Preventing Opportunistic Infections in Patients With HIV 

Updated: Mar 03, 2016
  • Author: David R Haburchak, MD, FACP; Chief Editor: John Bartlett, MD  more...
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General Guidelines for Prophylaxis

Prevention of opportunistic infections in patients with HIV disease is important to optimize outcome. All HIV-related infections and malignancies escalate in frequency and morbidity as the absolute CD4 T-lymphocyte count falls toward 200 cells/μL and below. Therefore, the CD4 count must be current to within 4 months to determine the risk of infection in a specific patient and serve as an impetus to drug prophylaxis or other interventions. Patients should be aware of their CD4 count and their risk of specific infections.

All HIV-infected individuals are susceptible to a wide array of opportunistic infections and are at higher risk to pathogenic organisms that plague the general population. Behaviors and the social environment of HIV-positive patients may place them at higher risk of venereal, skin, pulmonary, gastrointestinal, and liver infections than the general population, as well as infectious-related malignancies such as lymphoma, cervical, anal, and liver cancer.

Besides causing morbidity and mortality by themselves, opportunistic infections accelerate the progression of HIV disease itself. [1] For this reason, current guidelines emphasize concurrent antiretroviral therapy (ART) with prophylaxis, treatment, secondary prophylaxis, or continuation therapy of opportunistic infections. Timing of ART warrants thoughtful consideration and knowledge of particular immunological, psychosocial, and economic considerations in the specific patient.

The most recent guidelines from the US Centers for Disease Control and Prevention, National Institutes of Health, and the Infectious Diseases Society of America (CDC/NIH/IDSA) emphasize early HIV detection and the supervised use of ART to maintain cellular immunity before reaching risky CD4 levels. Additionally, early effective HIV viral suppression is recommended to possibly decrease the rate of HIV transmission to others. [1]

The recommendations below use evidence-based criteria as published by the CDC/NIH/IDSA that summarize the strength of the recommendation and quality of the evidence as of December 2015: [1]

Strength of recommendation is as follows:

  • A: Strong recommendation for the statement
  • B: Moderate recommendation for the statement
  • C: Optional recommendation for the statement

Quality of evidence for the recommendation is as follows:

  • I: One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
  • II: One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
  • III: Expert opinion
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Exposure Avoidance

Recommending exposure avoidance is always appropriate, but usually difficult to implement except in the most compulsive patients. Nevertheless, persons infected with HIV should practice appropriate hygiene and dietary precautions, such as avoiding the following: [1]

  • Cat litter and excreta or saliva of farm animals, wild animals, and pets
  • Animal bites and scratches
  • Persons with skin infections
  • Raw meats, eggs, and shellfish; unwashed raw fruits and vegetables
  • Unpasteurized dairy products
  • Drinking untreated lake or river water
  • Human fecal-oral contact

HIV-infected individuals should also limit occupational or recreational exposure to dirt as much as possible in geographical locales with hyperendemic fungal disease (eg, histoplasmosis, coccidioidomycosis, Penicillium marneffei infection). [2]

Specially treated water is not helpful. [1]

Use of male latex condoms is strongly recommended for preventing transmission of HPV and other sexually transmitted diseases. In situations in which male latex condoms cannot be used properly, an FC1 or FC2 Female Condom should be considered for heterosexual vaginal intercourse (AII recommendation) or male same-sex anal intercourse (BIII recommendation). [1]

Drug, alcohol, and tobacco abuse prevention and therapy should be part of any HIV disease management program.

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Initiation of Prophylaxis and Treatment

Despite increasingly widespread HIV screening, many HIV infections continue to be diagnosed late and after opportunistic infections have already developed. [3] Such patients usually have very low CD4 counts and need prompt treatment and secondary prophylaxis for the presenting opportunistic infection, as well as additional CD4 count–appropriate primary prophylaxis.

