Acute Otitis Media
Co-trimoxazole is used in adults and children for the treatment of acute otitis media (AOM) caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when the clinician makes the judgment that the drug offers some advantage over use of a single anti-infective. Data are limited to date regarding safety of repeated use of co-trimoxazole in pediatric patients younger than 2 years of age; the drug should not be administered prophylactically or for prolonged periods for the treatment of otitis media in any age group.
Various anti-infectives, including oral amoxicillin, oral amoxicillin and clavulanate potassium, various oral cephalosporins (cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin), IM ceftriaxone, oral co-trimoxazole, oral erythromycin-sulfisoxazole, oral azithromycin, oral clarithromycin, and oral loracarbef, have been used in the treatment of AOM. The AAP, CDC, and other clinicians state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, and is well tolerated and inexpensive.
Co-trimoxazole is not considered a first-line agent for treatment of AOM, but is recommended as an alternative for individuals with type I penicillin hypersensitivity. Because S. pneumoniae resistant to amoxicillin also frequently are resistant to co-trimoxazole, clarithromycin, and azithromycin, these drugs may not be effective in patients with AOM who fail to respond to amoxicillin. For additional information regarding treatment of AOM and information regarding prophylaxis of recurrent AOM, treatment of persistent or recurrent AOM, and treatment of otitis media with effusion (OME), .
Oral co-trimoxazole is used in adults and children for the treatment of enteritis caused by enterotoxigenic Escherichia coli that occurs during or soon after travel to developing countries or other areas where hygiene is poor (travelers' diarrhea). Travelers' diarrhea is a condition characterized by a twofold or greater increase in the frequency of unformed bowel movements; other manifestations may include abdominal cramps, nausea, bloating, urgency, fever, and malaise. The principal cause of travelers' diarrhea is infection with enterotoxigenic E. coli, but other infectious agents (e.g., Shigella, Salmonella, Campylobacter spp.) have also been associated with the disease.
Treatment of the condition depends on severity of the illness; travelers' diarrhea is usually a mild, self-limited disorder. In individuals with mild to moderate disease, replacement therapy with oral fluids and electrolytes may be sufficient, although therapy with nonspecific or antimotility agents (e.g., bismuth subsalicylate, loperamide) may be useful for temporary relief of associated symptoms (e.g., abdominal cramps and diarrhea). Travelers who develop diarrhea with at least 3 loose stools in an 8-hour period, especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in the stools, may benefit from short-term treatment with an anti-infective agent. Fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin ofloxacin) usually are considered the drugs of choice when treatment of travelers' diarrhea is indicated. Co-trimoxazole can be used as an alternative in children who cannot receive fluoroquinolones; however, resistance to co-trimoxazole has been reported in many areas.
Efficacy of anti-infective therapy may depend on the etiologic agent and its susceptibility to antibiotics. In several controlled studies, therapy for 3-5 days with oral co-trimoxazole or trimethoprim alone substantially reduced the duration of abdominal pain and nausea and the number of unformed stools in individuals with the disease; mild rash occurred infrequently with both therapies. In another controlled study, concomitant therapy with co-trimoxazole and loperamide for 3 days provided more rapid relief of travelers' diarrhea than therapy with either drug alone, and co-trimoxazole given alone as a single dose (320 mg of trimethoprim given as co-trimoxazole) was also more effective than placebo in treating the condition. However, because of the development of resistance to co-trimoxazole in many areas, other anti-infective agents (e.g., ciprofloxacin, levofloxacin, ofloxacin), which also have been used with success in the treatment of travelers' diarrhea, may be considered first. Nausea and vomiting without diarrhea should not be treated with anti-infectives. Individuals with persistent diarrhea and severe fluid loss, fever, and blood or mucus in the stools should seek medical attention.
