Bacterial Resistance

Bacterial resistance increasingly complicates treatment and often results from the acquisition of a plasmid that encodes an altered dihydrofolate reductase. Emergence of trimethoprim— sulfamethoxazole—resistant Staphylococcus aureus and Enterobacteriaceae is a special problem in AIDS patients receiving the drug for prophylaxis of Pneumocystis jiroveci (formerly called Pneumocystis carinii) pneumonia.

ABSORPTION, DISTRIBUTION, AND EXCRETION The pharmacokinetic profiles of sulfamethoxazole and trimethoprim are closely but not perfectly matched to achieve a constant ratio of 20:1 in their concentrations in blood and tissues. The ratio in blood is often greater than 20:1, while that in tissues is frequently less. After a single oral dose of the combined preparation, peak blood concentrations of trimethoprim usually occur by 2 hours, whereas peak concentrations of sul-famethoxazole require 4 hours. The half-lives of trimethoprim and sulfamethoxazole are ~11 and 10 hours, respectively.

When 800 mg sulfamethoxazole is given with 160 mg trimethoprim (the conventional 5:1 ratio) twice daily, the peak concentrations of the drugs in plasma approximate the optimal ratio. Peak concentrations are similar after intravenous infusion of 800 mg sulfamethoxazole/160 mg trimetho-prim over a period of 1 hour.

Trimethoprim is distributed and concentrated rapidly in tissues, and ~40% is bound to plasma protein in the presence of sulfamethoxazole. The volume of distribution of trimethoprim is almost nine times that of sulfamethoxazole. The drug readily enters CSF and sputum. High concentrations of each component also are found in bile. About 65% of sulfamethoxazole is bound to plasma protein.

About 60% of administered trimethoprim and from 25% to 50% of administered sulfamethox-azole are excreted in the urine in 24 hours. Two-thirds of the sulfonamide is unconjugated. Metabolites of trimethoprim also are excreted. The rates of excretion and the concentrations of both compounds in the urine are reduced significantly in patients with uremia.

THERAPEUTIC USES Urinary Tract Infections

Treatment of uncomplicated lower urinary tract infections with trimethoprim—sulfamethoxazole often is highly effective for sensitive bacteria, usually for a minimum of 3 days. The combination is especially useful in chronic and recurrent infections of the urinary tract. Trimethoprim also is found in therapeutic concentrations in prostatic secretions, and trimethoprim—sulfamethoxazole is often effective for bacterial prostatitis.

Bacterial Respiratory Tract Infections

Trimethoprim—sulfamethoxazole is effective for acute exacerbations of chronic bronchitis. Administration of800—1200 mg sulfamethoxazole plus 160—240 mg trimethoprim twice a day appears to be effective in decreasing fever, purulence and volume of sputum, and sputum bacterial count. Trimethoprim— sulfamethoxazole should not be used to treat streptococcal pharyngitis because it does not eradicate the microorganism. It is effective for acute otitis media in children and acute maxillary sinusitis in adults caused by susceptible strains of Haemophilus influenzae and Streptococcus pneumoniae.

Gastrointestinal Infections

The combination is an alternative to fluoroquinolone for treatment of shigellosis, but resistance to trimethoprim—sulfamethoxazole is increasingly common.

Trimethoprim—sulfamethoxazole appears to be effective in the management of carriers of sensitive strains of Salmonella typhi and other Salmonella spp., but failures have occurred. Chronic disease of the gallbladder may be associated with a high incidence of failure to clear the carrier state. Acute diarrhea owing to sensitive strains of enteropathogenic Escherichia coli can be treated or prevented with either trimethoprim or trimethoprim plus sulfamethoxazole. However, antibiotic treatment (either trimethoprim—sulfamethoxazole or cephalosporin) of diarrheal illness due to enterohemorrhagic E. coli O157:H7 may increase the risk of hemolytic-uremic syndrome, perhaps by increasing the release of Shiga toxin.

Infection by Pneumocystis jiroveci

High-dose therapy (trimethoprim 15 mg/kg/day plus sulfamethoxazole 100 mg/kg/day in three or four divided doses) is effective for this severe infection in patients with AIDS. Adjunctive glucocorticoids should be given in patients with a Po2 of <70 mm Hg or an alveolar-arterial gradient of >35 mm Hg. The incidence of side effects is high. Lower-dose oral therapy with 800 mg sulfamethoxazole plus 160 mg trimethoprim (given twice daily) has been used successfully in AIDS patients with less severe pneumonia (Po2 >70 mm Hg). Prophylaxis with 800 mg sulfamethoxazole and 160 mg trimethoprim once daily or three times a week is effective in preventing pneumonia caused by this organism in patients with AIDS. Adverse reactions are less frequent with the lower prophylactic doses of trimethoprim-sulfamethoxazole. The most common problems are rash, fever, leukopenia, and hepatitis.

Prophylaxis in Neutropenic Patients

Low-dose therapy (i.e., 150 mg/m2 of body surface area of trimethoprim and 750 mg/m2 of body surface area of sulfamethoxazole) is effective for the prophylaxis of infection by P. jiroveci. Significant protection against sepsis caused by gram-negative bacteria also was noted when 800 mg sulfamethoxazole and 160 mg trimethoprim were given twice daily to severely neutropenic patients. The emergence of resistant bacteria may limit the usefulness of trimethoprim- sulfamethoxazole for prophylaxis.

Miscellaneous Infections

Nocardia infections have been treated successfully, but failures also have been reported. Although a combination of doxycycline and streptomycin or gentamicin is considered the treatment of choice for brucellosis, trimethoprim-sulfamethoxazole may be an effective substitute for the doxycycline combination. Trimethoprim-sulfamethoxazole also has been used successfully for Whipple's disease, Stenotrophomonas maltophilia infection, and infection by the intestinal parasites Cyclospora and Isospora.

UNTOWARD EFFECTS The margin between toxicity for bacteria and that for human beings may be narrowed when the patient is folate deficient. In such cases, trimethoprim-sulfamethoxazole may cause or precipitate megaloblastosis, leukopenia, or thrombocytopenia. About 75% of the untoward effects involve the skin. Trimethoprim-sulfamethoxazole has been reported to cause up to three times as many dermatological reactions as does sulfisoxazole when given alone (5.9% vs. 1.7%). Severe dermatologic reactions primarily occur in older individuals. Nausea and vomiting constitute the bulk of GI reactions; diarrhea is rare. Glossitis and stomatitis are relatively common. Transient jaundice with histological features of allergic cholestatic hepatitis has been noted. CNS reactions consist of headache, depression, and hallucinations. Hematological reactions include various anemias (including aplastic, hemolytic, and macrocytic), coagulation disorders, granulocytopenia, agranulocytosis, purpura, and sulfhemoglobinemia. Permanent impairment of renal function may follow the use of trimethoprim-sulfamethoxazole in patients with renal disease, and a reversible decrease in creatinine clearance has been noted in patients with normal renal function.

Patients with AIDS frequently have hypersensitivity reactions to trimethoprim-sulfamethoxazole, including rash, neutropenia, Stevens-Johnson syndrome, Sweet's syndrome, and pulmonary infiltrates. It may be possible to continue therapy in such patients following rapid oral desensitization.

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