In most instances, such preventive therapy is applied prior to the initiation of antiretroviral therapy (ART). Many of these patients have significant psychiatric, social, and economic problems, as well as major medical comorbidities and drug abuse. The healthcare team must address and control these issues if prophylaxis is to be successful; this requires motivation and cooperation on the part of the patient. [4]

Clinicians should withhold ART from asymptomatic patients until the patient has demonstrated mastery of the prophylactic regimen or directly observed therapy can be assured. Exceptions include cases in which renal, hematologic, or neurologic disease is directly attributed to HIV viremia.

Clinicians must weigh the complexity of pill burden, risk of toxicity, and the benefits of co-initiation of ART for patients first presenting with opportunistic infection and Kaposi sarcoma at the time of presentation. Early ART (within 2 wk) is indicated for patients presenting with Pneumocystis carinii pneumonia (PCP), toxoplasmosis encephalitis, and pulmonary tuberculosis. Patients not taking ART who present with disseminated Mycobacterium avium complex (MAC) infection should be treated for the infection without ART for 2 weeks, and then started as soon as possible on ART while monitored closely for symptoms of the immune reconstitution inflammatory syndrome (IRIS). Severe IRIS has also been reported after early ART in the management of cryptococcal and tuberculous meningitis, and it has been suggested that such patients delay ART until 4-6 weeks after control of the opportunistic infection. Patients with CD4 counts of less than 50 cells/μL at presentation should be considered for cryptococcal antigen testing, and, among those diagnosed with cryptococcal meningitis, initial ART should be delayed at least 2 weeks into cryptococcal therapy and as long as 10 weeks. [1]

The following CD4 counts are useful landmarks for initiation of antimicrobial prophylaxis:

  • Less than 250 cells/μL - Coccidioidomycosis prophylaxis if seropositive in high-risk area
  • Less than 200 cells/μL - PCP prophylaxis
  • Less than 150 cells/μL - Histoplasmosis prophylaxis if high-risk exposure
  • Less than 100 cells/μL - Toxoplasmosis prophylaxis (if seropositive)
  • Less than 100 cells/μL - Penicilliosis prophylaxis if living in high-risk area
  • Less than 50 cells/μL - MAC infection prophylaxis
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Risks of Prophylaxis

Prior to initiation of prophylaxis, the clinician should attempt to clinically exclude active disease, as the prophylactic regimen may not suffice in aborting uncontrolled infection or may even mask signs of infection. In most cases, obtaining a thorough history and conducting an examination with symptom-targeted laboratory and radiologic tests are enough to exclude active P carinii pneumonia (PCP), M avium complex (MAC) infection, and tuberculosis.

Adverse drug reactions to prophylactic therapy are common and should be expected. Patients should completely understand the purpose of the prophylaxis, the possible adverse effects, and what to do if they occur. Typical toxicities include the following:

  • Trimethoprim-sulfamethoxazole - Rash and neutropenia
  • Dapsone - Rash; anemia; methemoglobinemia, especially if G-6-PD deficient
  • Azithromycin - Gastrointestinal distress (pain and diarrhea)
  • Pyrimethamine - Leukopenia
  • Itraconazole - Hepatitis (hepatitis is less likely with fluconazole)
  • Atovaquone - Headache, nausea, diarrhea, rash, transaminase elevation

As patients live longer with long-term immunosuppression and control of the HIV virus, they often accumulate multiple comorbid conditions associated with early aging. These include renal and hepatic disease, hyperlipidemia, lung disease, and heart disease. Drug-drug interactions with antiretroviral therapy and prophylactic drugs is inevitable. Automated drug screens used by pharmacies often alert the physician to unanticipated potential interactions of variable significance. Finding one's way through the maze of therapy benefits from the assistance of a pharmacy HIV specialist, especially in moderate to large clinics.

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Initial Tests and Prophylactic Regimens

On the patient's first visit, serologies for syphilis; hepatitis A, B, and C; and toxoplasmosis should be obtained. Although some authorities recommend that cytomegalovirus (CMV) serology be performed, in 30 years, the author has very rarely encountered patients with negative results.

