InternalMed_Harrison

InternalMed_Harrison. NTM can be detected on acid-fast or fluorochrome smears of sputum or other body fluids. When the organism burden is high, the organisms may appear as gram-positive beaded rods, but this finding is unreliable. (In contrast, nocardiae may appear as gram-positive and beaded but filamentous bacteria.) Again, the requisite and most sensitive step in the diagnosis of any mycobacterial disease is to think of including it in the differential. In almost all laboratories, mycobacterial sample processing, staining, and culture are conducted separately from routine bacteriologic tests; thus many infections go undiagnosed because of the physician’s failure to request the appropriate test. In addition, mycobacteria usually require separate blood culture media. NTM are broadly differentiated into rapidly growing (<7 days) and slowly growing (≥7 days) forms. Because M. tuberculosis typically takes ≥2 weeks to grow, many laboratories refuse to consider culture results final until 6 weeks have elapsed.


InternalMed_Harrison

InternalMed_Harrison. growing (<7 days) and slowly growing (≥7 days) forms. Because M. tuberculosis typically takes ≥2 weeks to grow, many laboratories refuse to consider culture results final until 6 weeks have elapsed. Newer techniques using liquid culture media permit more rapid isolation of mycobacteria from specimens than is possible with traditional media. Species more readily detected with incubation at 30°C include M. marinum, M. haemophilum, and M. ulcerans. M. haemophilum prefers iron supplementation or blood, whereas M. genavense requires supplemented medium with the additive mycobactin J. Bacterial formation of pigment in light conditions (photochromogenicity) or dark conditions (scotochromogenicity) or a lack of bacterial pigment formation (nonchromogenicity) has been used to help categorize NTM. In contrast to NTM colonies, M. tuberculosis colonies are beige, rough, dry, and flat. Current identification schemes can reliably use biochemical, nucleic acid, or cell wall composition, as assessed


InternalMed_Harrison

InternalMed_Harrison. In contrast to NTM colonies, M. tuberculosis colonies are beige, rough, dry, and flat. Current identification schemes can reliably use biochemical, nucleic acid, or cell wall composition, as assessed by high-performance liquid chromatography or mass spectrometry, for speciation. With the remarkable decline in U.S. cases of tuberculosis over recent decades, NTM have become the mycobacteria most commonly isolated from humans in North America. However, not all isolations of NTM, especially from the lung, reflect pathology and require treatment. Whereas identification of an organism in a blood or organ biopsy specimen in a compatible clinical setting is diagnostic, the American Thoracic Society recommends that pulmonary infection due to NTM be diagnosed only when disease is clearly demonstrable—i.e., in an appropriate clinical and radiographic setting (nodules, bronchiectasis, cavities) and with repeated isolation of NTM from expectorated sputum or recovery of NTM from bronchoscopy or


InternalMed_Harrison

InternalMed_Harrison. in an appropriate clinical and radiographic setting (nodules, bronchiectasis, cavities) and with repeated isolation of NTM from expectorated sputum or recovery of NTM from bronchoscopy or biopsy specimens. Given the large number of species of NTM and the importance of accurate diagnosis for the implementation of proper therapy, identification of these organisms is ideally taken to the species level.


InternalMed_Harrison

InternalMed_Harrison. The purified protein derivative (PPD) of tuberculin is delivered intradermally to evoke a memory T cell response to mycobacterial antigens. This test is variously referred to as the PPD test, the tuberculin skin test, and the Mantoux test, among other designations. Unfortunately, the cutaneous immune response to these tuberculosis-derived filtrate proteins does not differentiate well between infection with NTM and that with M. tuberculosis. Because intermediate reactions (~10 mm) to PPD in latent tuberculosis and nontuberculous mycobacterial infections can overlap significantly, the progressive decline in active tuberculosis in the United States means that NTM probably account for increasing proportions of PPD reactivity. In addition, bacille Calmette-Guérin (BCG) can cause some degree of cross-reactivity, posing problems of interpretation for patients who have received BCG vaccine. Assays to measure the elaboration of IFN-γ in response to the relatively tuberculosis-specific proteins


InternalMed_Harrison

InternalMed_Harrison. cross-reactivity, posing problems of interpretation for patients who have received BCG vaccine. Assays to measure the elaboration of IFN-γ in response to the relatively tuberculosis-specific proteins ESAT6 and CFP10 form the basis for IFN-γ-release assays (IGRAs). These assays can be performed with whole blood or on membranes. It is important to note that M. marinum, M. kansasii, and M. szulgai also have ESAT6 and CFP10 and may cause false-positive reactions in IGRAs. Despite cross-reactivity with NTM, large PPD reactions (>15 mm) most commonly signify tuberculosis.