Oral co-trimoxazole also has been used effectively to prevent travelers' diarrhea in individuals traveling for relatively short periods to areas where enterotoxigenic E. coli and other causative bacterial pathogens (e.g., Shigella) are known to be susceptible to the drug. Because travelers' diarrhea is a relatively nonthreatening illness that is usually mild and self-limiting and can be effectively treated and because of the risks of widespread use of anti-infective agents prophylactically (i.e., potential adverse drug reactions, selection of resistant organisms and increased susceptibility to infections caused by these or other organisms), the US Centers for Disease Control and Prevention (CDC) and most experts recommend that anti-infectives not be used prophylactically by most individuals traveling to areas of risk. In addition, although controlled studies have indicated that various anti-infectives when taken prophylactically have been 52-95% effective in preventing travelers' diarrhea in several developing areas of the world, efficacy depends on resistance patterns of pathogenic bacteria in each travel area, and such information seldom is available. While fluoroquinolone resistance for bacteria causing travelers' diarrhea currently is least common, this could change as use of these drugs increases worldwide. The CDC states that although use of anti-infective agents for prophylaxis of travelers' diarrhea in certain high-risk groups, such as travelers with immunosuppression or immunodeficiency, may seem reasonable, there currently are no specific data to support such prevention in these populations. (For information on prophylaxis of travelers' diarrhea in HIV-infected individuals, .) Anti-infectives that have been used for prophylaxis of travelers' diarrhea are not effective in preventing diarrhea caused by viral or parasitic infections, and use of such prophylaxis may give a false sense of security to the traveler about the risk associated with consuming certain local foods and beverages. The principal preventive measure is prudent dietary practices. If prophylaxis is used, ciprofloxacin, levofloxacin, ofloxacin, or norfloxacin can be given for a maximum of 3 weeks.
Co-trimoxazole is used IV or orally for the treatment of enteritis caused by susceptible strains of Shigella flexneri or S. sonnei. Choice of anti-infective therapy should be based on drug susceptibility of the isolated organism. Although therapy may be initiated based on local susceptibility patterns pending results of susceptibility testing, some clinicians currently state that, when the susceptibility of the isolate is unknown, fluoroquinolones are the anti-infectives of choice with co-trimoxazole as an alternate, especially in areas where ampicillin-resistant strains of Shigella have been reported. Fluoroquinolones are the drugs of choice and co-trimoxazole an alternate for the treatment of shigellosis when the organism is resistant to ampicillin or the patient is allergic to ampicillin.
Escherichia coli Infections
Co-trimoxazole has been used in the treatment of GI infections caused by Escherichia coli.
Optimal therapy for diarrhea caused by enterotoxigenic E. coli (ETEC) is not established and resistance is common. AAP states that if diarrhea caused by ETEC is suspected in a traveler to a resource-limited country, use of co-trimoxazole, azithromycin, or ciprofloxacin should be considered if diarrhea is severe or intractable and if in vitro testing indicates that the causative organism is susceptible. A parenteral regimen should be used if systemic infection is suspected.
For the treatment of dysentery caused by enteroinvasive E. coli (EIEC), the AAP suggests than an oral anti-infective (e.g., co-trimoxazole, azithromycin, ciprofloxacin) can be used if in vitro tests indicate the causative organism is susceptible.
The role of anti-infectives in patients with hemorrhagic colitis caused by shiga toxin-producing Escherichia coli (STEC; formerly known as enterohemorrhagic E. coli) is unclear and most experts do not recommend use of anti-infectives for treatment of children with enteritis caused by E. coli 0157:H7.
Co-trimoxazole is used in adults for treatment of acute exacerbation of chronic bronchitis caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when the clinician makes the judgment that the drug offers some advantage over use of a single anti-infective. Co-trimoxazole is considered by many clinicians to be the drug of choice for the treatment of upper respiratory tract infections and bronchitis caused by H. influenzae. The drug also is used as an alternative to penicillin G or penicillin V for the treatment of respiratory tract infections caused by Streptococcus pneumoniae. Co-trimoxazole is as effective as amoxicillin, ampicillin, erythromycin, or tetracycline in the treatment of acute exacerbations of chronic bronchitis.
Many clinicians consider co-trimoxazole an alternative for the treatment of infections caused by Legionella micdadei (L. pittsburgensis) or L. pneumophila.
Co-trimoxazole should not be used in the treatment of pharyngitis caused by S. pyogenes (group A β-hemolytic streptococci); results of clinical studies indicate that co-trimoxazole therapy is associated with a higher bacteriologic failure rate (as evidenced by failure to eradicate S. pyogenes from the tonsillopharyngeal area) than penicillin therapy.
Urinary Tract Infections
Co-trimoxazole is used for the treatment of urinary tract infections (UTIs) caused by susceptible strains of E. coli, Proteus (indole-positive or -negative), Klebsiella, Morganella morganii, or Enterobacter.