Urine chlamydial and gonorrheal nucleic acid amplification testing should be performed in all patients with newly diagnosed HIV infection; however, positive results should be confirmed because of relatively low specificity. Similarly, patients who participate in oral or anal receptive intercourse should undergo chlamydial and gonorrheal nucleic acid amplification testing. Women should be evaluated for trichomoniasis. A purified-protein derivative (PPD) skin test should be placed unless a prior positive result for tuberculosis has been documented. An interferon-gamma release assay may be sufficiently sensitive for one-step testing, [5] but false-negative test results are common in advanced immunodeficiency. [1]

Pneumococcal PCV13 vaccine should be administered on the first visit, and on subsequent visits, vaccines for hepatitis A, hepatitis B, diphtheria-tetanus, and influenza should be administered as indicated by serology results, history, and season, respectively. Patients should be given the PPV23 vaccine at least 8 weeks after the PCV13, if it has not already been administered. All live vaccines should be avoided in HIV-infected patients, with the possible exception of measles and varicella vaccines in immunocompetent patients (in general, CD4 count >200 cells/μL). [1] (For general information on vaccines, see the Medscape Vaccines Resource Center.)

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Monitoring Patient Compliance

Once initiated, prophylaxis should be accompanied by education from a trained educator and such teaching documented. The same educator should reinforce later antiretroviral therapy (ART). At each visit, patients should bring their prescription bottles and explain their purpose. Failure to give correct answers or to bring bottles warrants a return visit to the educator.

As patients improve and CD4 counts rise, prophylaxis can often be terminated. The containers of terminated drugs may need to be removed from patients’ possession, and repeated calls and email messages may need to be sent to the pharmacy to ensure cessation of delivery of the drugs to the patient. Continuing unnecessary medication could be a significant problem, especially with computerized prescribing, unless specific efforts are made to stop the drug.

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Clinical Landmarks for Terminating Primary Prophylaxis

Mycobacterium avium-intracellulare (MAI) infection prophylaxis, once started, should be continued with antiretroviral therapy (ART) until the CD4 count exceeds 100 cells/μL for 3 months. [6] Similarly, P carinii pneumonia (PCP)and toxoplasmosis prophylaxis should be continued until the CD4 count exceeds 200 cells/μL for 3 months. [7] Histoplasmosis prophylaxis can be discontinued when the CD4 count has exceeded 150 cells/μL for 6 months, coccidioidomycosis prophylaxis when CD4 counts exceed 250 cells/μL for 6 months, and penicilliosis prophylaxis when CD4 counts exceed 100 cells/μL for 6 months.

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Primary Prophylaxis as the Standard of Care

P carinii pneumonia (PCP)

Indications for prophylaxis include a CD4 cell count of fewer than 200 cells/μL (AI recommendation) or history of oropharyngeal candidiasis (AII recommendation). The preferred regimen is trimethoprim-sulfamethoxazole 1 double-strength tablet orally daily or 1 double-strength tablet orally 3 times weekly. Alternatives include dapsone 100 mg orally daily (however, see toxoplasmosis), aerosolized pentamidine 300 mg administered via the Respirgard II nebulizer monthly, or atovaquone suspension 750 mg (5 mL) orally twice daily.

Latent Mycobacterium tuberculosis infection (LTBI) and exposure

Screening for tuberculosis in the HIV-infected population has been suboptimal, with only 47-65% of patients completing screening. The most common predisposition for tuberculosis now is birth or residence outside of the United States. [1]

A course of prophylaxis (LTBI treatment) is indicated for all patients with a history of a positive tuberculin skin test result of 5 mm or greater or a US Food and Drug Administration (FDA)–approved interferon-gamma release assay who have not previously received such therapy (AI recommendation). HIV patients who are close contacts of a person with infectious tuberculosis, yet show no signs themselves of active tuberculosis, should be administered LTBI treatment regardless of screening results (AII recommendation). [1]

Active tuberculosis should be excluded by lack of symptoms and negative chest radiograph before prophylactic regimens are started. Active tuberculosis may be more likely in a patient with previous active tuberculosis (treated or untreated) than in a patient without a history of tuberculosis. [9, 10]

Regimens depend on the likelihood that the patient is infected with resistant tuberculous bacilli. The preferred regimen for probable infection with latent isoniazid-sensitive bacilli is isoniazid 300 mg plus pyridoxine 25 mg orally daily for 9 months (AII recommendation).