InternalMed_Harrison

InternalMed_Harrison. Isolation of NTM from blood specimens is clear evidence of disease. Whereas rapidly growing mycobacteria may proliferate in routine blood culture media, slow-growing NTM typically do not; thus it is imperative to suspect the diagnosis and to use the correct bottles for cultures. Isolation of NTM from a biopsy specimen constitutes strong evidence for infection, but cases of laboratory contamination do occur. Identification of organisms on stained sections of biopsy material confirms the authenticity of the culture. Certain NTM require lower incubation temperatures (M. genavense) or special additives (M. haemophilum) for growth. Some NTM (e.g., M. tilburgii) remain noncultivable but can be identified molecularly in clinical samples.


InternalMed_Harrison

InternalMed_Harrison. The radiographic appearance of nontuberculous mycobacterial disease in the lung depends on the underlying disease, the severity of the infection, and the imaging modality used. The advent and increase in the use of computed tomography (CT) has allowed the identification of characteristic changes that are highly consistent with nontuberculous mycobacterial infection, such as the “tree-in-bud” pattern of bronchiolar inflammation (Fig. 204-2). Involvement of the lingual and right-middle lobes is commonly seen on chest CT but is difficult to appreciate on plain film. Severe bronchiectasis and cavity formation are common in more advanced disease. Isolation of NTM from respiratory samples can be confusing. M. gordonae is often recovered from respiratory samples but is not usually seen on smear and is almost never a pathogen. Patients with bronchiectasis occasionally have NTM recovered from sputum culture with a negative smear. The American Thoracic Society has developed guidelines for the


InternalMed_Harrison

InternalMed_Harrison. and is almost never a pathogen. Patients with bronchiectasis occasionally have NTM recovered from sputum culture with a negative smear. The American Thoracic Society has developed guidelines for the diagnosis of infection with MAC, M. abscessus, and M. kansasii. A positive diagnosis requires the growth of NTM from two of three sputum samples, regardless of smear findings; a positive bronchoscopic alveolar sample, regardless of smear findings; or a pulmonary parenchyma biopsy sample with granulomatous inflammation or mycobacteria found on section and NTM found on culture. These guidelines probably apply to other NTM as well.


InternalMed_Harrison

InternalMed_Harrison. Although many laboratories use DNA probes to identify M. tuberculosis, MAC, M. gordonae, and M. kansasii, speciation of NTM helps determine the antimycobacterial therapy to be used. Only testing of MAC organisms for susceptibility to clarithromycin and of M. kansasii for susceptibility to rifampin is indicated; few data support other in vitro susceptibility tests, attractive though they appear. MAC isolates that have not been exposed to macrolides are almost always susceptible. NTM that have persisted beyond a course of antimicrobial therapy are often tested for antibiotic susceptibility, but the value and meaning of these tests are undetermined. FIGuRE 204-2 Chest computed tomography of a patient with pul-monary Mycobacterium avium complex infection. Arrows indicate the “tree-in-bud” pattern of bronchiolar inflammation (peripheral right lung) and bronchiectasis (central right and left lungs).


InternalMed_Harrison

InternalMed_Harrison. Prophylaxis of MAC disease in patients infected with HIV is started when the CD4+ T lymphocyte count falls to <50/μL. Azithromycin (1200 mg weekly), clarithromycin (1000 mg daily), or rifabutin (300 mg daily) is effective. Macrolide prophylaxis in immunodeficient patients who are susceptible to NTM (e.g., those with defects in the IFN-γ/IL-12 axis) has not been prospectively validated but seems prudent. NTM cause chronic infections that evolve relatively slowly over a period of weeks to years. Therefore, it is rarely necessary to initiate treatment on an emergent basis before the diagnosis is clear and the infecting species is known. Treatment of NTM is complex, often poorly tolerated, and potentially toxic. Just as in tuberculosis, inadequate single-drug therapy is almost always associated with the emergence of antimicrobial resistance and relapse.