Co-trimoxazole, given in single doses, as 3-day therapy, or for 7-10 days, is effective in the treatment of acute uncomplicated UTIs. Some clinicians consider a 3-day regimen of co-trimoxazole the treatment of choice for the empiric treatment of acute uncomplicated UTIs. Co-trimoxazole also is used for the treatment of acute complicated UTIs (e.g., UTIs associated with abnormalities of the urinary tract or neurogenic bladder), but other anti-infectives are preferred by most clinicians. For the treatment of acute pyelonephritis, some clinicians recommend anti-infective treatment for 7-14 days. Mild cases of pyelonephritis in women can be treated with an oral fluoroquinolone or with co-trimoxazole (if the causative organism in known to be susceptible). If the infection is likely to be caused by gram-positive bacteria, amoxicillin or amoxicillin and clavulanate potassium may be used. Patients with more severe infections should be hospitalized and therapy should be initiated using a parenteral regimen. Some clinicians recommend that acute pyelonephritis be treated with a parenteral fluoroquinolone or, alternatively, an aminoglycoside with or without ampicillin or an extended-spectrum cephalosporin; an aminoglycoside with or without ampicillin sodium and sulbactam sodium is recommended if the infection is likely to be caused by gram-positive bacteria. When treating acute uncomplicated UTI, the causative organism should be cultured and susceptibility tests conducted prior to initiation of co-trimoxazole therapy; co-trimoxazole may be initiated, however, before obtaining the results of these tests. Some clinicians also recommend obtaining follow-up urine cultures after discontinuance of anti-infective therapy to determine whether the bacteria have been eliminated.
Most clinicians reserve co-trimoxazole for the treatment of chronic or recurrent UTIs. In chronic or recurrent UTIs, the drug suppresses fecal and vaginal flora and usually does not select out resistant coliforms. For the treatment of chronic or recurrent UTIs resulting from reinfection or relapse in women, low doses of co-trimoxazole (e.g., 40 mg of trimethoprim and 200 mg of sulfamethoxazole given nightly or 3 times weekly) are as effective as other anti-infectives (e.g., methenamine mandelate, nalidixic acid, nitrofurantoin) and are preferred by many clinicians. Men with prostatitis-associated recurrent UTIs usually respond poorly to anti-infectives. Although 14-day courses of co-trimoxazole in such patients reportedly are associated with failure rates of greater than 60%, efficacy of the drug appears to be increased markedly with treatment courses of 3-6 months.
Oral co-trimoxazole is considered an alternative to tetracyclines for the treatment of brucellosis when tetracyclines are contraindicated, including brucellosis in pediatric patients. To decrease the incidence of relapse, many clinicians recommend that rifampin be used in conjunction with co-trimoxazole or a tetracycline. For treatment of serious brucellosis or when there are complications, including endocarditis, meningitis, or osteomyelitis, some clinicians recommend that an aminoglycoside (streptomycin or gentamicin) be used concomitantly with co-trimoxazole or a tetracycline for the first 7-14 days of therapy; rifampin can also be included in the regimen to reduce the risk of relapse.
Co-trimoxazole is used for the treatment of infections caused by Burkholderia cepacia. Co-trimoxazole is considered the drug of choice and ceftazidime, chloramphenicol, or imipenem are alternatives for these infections.
Co-trimoxaozle is used for the treatment of melioidosis caused by susceptible B. pseudomallei, usually in a multiple-drug regimen with chloramphenicol and doxycycline. Ceftazidime or imipenem monotherapy is recommended as the drug of choice for these infections.B. pseudomallei is difficult to eradicate and relapse of melioidosis is common.
Co-trimoxazole is used in the treatment of cholera when anti-infective therapy is indicated as an adjunct to fluid and electrolyte replacement. Tetracyclines usually are considered the drugs of choice for the treatment of cholera, and co-trimoxazole, a fluoroquinolone, erythromycin, or furazolidone (no longer commercially available in the US) is recommended when tetracyclines are contraindicated or when the infection is caused by tetracycline-resistant Vibrio cholerae.V. cholerae serogroup 0139 Bengal may not be susceptible to co-trimoxazole or furazolidone.
The CDC and others consider co-trimoxazole the treatment of choice for cyclosporiasis infection caused by Cyclospora cayetanensis, a coccidian parasite that causes severe, generally self-limiting, diarrhea.