Patients with suspected isoniazid-resistant infection should receive prophylaxis with rifampin 600 mg daily for 4 months or rifabutin dose adjusted based on concomitant antiretroviral therapy (ART) used (BIII recommendation).

In patients with multidrug-resistant (MDR) tuberculosis or extensively drug-resistant (XDR) tuberculosis, public health authorities should be consulted for recommended regimens and supervision (AII recommendation). [1]

LTBI therapy and ART act independently to decrease the risk of active tuberculosis. Therefore, both should be used, but rifamycin drug interactions should be expected. Rifampin use requires increased dosing of raltegravir and maraviroc and discontinuation of etravirine, while rifabutin requires higher dosing with efavirenz, lower dosing with ritonavir-boosted protease inhibitors, and lower dose of maraviroc ART. [1]

Monthly monitoring of liver-associated enzymes during LTBI therapy is appropriate.

M avium complex (MAC) infection

Patients with CD4 count of fewer than 50 cells/μL should be given azithromycin 1200 mg orally weekly after ruling out disseminated MAC infection on clinical assessment (AI recommendation). Alternatives include clarithromycin 500 mg orally twice daily (AI recommendation) or rifabutin 300 mg orally daily with drug dose modifications noted above (BI recommendation).

Toxoplasma gondii infection

Patients with a CD4 count below 100 cells/μL who are not previously known to be seronegative for toxoplasmal immunoglobulin G (IgG) should receive prophylaxis for toxoplasmosis. Trimethoprim-sulfamethoxazole, one double-strength tablet orally once daily is preferred (AII recommendation). Dapsone alone is ineffective against toxoplasmosis. Therefore, dapsone 50 mg orally daily plus pyrimethamine 50 mg orally weekly plus leucovorin 25 mg orally weekly is appropriate for both PCP and toxoplasmosis (BI recommendation). Alternatively, atovaquone with or without pyrimethamine/leucovorin can be considered. [1]

Varicella-zoster virus infection

HIV-infected patients should generally avoid close contact with persons with zoster or chickenpox.

Because the varicella and zoster vaccines are live-virus vaccines, they should not be administered to persons with HIV and CD4 counts lower than 200 cells/µL (AIII recommendation). Persons without a prior history of chickenpox or previous vaccination who have a significant exposure to zoster or chickenpox should receive varicella-zoster immune globulin (VZIG) within 10 days (AIII recommendation) using a treatment IND (800-843-477, FFF Enterprises). [1]

Syphilis

Patients exposed to a sex partner with a diagnosis of primary, secondary, or early latent syphilis within the past 90 days should receive benzathine penicillin G 2.4 million units intramuscularly as a single dose (AII recommendation). [1]

Histoplasmosis

Patients with a CD4 count of less than 150 cells/μL at high risk for exposure or who live in a hyperendemic area should receive itraconazole 200 mg PO daily (BI recommendation). [1]

Coccidioidomycosis

Patients with a new positive immunoglobulin M (IgM) or IgG serologic test result who live in endemic areas and have a CD4 count of less than 250 cells/μL should receive fluconazole 400 mg PO daily (BIII recommendation). [1]

Penicilliosis

Patients with a CD4 count of less than 100 cells/μL living or staying in rural endemic areas of Southeast Asia should receive itraconazole 200 mg PO daily (BI recommendation). [1]

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Generally Recommended Vaccines

The availability of protein conjugated pneumococcal vaccine PCV13 has prompted change in the CDC/NIH/IDSA Guidelines for pneumococcal immunization. [1] All HIV-positive adolescents and adults who have never had a pneumococcal vaccine should receive a single dose of PCV13 at presentation (AI recommendation). If CD4 cell count is higher than 200 cells/µL, they should receive a 23 valent polysaccharide vaccine (PPV23) at least 8 weeks later (AII recommendation). Those with a CD4 cell count of less than 200 cells/µL should preferably wait until the CD4 count is higher than 200 cells/µL with antiretroviral therapy (ART) before receiving the PPV23 (BIII recommendation). PCV13 should be given to patients who have previously received PV23 (AII recommendation) more than a year prior (AII recommendation). [1]

