Treatment

Patients with AFB positive smears from sputum samples should be started on anti-TB therapy while awaiting results of PCR and cultures. The treatment of TB always uses multiple agents with anti-TB activity. Single agents should never be used. The standard first-line agents are isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Figure 16-3 and Table 16-6). If administered, INH should be given with pyridoxine (vitamin B6; 25-50 mg orally daily) to prevent neuropathy. Treatment of active pulmonary TB is generally for 6 months regardless of HIV status, but treatment may need to be extended in certain situations.

Directly observed therapy (DOT) is the preferred mechanism of administration to ensure compliance. Many local county and state health departments have systems for DOT. Treatment of HIV-seropositive patients with TB who are receiving an antiretroviral (ARV) regimen that contains a protease inhibitor is complicated by the latter's interaction with rifa-mycins (particularly rifampin). Management of such patients should be coordinated with an infectious diseases specialist, who also should manage drug-resistant TB treatment.

Latent Tuberculosis Infection and Purified Protein Derivative

In the United States, latent tuberculosis infection (LTBI) is the most prevalent form of tuberculosis. LTBI is the term given to patients with a positive purified protein derivative (PPD) skin test without evidence of active TB. PPD has been used for more than 100 years and relies on delayed-type hypersensitivity (DTH) to M. tuberculosis cellular proteins.

Time (months)

Figure 16-3 Treatment algorithm for tuberculosis. Patients in whom TB is proved or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph or the acid-fast smear is positive at completion of 2 months of treatment, the continuation phase of treatment should consist of isoniazid and rifampin daily or twice weekly for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial chest radiograph and the culture at completion of 2 months' therapy is positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4+ cell count is less than 100/mm3, the continuation phase should consist of daily or three-times-weekly isoniazid and rifampin. In HIV-uninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once-weekly isoniazid and rifapentine, or daily or twice-weekly isoniazid and rifampin, to complete a total of 6 months (bottom). Patients receiving isoniazid and rifapentine, and whose 2-month cultures are positive, should have treatment extended by an additional 3 months (total of 9 months). "EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. tPZA may be discontinued after it has been taken for 2 months (56 doses).

¿RPT should not be used in HIV-infected patients with TB or in patients with extrapulmonary TB. Therapy should be extended to 9 months if 2-month culture is positive. AFB, Acid-fast bacilli; CXR, chest radiograph (x-ray); EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine.

From Centers for Disease Control and Prevention (CDC), Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America, MMWR 2003;52(RR-ll):l-88,

Because PPD relies on DTH, any factor that reduces the DTH affects the host response to PPD. The most common clinical example is use of corticosteroids, which blunt the DTH response and can complicate PPD interpretation. Therefore, PPD testing should not be performed while a patient is taking corticosteroids. Also, TB testing should be targeted to those with higher risk of infection and should not routinely be done in those with low risk (ATS/CDC, 2000).

The PPD can also give false-positive results in patients with previous bacille Calmette-Guérin (BCG) vaccination or with infection by other mycobacterial infections. In the United States, this may cause difficulties in testing immigrants from countries who routinely use BCG vaccination programs. However, previous BCG vaccination should not change the interpretation of the PPD or willingness to treat such individuals accordingly.

Table 16-6 Recommended Treatment Regimens for Pulmonary Tuberculosis

Initial Phase

Continuation Phase

Rating* (Evidence)*

Drugs

Interval and doses| (minimal duration)

Regimen

Drugs

Interval and doses| § (minimal duration)

Range of total doses (minimal duration)

HIV Positive

HIV Negative

PZA

7 days per week for 55 doses (8 wk) or 5 d/wk for 40 doses (8 wk)11

1a

INH/RIF

7 d/wk for 126 doses (18 wk) or 5 d/wk for 90 doses (18 wk)1

182-130(26 wk)

A (I)

A (II)

EMB

1b

INH/RIF

Twice weekly for 36 doses(18 wk)

92-76(26 wk)

A (I)

A (II)1

1c"

INH/RPT

Once weekly for 18 doses(18 wk)

74-58(26 wk)

B (I)

E (I)

Regimen 2

INH RIF

7 days per week for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 d/wk for 10 doses (2 wk),1 then twice weekly for 12 doses (6 wk)

2a

INH/RIF

Twice weekly for 36 doses (18 wk)

62-58(26 wk)

A (II)

B (II)1

PZA EMB

2 b"

INH/RPT

Once weekly for 18 doses(18 wk)

44-40(26 wk)

B (I)

E(I)

PZA EMB

Three times weekly for 24 doses (8wk)

3

INH/RIF

Three times weekly for 54 doses (18wk)

78 (26 wk)

B (I)

B(II)

Regimen 4

INH RIF EMB

7 days per week for 56 doses (8wk) or 5d/wk for 40 doses (8wk) 1

4a

INH/RIF

7 days per week for 217 doses (31wk) or 5d/wk for 155 doses (31 wk)11

273-195(39 wk)

C (I)

C (III)

4b

INH/RIF

Twice weekly for 62 doses (31wk)

118-102(39 wk)

C (I)

C (III)

From American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR 2003;52:1-77.

DOT, Directly observed therapy; EMB, ethambutol, INH, isoniazid; PZA, pyrazinamide; RIE, rifampin; RPT, rifapentine.

'Definitions of evidence ratings: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; E, should never be given.

definition of evidence ratings: I, randomized clinical trial; II, data from clinical trials that were not randomized or were conducted in other populations; III, expert opinion. ¿When DOT is used, drugs may be given 5 days per week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice.

§Patients with cavitation on initial chest radiograph and positive cultures on completion of 2 months of therapy should receive a 7-month (31 weeks, either 217 doses [daily] or 62 doses [twice weekly]) continuation phase.