Granuloma Inguinale (Donovanosis)
Co-trimoxazole is used for the treatment of granuloma inguinale (donovanosis) caused by Calymmatobacterium granulomatis. The CDC recommends that donovanosis be treated with a regimen of oral co-trimoxazole or oral doxycycline or, alternatively, a regimen of oral ciprofloxacin, oral erythromycin, or oral azithromycin. Anti-infective treatment of donovanosis should be continued until all lesions have healed completely; a minimum of 3 weeks of treatment usually is necessary. If lesions do not respond within the first few days of therapy, the CDC recommends that addition of a parenteral aminoglycoside (e.g., 1 mg/kg of gentamicin IV every 8 hours) to the regimen be considered. Erythromycin should be used to treat donovanosis in pregnant and lactating women; addition of a parenteral aminoglycoside (e.g., gentamicin) to the regimen should be strongly considered in these women. Anti-infective treatment appears to halt progressive destruction of tissue, although prolonged duration of therapy often is required to enable granulation and reepithelialization of ulcers. Despite effective anti-infective therapy, donovanosis may relapse 6-18 months later.
Individuals with HIV infection should receive the same treatment regimens recommended for other individuals with donovanosis; however, the CDC suggests that addition of a parenteral aminoglycoside (e.g., gentamicin) to the regimen should be strongly considered in HIV-infected patients.
Any individual who had sexual contact with a patient with donovanosis should be examined and treated if they had sexual contact with the patient during the 60 days preceding the onset of symptoms in the patient and they have clinical signs and symptoms of the disease.
Many clinicians consider co-trimoxazole the drug of choice for the treatment of isosporiasis caused by Isospora belli.
Co-trimoxazole has been used successfully in the treatment of meningitis caused by Listeria monocytogenes, and some clinicians consider the drug the preferred alternative for the treatment of listeria infections (except endocarditis) in penicillin-allergic patients.
Co-trimoxazole has been used in the treatment of cutaneous infections caused by Mycobacterium marinum and is considered an alternative to minocycline.
Co-trimoxazole has been used in the treatment of infections caused by Nocardia, including N. asteroides, N. brasiliensis, and N. caviae.Co-trimoxazole or a sulfonamide alone (e.g., sulfisoxazole, sulfamethoxazole) are considered drugs of choice for the treatment of nocardiosis. Alternative anti-infectives for the treatment of nocardiosis include a tetracycline (should not be used in pregnant women or children younger than 8 years of age), amoxicillin and clavulanate potassium, imipenem, meropenem, amikacin, cycloserine, or linezolid. Amikacin and cycloserine generally should be reserved for use in the treatment of severe infections when other drugs are ineffective. Some clinicians suggest that in patients with nocardiosis involving the CNS or when the infection is disseminated or overwhelming, amikacin be included during the first 4-12 weeks of therapy or until there is clinical improvement. In vitro susceptibility testing, if available, is recommended to guide selection of an anti-infective agent for the treatment of severe nocardiosis or for the treatment of patients unable to tolerate a sulfonamide.
Nocardiosis in immunocompetent patients with lymphocutaneous disease usually responds after 6-12 weeks of appropriate anti-infective therapy. Immunocompromised patients and those with invasive disease require 6-12 months of anti-infective therapy and, because of the possibility of relapse, therapy should be continued for at least 3 months after apparent cure; nocardiosis in patients with human immunodeficiency virus (HIV) infection may require even longer therapy. Drainage of abscesses may be beneficial, especially in immunocompromised patients.
Although efficacy of the drug remains to be fully determined, the CDC and other experts currently consider co-trimoxazole an alternative to erythromycin for the treatment of the catarrhal stage of pertussis to potentially ameliorate the disease and reduce its communicability. Co-trimoxazole also is considered an alternative to erythromycin for the prevention of pertussis in household and other close contacts (e.g., day-care facility attendees) of patients with the disease.
Co-trimoxazole has been used for postexposure prophylaxis of plague. Although recommended by the CDC and other clinicians as an alternative agent for such prophylaxis in infants and children younger than 8 years of age, efficacy of the drug for prevention of plague is unknown. Most experts (e.g., CDC, AAP, US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend oral ciprofloxacin or doxycycline for postexposure prophylaxis in adults and most children. Postexposure prophylaxis with anti-infectives is recommended after high-risk exposures to plague, including close exposure to individuals with naturally occurring plague, during unprotected travel in active epizootic or epidemic areas, or laboratory exposure to viable Yersinia pestis.