Other recommended vaccinations are as follows:

  • Hepatitis B virus infection - All susceptible (anti-HBc-negative) patients should receive the 3-dose hepatitis B vaccine (AII recommendation)
  • Influenza virus infection- All patients should receive inactivated trivalent influenza vaccine annually before the influenza season (AIII recommendation)
  • Hepatitis A virus infection - All susceptible (anti-HAV-negative) patients should receive the 2-dose hepatitis A vaccine (AII recommendation)
  • Human papillomavirus (HPV) vaccine is now recommended by CDC/NIH/IDSA guidelines for 13- to 26-year–old HIV-positive males (quadrivalent or 9-valent) and females (bivalent or quadrivalent or 9-valent) (BIII recommendation) [1]  
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Rarely Indicated Primary Prophylaxis

Fungal or yeast infections

According to current guidelines, Cryptococcus neoformans and Candida infections do not warrant primary prophylaxis. [1]

Fortunately, aspergillosis and phycomycosis (mucormycosis) are rare in individuals infected with HIV. These infections should be considered in patients with invasive sinusitis and focal pulmonary lesions but do not warrant prophylaxis.

Travelers to malaria-prone areas should have malaria prophylaxis, and those who live in such areas should practice preventative measures, such as the use of treated mosquito netting.

Bacterial infections

Prophylaxis (primary or secondary) for the following community-acquired and healthcare-associated infections is seldom indicated, although these infections are not uncommon in patients infected with HIV:

Persons infected with HIV are at high risk for sexually transmitted diseases such as syphilis, chlamydia, and gonorrhea. These should be reported to authorities and treated with documented cure and provision of counseling to avoid reinfection. Individuals exposed to a sex partner with a diagnosis of primary, secondary, or tertiary syphilis should be treated prophylactically with benzathine penicillin G 2.4 million units intramuscularly one time (AII recommendation).

Nocardia infection is rare in even late stages of AIDS, probably because it is inhibited serendipitously by P carinii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole.

Protozoal and helminthic infections

Patients infected with HIV are at risk for infections with Cryptosporidium species, Giardia species, Isospora species, Cyclospora species, and Microsporidia species, as well as Entamoeba species and Strongyloidiasis species in some locales. Neither primary nor secondary prophylaxis is indicated. Concomitant malaria and HIV disease is a major problem in Africa, but trimethoprim-sulfamethoxazole may have some prophylactic benefit. [11]

Other viral infections

Recurrent genital and, occasionally, oral herpes simplex infections, zoster, molluscum contagiosum, and human papillomavirus infections are common. Primary infections are best avoided. Recurrent herpes simplex and zoster may be prevented with acyclovir 400 mg twice daily, continued indefinitely (AI recommendation). The efficacy of the human papillomavirus (HPV) vaccine to prevent warts and neoplasia is unknown in adult patients infected with HIV, but it is recommended for men and women aged 13-26 years (see above). [1]

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Secondary Prophylaxis

Secondary prophylaxis (now called maintenance therapy in the NIH/CDC guidelines) consists of therapy given to prevent relapse of known and appropriately treated opportunistic infections that have occurred prior to effective antiretroviral therapy (ART). For most of these infections, the initial treatment is much more intensive and may last for 2-4 weeks, followed by the secondary prophylaxis regimen. This is particularly noteworthy for cryptococcal meningitis, which must be treated initially with amphotericin and flucytosine.

For P carinii pneumonia (PCP), the recommended secondary prophylaxis is trimethoprim-sulfamethoxazole, a double-strength tablet orally daily (AI recommendation), until the CD4 count exceeds 200 cells/μL for 3 months (BII recommendation).

For toxoplasmosis, the following is recommended: sulfadiazine 500-1000 mg orally 4 times daily plus pyrimethamine 25-50 mg orally daily and leucovorin 10-25 mg orally daily (AI recommendation) until the CD4 count exceeds 200 cells/μL for 6 months (AIII recommendation). An additional agent must be added to prevent PCP.