1Five-days-a-week administration is always given by DOT. Rating for 5 day per week regimens is AIII. 11Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/^L.

**Options 1c and 2 b should be used only in HIV-negative patients who have negative sputum smears at completion of 2 months of therapy and who do not have cavitation on initial chest radiograph. For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months.

The DTH response can wane over time. To overcome this problem, nonreacting patients may undergo repeat PPD 1 week after their initial PPD. The diagnosis of LTBI is made by interpretation of a PPD and by ascertaining the patient's risk factors for progression to active TB if left untreated (Box 16-3). Interpretation of the PPD should be based on the area of induration and not the area of surrounding erythema. Persons whose PPDs have converted from negative to positive within 2 years are presumed to have been infected recently. The decision to use PPD means treating the patient for LTBI if the PPD test is positive.

Patients at increased risk for progression to active TB include those who have been recently infected (recent PPD converters); patients who are HIV seropositive; patients who have silicosis, diabetes, or chronic renal failure (including those receiving hemodialysis); solid-organ transplant recipients; patients with gastrectomy or jejunoileal bypass or head and neck cancer; injection drug users; patients with chest radiograph evidence of prior TB; and patients who weigh at least 5% less than ideal body weight. Patients taking chronic corticosteroid therapy and those who are to receive tumor necrosis factor alpha (TNF-a) blockers (e.g., infliximab) are also at risk. Patients taking corticosteroids also have higher risk of progression to active TB with larger doses and longer courses of corticosteroids.

Standard therapy for LTBI is INH, 300 mg orally daily for 9 months, regardless of HIV status. Again, INH should always be administered with pyridoxine to prevent neuropathy.

Interferon-y Release Assays

To overcome the false-positive results and confusion of PPD testing in certain populations, newer interferon-gamma (IFN-y) release assays such as the Quantiferon-TB Gold (QFT-G) test have been developed to detect latent M. tuberculosis.

Box 16-3 Criteria for Tuberculin Positivity by Risk Group

Reaction >5mm of Induration

HIV-positive persons

Recent contacts of tuberculosis patients

Fibrotic changes on chest radiography consistent with prior tuberculosis

Patients with organ transplants and other immunosuppressed patients (receiving equivalent of >15 mg/day of prednisone for at least 1 month)

Reaction >10 mm of Induration

Recent immigrants (within 5 years) from high-prevalence countries Injection drug users

Residents and employees of high-risk congregate settings (prisons and jails, nursing homes, hospitals and other health care facilities, residential facilities for patients with AIDS, and homeless shelters) Children less than 4 years of age, or infants, children, and adolescents exposed to adults at high risk.

Reaction >15 mm of Induration

Person with no risk factors for tuberculosis

Modified from Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR 2000;49(RR-6):1-51.

QFT-G quantifies the release of IFN-y from lymphocytes of the host's blood in response to three M. tuberculosis target antigens that are absent from BCG and most other nontuber-culous Mycobacterium spp. The advantages of using QFT-G include one-time blood testing without the need for follow-up visit, no triggering of amnestic responses, and possibly more specific response to M. tuberculosis. However, QTF-G use in immunocompromised or anergic patients is limited, with indeterminate results. Some studies also show discordant results in individuals tested with both PPD and QTF-G. In general, QTF-G may be used in all circumstances in which the PPD is used. However, whether the QTF-G is truly more specific or sensitive than the PPD in latent or active TB is yet to be determined.

KEY TREATMENT

The treatment of choice for latent TB infection is daily isoniazid (INH) for 9 months (ATS/CDC, 2000) (SOR: A). Short-course rifampin (Rifadin) plus INH (3 months) is equivalent to standard INH therapy and may increase compliance in patients with latent TB infection (Ena and Valls, 2005) (SOR: B). Although uncommon in the United States, drug-resistant TB and multidrug-resistant TB underscore the need for combination drug therapy and directly observed therapy in patients with tuberculosis (CDC, 2007) (SOR: C).

SEXUALLY TRANSMITTED INFECTIONS

David R. McBride Key Points

• The U.S. Preventive Services Task Force recommends "high-intensity" behavioral counseling to at-risk adults and adolescents to prevent sexually transmitted infections.

• Be specific in addressing patients' sexual practices so as to provide appropriate prevention advice.

• Regular screening for Chlamydia infection is recommended for all sexually active women under age 24, all pregnant women under 24, and at-risk pregnant and nonpregnant women over 24.

• The presence of STIs such as gonorrhea, Chlamydia, and herpes increases the likelihood of HIV transmission.

• Testing for HIV should be offered on an "opt out" basis in all health care settings.

• The majority of patients with herpes simplex virus infection will not show recognizable symptoms. Screening for HSV immunity is of questionable value.

• Urine is an acceptable specimen to test for gonorrhea and Chlamydia in both men and women.

• The human papillomavirus vaccine is effective in reducing incidence of HPV infection, and physicians should discuss the vaccine with young women and men and their families.

• Routine screening for the mere presence of HPV is not recommended outside the context of cervical cancer screening.

The CDC estimates that 19 million new cases of sexually transmitted infections (STIs) occur each year. More than half are in young people age 15 to 24 years. The most important development in the primary prevention of STIs is immunization against human papillomavirus (HPV). The vaccine can prevent infection with certain strains of HPV that cause cervical cancer and genital warts. Trials are ongoing to determine the effectiveness of daily ARV therapy in preventing transmission of HIV. Vaccination investigation is ongoing for herpes simplex, Chlamydia trachomatis, and HIV. This breadth of research effort holds promise for the future in the prevention of STIs.

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