Co-trimoxazole also has been used in the treatment of plague, but appears to be less effective than other anti-infectives used for treatment of the disease (e.g., streptomycin, gentamicin). Because of lack of efficacy, some experts state that co-trimoxazole should not be used for the treatment of pneumonic plague.
For more information on the management of plague exposure, .
Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
Co-trimoxazole is used for the treatment of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP). When given IV or orally, the drug has a cure rate of 70-80% in patients with PCP. Because co-trimoxazole has excellent tissue penetration and therapy with the agent is associated with rapid clinical response (i.e., 3-5 days in patients with mild to moderate infection), co-trimoxazole currently is considered the initial drug of choice for most patients with this infection. Co-trimoxazole also is considered the drug of choice for the treatment of PCP in patients with acquired immunodeficiency syndrome (AIDS); however, in patients with AIDS, co-trimoxazole is associated with an increased incidence of adverse reactions (especially fever and adverse dermatologic and hematologic reactions). In patients who are intolerant of co-trimoxazole, treatment alternatives include pentamidine isethionate (IV), trimetrexate glucuronate, trimethoprim and dapsone, clindamycin and primaquine, or atovaquone.
Co-trimoxazole is used for the prophylaxis of PCP, both for the prevention of initial episodes (primary prevention) and for the prevention of recurrence (secondary prevention or chronic maintenance therapy) following an initial episode, in immunosuppressed individuals considered to be at increased risk of developing PCP. Some clinicians consider HIV-infected patients, patients with cancer (especially children with acute lymphocytic leukemia receiving maintenance chemotherapy), or renal transplant recipients with active cytomegalovirus infections to be candidates for co-trimoxazole prophylaxis.
Co-trimoxazole is used for prophylaxis of PCP in patients with HIV infection, although an increased risk of toxicity in these patients has been reported. Some evidence indicates that co-trimoxazole may be better tolerated in HIV-infected children than adults. In addition, patients receiving the drug for prophylaxis of PCP appear to tolerate the drug better than those patients receiving it for treatment of PCP. In a placebo-controlled study in adults with AIDS and newly diagnosed Kaposi's sarcoma but no history of opportunistic infections, no cases of PCP were observed in patients receiving co-trimoxazole (primary prevention) for a mean survival period of about 2 years; such pneumonia occurred in 53% of patients receiving placebo and developed within 5 months in 80% of patients who discontinued co-trimoxazole because of toxicity.
Data from a study of 2 cohorts of HIV-positive men whose cases were followed for more than 9 years demonstrated that the largest increase in survival time from the development of a helper/inducer (CD4, T4) T-cell count of 200 cells/ mm was in patients diagnosed with PCP, suggesting that the combination of prophylaxis and antiretroviral therapy was a more important factor than antiretroviral therapy alone in prolonging survival. In another cohort of HIV-infected men, such prophylaxis was associated with a decreased incidence of PCP as the initial AIDS-related illness and, because of this beneficial effect and resultant delays in the onset of initial AIDS-related illness, was associated with increases in the rates of other less common opportunistic infections as the initial AIDS-related illness, including Mycobacterium aviumcomplex, wasting syndrome, esophageal candidiasis, and cytomegalovirus infection. It was suggested that PCP prophylaxis may delay the development of the first AIDS-defining illness by 6-12 months. Although the generalizability of these data to other HIV-positive populations (e.g., women) is unclear, they suggest that PCP prophylaxis may have a role in prolonging survival and/or in delaying the development of AIDS-related illness in HIV-infected patients.
The Prevention of Opportunistic Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) recommends primary prophylaxis against PCP in HIV-infected adults and adolescents with CD4 T-cell counts less than 200/ mm or a history of oropharyngeal candidiasis. HIV-infected adults and adolescents with a CD4 T-cell percentage of less than 14% or a history of an AIDS-defining illness who do not otherwise qualify for prophylaxis also should be considered for primary prophylaxis. If CD4 T-cell counts are monitored less frequently than every 3 months, individuals with CD4 T-cell counts of greater than 200 but less than 250/ mm also should be considered for primary prophylaxis.