For tuberculosis, it is important to collect specimens for culture and probes before therapy is started. Initial-phase therapy consists of 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol daily or 5-7 times per week per directly observed therapy (AI recommendation). The continuation phase, after ensuring drug susceptibility and repeat cultures, consists of daily isoniazid and rifampin or rifabutin for 6 months for pulmonary tuberculosis, 9 months for pulmonary tuberculosis in which cultures remained positive after the initial two months of therapy, 9-12 months for extrapulmonary tuberculosis with CNS involvement, 6-9 months for extrapulmonary tuberculosis with bone or joint involvement, and 6 months for disease limited to other sites (all BII recommendations).

For M avium complex (MAC) infection, the following is recommended: clarithromycin 500 mg orally twice daily plus ethambutol 15 mg/kg orally daily with or without rifabutin 300 mg orally daily for 12 months until patients have no signs or symptoms of MAC disease and until the CD4 count is greater than 100 cells/μL for 6 months (AII recommendation).

For cytomegalovirus (CMV) retinitis, maintenance therapy for immediate vision-threatening lesions close to the fovea consists of intravitreal injections of ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection) for 1-4 doses over 7-10 days (AIII recommendation) plus valganciclovir 900 mg PO BID for 14-21 days, then 900 mg PO once daily (AI recommendation). Therapy for peripheral lesions consists of systemic antiviral therapy (various regimens of ganciclovir, valganciclovir, foscarnet, and cidofovir) (AII recommendation). Maintenance therapy for central or peripheral lesions should be continued for at least 3-6 months and until lesions are inactive and the CD4 count has risen to more than 100 cells/μL (AII recommendation). Maintenance therapy should be stopped only after ophthalmological consultation. Quarterly retinal examinations are indicated during the follow-up period after stopping therapy (AIII recommendation). The duration of initial therapy for CMV gastrointestinal disease is 21-42 days or until signs and symptoms have resolved (CII recommendation). The use of maintenance therapy for CMV gastrointestinal, pulmonary, or neurological disease is not established but should probably be individualized, especially during relapses or immune reconstitution reactions.

For cryptococcal meningitis, after initial liposomal amphotericin and flucytosine therapy for at least 2 weeks, give fluconazole 400 mg orally or intravenously daily as "consolidation" therapy (AI recommendation). This should be followed by "maintenance" therapy with fluconazole 200 mg PO daily for at least 1 year (AI recommendation) and until the CD4 count exceeds 100 cells/μL for 3 months (BII recommendation).

Similarly, initial treatment for moderate to severely disseminated histoplasmosis consists of liposomal amphotericin B for induction of at least two weeks, followed by maintenance therapy consisting of itraconazole 200 mg TID for 3 days and then 200 mg BID for 12 months (AII recommendation).

Coccidioidomycosis infections are usually treated with fluconazole for mild disease or amphotericin for severe disease, followed by long-term suppressive therapy with oral fluconazole 400 mg daily or oral itraconazole 200 mg PO BID (AII recommendation).

For mucocutaneous and esophageal Candida infection, long-term suppressive therapy is usually not indicated or necessary, especially if the CD4 count rises above 200 cells/μL (BIII recommendation). Frequent or long-term therapy can result in resistance. If the decision is made to use suppressive therapy, use fluconazole 100 mg orally daily or 3 times weekly for oropharyngeal disease (BI recommendation), fluconazole 100-200 mg orally daily for esophageal disease (BI recommendation), or fluconazole 150 mg orally weekly for vulvovaginal disease (BII recommendation).

For recurrent herpes simplex infection, valacyclovir 500 mg PO BID or acyclovir 400 mg PO daily is recommended as long-term suppression (AI recommendation). The ongoing need for continued suppression should be evaluated yearly as the CD4 cell count rises with antiretroviral therapy.

For recurrent methicillin-resistant S aureus (MRSA) infection, the recommendation is mupirocin 2% nasal ointment to each nostril twice daily for 5 days if colonization is documented. Long-term efficacy is uncertain, and resistance may develop. Germicidal soaps have been recommended for perineal colonization, but little evidence suggests efficacy. Hygienic measures should be emphasized [12] for this epidemic problem. [13]

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