InternalMed_Harrison

InternalMed_Harrison. MAC infection often requires multidrug therapy, the foundation of which is a macrolide (clarithromycin or azithromycin), ethambutol, and a rifamycin (rifampin or rifabutin). For disseminated nontuberculous mycobacterial disease in HIV-infected patients, the use of rifamycins poses special problems—i.e., rifamycin interactions with protease inhibitors. For pulmonary MAC disease, thrice-weekly administration of a macrolide, a rifamycin, and ethambutol has been successful. Therapy is prolonged, generally continuing for 12 months after culture conversion; typically, a course lasts for at least 18 months. Other drugs with activity against MAC organisms include IV and aerosolized aminoglycosides, fluoroquinolones, and clofazimine. In elderly patients, rifabutin can exert significant toxicity. However, with only modest efforts, most antimycobacterial regimens are well tolerated by most patients. Resection of cavitary lesions or severely bronchiectatic segments has been advocated for some


InternalMed_Harrison

InternalMed_Harrison. However, with only modest efforts, most antimycobacterial regimens are well tolerated by most patients. Resection of cavitary lesions or severely bronchiectatic segments has been advocated for some patients, especially those with macrolide-resistant infections. The success of therapy for pulmonary MAC infections depends on whether disease is nodular or cavitary and on whether it is early or advanced, ranging from 20% to 80%.


InternalMed_Harrison

InternalMed_Harrison. M. kansasii lung disease is similar to tuberculosis in many ways and is also effectively treated with isoniazid (300 mg/d), rifampin (600 mg/d), and ethambutol (15 mg/kg per day). Other drugs with very high-level activity against M. kansasii include clarithromycin, fluoroquinolones, and aminoglycosides. Treatment should continue until 1132 cultures have been negative for at least 1 year. In most instances, M. kansasii infection is easily cured.


InternalMed_Harrison

InternalMed_Harrison. apidly growing mycobacteria pose special therapeutic problems. Extrapulmonary disease in an immunocompetent host is usually due to inoculation (e.g., via surgery, injections, or trauma) or to line infection and is often treated successfully with a macrolide and another drug (with the choice based on in vitro susceptibility), along with removal of the offending focus. In contrast, pulmonary disease, especially that caused by M. abscessus, is extremely difficult to cure. epeated courses of treatment are usually effective in reducing the infectious burden and symptoms. Therapy generally includes a macrolide along with an Iadministered agent such as amikacin, a carbapenem, cefoxitin, or tigecycline. ther oral agents (used according to in vitro susceptibility testing and tolerance) include fluorouinolones, doxycycline, and linezolid. ecause nontuberculous mycobacterial infections are chronic, care must be taken in the long-term use of drugs with neurotoxicities, such as linezolid and


InternalMed_Harrison

InternalMed_Harrison. fluorouinolones, doxycycline, and linezolid. ecause nontuberculous mycobacterial infections are chronic, care must be taken in the long-term use of drugs with neurotoxicities, such as linezolid and ethambutol. Prophylactic pyridoxine has been suggested in these cases. Durations of therapy for M. abscessus lung disease are difficult to predict because so many cases are chronic and reuire intermittent therapy. Expert consultation and management are strongly recommended.


InternalMed_Harrison

InternalMed_Harrison. nce recognized, M. marinum infection is highly responsive to antimicrobial therapy and is cured relatively easily with any combination of a macrolide, ethambutol, and a rifamycin. Therapy should be continued for 1–2 months after clinical resolution of isolated soft tissue diseasetendon and bone involvement may reuire longer courses in light of clinical evolution. ther drugs with activity against M. marinum include sulfonamides, trimethoprim-sulfamethoxazole, doxycycline, and minocycline. Treatment of the other TM is less well defined, but macrolides and aminoglycosides are usually effective, with other agents added as indicated. Expert consultation is strongly encouraged for difficult or unusual infections due to TM.


InternalMed_Harrison

InternalMed_Harrison. The outcomes of nontuberculous mycobacterial infections are closely tied to the underlying condition (e.g., IFN-a/IL-12 pathway defect, cystic fibrosis) and can range from recovery to death. With no or inadequate treatment, symptoms and signs can be debilitating, including persistent cough, fever, anorexia, and severe lung destruction. With treatment, patients typically regain strength and energy. The optimal duration of therapy when NTM persist in sputum is unknown, but treatment in this situation can be prolonged.