The USPHS/IDSA recommends oral co-trimoxazole as the drug of choice for primary prophylaxis of PCP in HIV-infected individuals. When co-trimoxazole is used for the primary prevention of PCP in adults and adolescents, the preferred dosage regimen is 160 mg of trimethoprim (as co-trimoxazole) daily. This regimen also provides prophylaxis against Toxoplasma gondii and some common respiratory bacterial infections. Alternatively, 80 mg of trimethoprim (as co-trimoxazole) daily or 160 mg of trimethoprim (as co-trimoxazole) 3 times a week can be used. For individuals who experience an adverse reaction to co-trimoxazole that is not life-threatening, the USPHS/IDSA recommends that the drug be continued if feasible; for individuals who have discontinued the drug because of an adverse effect, reinstitution of co-trimoxazole should be considered once the adverse effect has resolved. Patients who have experienced adverse effects, especially fever and rash, may tolerate reintroduction of co-trimoxazole better with a gradual increase in dose (desensitization) or reintroduction of the drug at a reduced dose or frequency of administration. Alternative regimens that can be used in patients who cannot tolerate co-trimoxazole include dapsone, dapsone with pyrimethamine and leucovorin, aerosolized pentamidine, or atovaquone.
Current evidence indicates that primary PCP prophylaxis can be discontinued in adults and adolescents responding to potent antiretroviral therapy who have a sustained (3 months or longer) increase in CD4 T-cell counts from less than 200/ mm to greater than 200/ mm. Patients included in studies evaluating discontinuance of prophylaxis generally were receiving primary prophylaxis and antiretroviral regimens that included HIV protease inhibitors; median follow-up ranged from 6-16 months and median CD4 T-cell count at the time prophylaxis was discontinued exceeded 300/ mm. In addition, at the time prophylaxis was discontinued, most patients had CD4 T-cell counts exceeding 200/ mm for at least 3 months and many patients had sustained plasma HIV-1 RNA levels below the detection limits of the available assays. The USPHS/IDSA states that discontinuance of primary PCP prophylaxis is recommended in patients who have sustained a CD4 T-cell count exceeding 200/ mm for at least 3 months because such prophylaxis appears to add little benefit in terms of disease prevention (PCP, toxoplasmosis, bacterial infections) and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost. However, the USPHS/IDSA states that primary PCP prophylaxis should be restarted if the CD4 T-cell count decreases to less than 200/ mm.
Prevention of Recurrence
The USPHS/IDSA recommends long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) in HIV-infected adults and adolescents who have a history of PCP to prevent recurrence. The same regimens recommended for primary prophylaxis are used for suppressive therapy. Secondary prophylaxis generally is administered for life, unless immune recovery has occurred as a result of potent antiretroviral therapy.
Current evidence indicates that secondary PCP prophylaxis can be discontinued in HIV-infected adults and adolescents responding to potent antiretroviral therapy who have a sustained (3 months or longer) increase in CD4 T-cell counts from less than 200/ mm to greater than 200/ mm. Patients in studies evaluating discontinuance of secondary prophylaxis had responded to potent antiretroviral therapy with an increase in CD4 T-cell count to greater than 200/ mm for at least 3 months. Most patients were receiving an antiretroviral regimen that included HIV protease inhibitors; the median CD4 T-cell count at the time prophylaxis was discontinued was greater than 300/ mm and most patients had sustained plasma HIV-1 RNA levels below the detection limits of the available assays. The longest follow-up was 13 months. The USPHS/IDSA states that discontinuance of secondary PCP prophylaxis in adults and adolescents who have a sustained (3 months or longer) increase in CD4 T-cell counts to greater than 200/ mm is recommended because such prophylaxis appears to add little benefit in terms of disease prevention (PCP, toxoplasmosis, bacterial infections) and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost. However, in patients who had PCP episodes when they had CD4 T-cell counts exceeding 200/ mm, it probably is prudent to continue secondary PCP prophylaxis for life regardless of how high the CD4 T-cell count increases in response to potent antiretroviral therapy.
If secondary PCP prophylaxis is discontinued in HIV-infected adults or adolescents meeting the recommended criteria, the USPHS/IDSA recommends that it be restarted if the CD4 T-cell count decreases to less than 200/ mm or if PCP recurs at a CD4 T-cell count exceeding 200/ mm.
