerebri.

Degraded tetracycline may cause renal dysfunction indistinguishable from Fanconi syndrome and skin reactions similar to those of lupus erythematosus. Capsules and tablets should therefore be kept in well-closed containers and protected from the light. Time-expired formulations should be discarded.

Contraindications

Tetracycline is contraindicated in:

• persons with known hypersensitivity,
• persons with pre-existing renal or hepatic dysfunction,
• children under 8 years of age,
• pregnant and nursing mothers (see above).

C. CLINDAMYCIN

Formulations

Capsules containing 75 mg, 150 mg or 300 mg of clindamycin base as hydrochloride.

Efficacy and use

Clindamycin is a semi-synthetic antibiotic derived from lincomycin. Like tetracycline, it is an efficient blood schizonticide with a relatively slow action and a similar spectrum of activity. Along with tetracycline and doxycycline, it is an option for use in combination with quinine for treatment of falciparum malaria when decreased susceptibility to quinine has been reported. However, it is more toxic and costly than tetracycline and doxycycline and should therefore only be used when these drugs are contraindicated or unavailable. It should not be used alone for the treatment of malaria because of its slow action. It is not suitable for chemoprophylaxis.

Recent studies have demonstrated high efficacy in 3-day courses of clindamycin in combination with quinine in Africa (299, 300) and in a 7-day course of the same combination in Thailand (301).

Recommended treatment

(see also section on quinine)

In areas where parasites are sensitive to quinine and adherence may be a problem

Quinine 8 mg of base per kg three times daily for 3 days

      plus

Clindamycin 300 mg four times daily for 5 days.

Clindamycin should be administered with food and copious amounts of water.

Use in pregnancy

Unlike tetracycline and doxycycline, clindamycin use has not been reported to cause adverse events in pregnancy, although it does cross the placenta and may be accumulated in the fetal liver. It is also excreted in breast milk but without any apparent effect. Therefore, clindamycin is not contraindicated for malaria therapy in pregnancy although experience in this regard is limited.

Drug disposition

About 90% of clindamycin is absorbed from the gastrointestinal tract, peak plasma concentrations after oral administration being reached in about 1 h. The drug is rapidly hydrolysed to the free base and widely distributed in body tissues and fluids. Over 90% of circulating clindamycin is bound to plasma proteins. The plasma half-life is 2-3 h although this may be extended in neonates and persons with renal impairment. Clindamycin is partly metabolized, probably in the liver, to active and inactive metabolites, but most of the drug is eliminated unchanged in the faeces. Elimination of metabolites is slow over several days.

Adverse effects

Nausea, vomiting, abdominal pain or cramps have been reported and some patients (2-20%) may experience diarrhoea. Pseudomembranous colitis, a potentially fatal condition caused by Clostridium difficile toxin, may develop in some cases. Hypersensitivity reactions, including skin rashes and urticaria, and neutropenia and thrombocytopenia occur rarely.

Clindamycin should be withdrawn if diarrhoea or colitis occurs. Vancomycin in doses of 125-500 mg every 6 h has been used successfully to treat pseudo-membranous colitis.

Contraindications

Clindamycin is contraindicated in persons:

• with hypersensitivity to clindamycin or lincomycin,
• with a history of gastrointestinal disease, particularly colitis,
• with severe hepatic or renal impairment.

D. AZITHROMYCIN

Azithromycin belongs to a new class of azalid macrolid antibiotics. It is structurally similar to erythromycin but is better tolerated, has a broader antimicrobial spectrum of action, and provides prolonged tissue levels. It is an efficient blood schizonticide but has a relatively slow action (P. Olliaro,
W. Taylor and J. Rigal, personal communication).

No data exist on the use of azithromycin as monotherapy. Two recent combination trials of artemisinin derivatives plus azithromycin for the treatment of P. falciparum malaria showed high parasitological failure rates (302, 303).

A large chemoprophylaxis trial in Kenya using 250 mg of azithromycin daily showed a protective efficacy of 80% for P. falciparum infections (304). In a similar trial in Indonesia the protective efficacy was 100% for P. vivax but was not high enough for P. falciparum to warrant further studies (305).

In the absence of further information, azithromycin cannot be recommended for the treatment or chemoprophylaxis of malaria, either alone or in combination.