Prophylaxis in HIV-Infected Children
The CDC, American Academy of Pediatrics (AAP), USPHS/IDSA, and most clinicians recommend antimicrobial prophylaxis for PCP in selected HIV-infected children. This recommendation is based on the high mortality rate associated with PCP in infants and children and the established efficacy of prophylaxis in HIV-infected adults; it is unlikely that placebo-controlled studies will ever be performed in HIV-infected children. PCP is the most common serious HIV-associated opportunistic infection among children, occurring in more than 50% of those with perinatally acquired HIV infection that progresses to AIDS within the first year of life, and in about 40% of pediatric AIDS cases overall. In children with perinatally acquired HIV infection, PCP occurs most often at 3-6 months of age. Despite the availability of effective anti-infectives for the treatment of P. jiroveci infections, the median survival from the first episode in infants and children is 1-4 months; among AIDS cases reported to CDC, 35% of children with PCP died within 2 months of diagnosis. Overall, about 90% of children with PCP died and 70% survived for less than 6 months in one retrospective study despite active treatment with co-trimoxazole and/or pentamidine. Therefore, current strategies should be aimed at preventing initial and subsequent infection with the protozoa in children at high risk for HIV infection by initiating early prophylactic therapy.
The CDC, USPHS/IDSA, AAP, and other experts recommend that all infants born to HIV-infected women receive primary PCP prophylaxis starting at 4-6 weeks of age, regardless of their CD4 T-cell count. Infants who are first identified as being HIV-exposed after 6 weeks of age should receive prophylaxis beginning at the time of identification. Because of the potential for adverse drug effects in neonates and the low incidence of P. jiroveci infection in this age group, primary but not secondary prophylaxis should be delayed until 1 month of age. Prophylaxis can be discontinued in children who are found not to be infected with HIV. All HIV-infected infants and infants whose infection status has not yet been determined should continue prophylaxis until 12 months of age.
The need for subsequent prophylaxis should be based on age-specific CD4 T-cell count thresholds. In HIV-infected children 1-5 years of age, primary prophylaxis against PCP should be initiated if CD4 T-cell counts are less than 500/ mm or the CD4 percentage is less than 15%. In HIV-infected children 6-12 years of age, primary prophylaxis against PCP should be initiated if CD4 T-cell counts are less than 200/ mm or the CD4 percentage is less than 15%.
The USPHS/IDSA recommends oral co-trimoxazole as the drug of choice for the primary and secondary (suppressive or chronic maintenance therapy) prevention of PCP in HIV-infected infants and children. When co-trimoxazole is used for the primary or secondary prevention of PCP, the preferred dosage regimen is 150 mg/m of trimethoprim (as co-trimoxazole) daily in 2 divided doses for 3 consecutive days each week. Alternatively, this dose can be administered as a single dose for 3 consecutive days each week, in 2 divided doses daily, or in 2 divided doses 3 times a week on alternate days. Alternative regimens that can be used in HIV-infected infants and children include dapsone, aerosolized pentamidine, or atovaquone.
The safety of discontinuing primary or secondary PCP prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied. Children who have a history PCP should receive life-long suppressive therapy to prevent recurrence.
The USPHS/IDSA recommends that, shortly after being diagnosed with HIV infection, all HIV-infected individuals be tested for IgG antibody to Toxoplasma to detect latent infection with T. gondii. HIV-infected individuals (particularly those seronegative for Toxoplasma antibody) should be counseled concerning the various sources of toxoplasmic infection and how best to avoid these sources, including avoiding raw or undercooked meat, washing raw vegetables, hand washing after contact with raw meat or soil, and hand washing after changing cat litter boxes. The USPHS/IDSA recommends that all HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and who have CD4 T-cell counts less than 100/ mm receive primary prophylaxis against toxoplasmic encephalitis. Primary prophylaxis against toxoplasmosis encephalitis generally is recommended for HIV-infected infants and children with severe immunosuppression who are seropositive for Toxoplasma IgG antibody. Co-trimoxazole is the drug of choice for primary prophylaxis against toxoplasmosis encephalitis and dosages of the drug recommended for prophylaxis against PCP appear to be effective against toxoplasmosis encephalitis. When co-trimoxazole is used for primary prevention of toxoplasmosis encephalitis in adults and adolescents, the preferred dosage regimen is 160 mg of trimethoprim (as co-trimoxazole) daily. In patients who cannot tolerate co-trimoxazole, regimens used for primary prophylaxis of PCP that consist of dapsone with pyrimethamine and leucovorin also provide protection against toxoplasmosis encephalitis. Atovaquone with or without pyrimethamine and leucovorin also can be used for primary prophylaxis against toxoplasmosisencephalitis. However, aerosolized pentamidine does not provide protection against toxoplasmosis encephalitis and regimens consisting of dapsone, pyrimethamine, azithromycin, or clarithromycin used alone cannot be recommended for prophylaxis against toxoplasmosis encephalitis based on current data.
HIV-infected individuals who are seronegative for Toxoplasma antibody and who are not currently receiving primary PCP prophylaxis with a regimen known to be active against toxoplasmosis encephalitis should be retested for Toxoplasma antibody if their CD4 T-cell count falls below 100/ mm to determine whether they have seroconverted, are now at risk for toxoplasmosis encephalitis, and have become candidates for primary prophylaxis against the infection.
Current evidence indicates that primary prophylaxis can be discontinued with minimal risk of developing toxoplasmic encephalitis in HIV-infected adults and adolescents responding to potent antiretroviral therapy who have a sustained (3 months or longer) increase in CD4 T-cell counts from less than 200/ mm to greater than 200/ mm. Patients included in these studies generally were receiving primary prophylaxis and antiretroviral regimens that included HIV-protease inhibitors; median follow-up ranged from 7-22 months and median CD4 T-cell count at the time prophylaxis was discontinued exceeded 300/ mm. At the time prophylaxis was discontinued, many patients had sustained plasma HIV-1 RNA levels below the detection limits of the available assays. While patients with CD4 T-cell counts below 100/ mm are at greatest risk for toxoplasmic encephalitis, the risk in patients whose CD4 T-cell counts have increased to 100-200/ mm has not been studied as extensively as in those whose CD4 T-cell counts have increased to greater than 200/ mm. Therefore, the recommendation to discontinue primary toxoplasmosis prophylaxis specifies that prophylaxis can be discontinued when the CD4 T-cell count exceeds 200/ mm. The USPHS/IDSA states that discontinuation of primary toxoplasmosis prophylaxis is recommended in adults and adolescents who have a sustained (3 months or longer) increase in CD4 T-cell counts to greater than 200/ mm because such prophylaxis appears to add little benefit in terms of disease prevention for toxoplasmosis, and discontinuance reduces the pill burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.
If primary toxoplasmosis prophylaxis is discontinued in adults and adolescents meeting the recommended criteria, the USPHS/IDSA states that it should be restarted if the CD4 T-cell count decreases to less than 100-200/ mm.
The safety of discontinuing primary toxoplasmosis prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.
Prevention of Recurrence
The USPHS/IDSA recommends that HIV-infected individuals who have had toxoplasmic encephalitis receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent relapse. Secondary toxoplasmosis prophylaxis generally is administered for life, unless immune recovery has occurred as a result of potent antiretroviral therapy.
The USPHS/IDSA states that the regimen of choice for secondary prophylaxis to prevent relapse of toxoplasmosis in HIV-infected adults, adolescents, infants, and children is a regimen of sulfadiazine and pyrimethamine (with leucovorin). In patients who cannot tolerate sulfonamides, a regimen of clindamycin and pyrimethamine (with leucovorin) is recommended; a regimen of atovaquone with or without pyrimethamine (with leucovorin) also is an alternative in adults and adolescents; Co-trimoxazole is not recommended for secondary toxoplasmosis prophylaxis.
For information on USPHS/IDSA recommendations regarding secondary prophylaxis of toxoplasmosis in HIV-infected individuals, including when to initiate or discontinue such prophylaxis,
Co-trimoxazole has reportedly produced beneficial responses in a limited number of patients with Wegener's granulomatosis, but further study is needed. Prolonged remissions have been observed in many of these patients, including some whose disease relapsed while receiving conventional therapy (e.g., cyclophosphamide), and co-trimoxazole therapy may reduce or eliminate the need for cytotoxic (e.g., cyclophosphamide) and corticosteroid therapy. Relapse has occurred occasionally during co-trimoxazole therapy but may respond to supplemental dosages of trimethoprim or the addition of small dosages of cytotoxic therapy. The precise role of co-trimoxazole in the management of Wegener's granulomatosis and the drug's effect on long-term morbidity and mortality remain to be determined, but the drug appears to be a useful alternative to more toxic drugs (e.g., cyclophosphamide) in some patients.
Co-trimoxazole is used in the treatment of Whipple's disease caused by Tropheryma whippelii.