InternalMed_Harrison

InternalMed_Harrison. In many countries, pulmonary tuberculosis is diagnosed by smear alone, which is also the method used for monitoring of response and relapse. However, examination of mycobacteria from the affected patients shows that a significant proportion of isolates are actually NTM. Overall, as rates of tuberculosis decline, the proportion of positive smears caused by NTM will increase. Advances in speciation will distinguish tuberculosis from nontuberculous mycobacterial infections and thereby affect rates of assumed relapse and resistance, leading to more targeted and appropriate therapy. Antimycobacterial Agents Max R. O'Donnell, Divya Reddy, Jussi J. Saukkonen Agents used for the treatment of mycobacterial infections, including tuberculosis (TB), leprosy, and infections due to nontuberculous mycobacteria (NTM), are administered in multiple-drug regimens for prolonged courses. Currently, more than 205e


InternalMed_Harrison

InternalMed_Harrison. Isoniazid 300 mg/d (5 mg/kg) 9 months Supplement with pyridoxine (25–50 mg daily). (6 months acceptable) Alternative: 900 mg twice weekly Twice-weekly regimens require directly observed therapy. (15 mg/kg) Rifampin 600 mg/d (10 mg/kg) 4 months Broader efficacy studies are needed. Isoniazid plus rifapentine 900 mg (15 mg/kg) weekly + 3 months Directly observed therapy is recommended for once-weekly 900 mg weekly treatment. This regimen may be supplemented with pyridoxine (25–50 mg/d). Sources: D Menzies et al: Ann Intern Med 149:689, 2008; American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Am J Respir Crit Care Med 167:603, 2003; T Sterling et al: N Engl J Med 365:2155, 2011.


InternalMed_Harrison

InternalMed_Harrison. 160 species of mycobacteria have been identified, the majority of which do not cause disease in humans. While the incidence of disease caused by Mycobacterium tuberculosis has been declining in the United States, TB remains a leading cause of morbidity and mortality in developing countries—particularly in sub-Saharan Africa, where the HIV epidemic rages. Effective drug regimens are not all that is needed; without a well-organized infrastructure for diagnosis and treatment of TB, therapeutic and control efforts are severely hampered (Chaps. 2 and 13e). Infections with NTM have gained in clinical prominence in the United States and other developed countries. These largely environmental organisms often establish infection in immunocompromised patients or in persons with structural lung disease.


InternalMed_Harrison

InternalMed_Harrison. The earliest recorded human case of TB dates back 9000 years. Early treatment modalities, such as bloodletting, were replaced by sanatorium regimens in the late nineteenth century. The discovery of streptomycin in 1943 launched the era of antibiotic treatment for TB. Over subsequent decades, the discovery of additional agents and the use of multiple-drug regimens allowed progressive shortening of the treatment course from years to as little as 6 months with the regimen for drug-susceptible TB. Latent TB infection (LTBI) and active TB disease are diagnosed by history, physical examination, radiographic imaging, tuberculin skin test, interferon γ release assays, acid-fast staining, mycobacterial cultures, and/or new molecular diagnostics. LTBI is treated with isoniazid (optimally given daily or twice weekly for 9 months), rifampin (daily for 4 months), or isoniazid plus rifapentine (weekly for 3 months) (Table 205e-1).


InternalMed_Harrison

InternalMed_Harrison. For active or suspected TB disease, clinical factors, including HIV co-infection, symptom duration, radiographic appearance, and public health concerns about TB transmission, drive diagnostic testing and treatment initiation. Multiple-drug regimens are used for the treatment of TB disease (Table 205e-2). Initially, an intensive phase consisting of four drugs—isoniazid, rifampin, pyrazinamide, and ethambutol—given for 2 months is followed by a continuation phase of isoniazid and rifampin for 4 months, for a total treatment duration of 6 months. The continuation phase is extended to 7 months (for a total treatment duration of 9 months) if the 2-month course of pyrazinamide is not completed or, for patients with cavitary pulmonary TB, if sputum cultures remain positive beyond 2 months of treatment (delayed culture conversion).


InternalMed_Harrison

InternalMed_Harrison. Treatment of TB in individuals co-infected with HIV poses significant challenges, but some progress is being made. Recent data show improved survival when antiretroviral therapy (ART) is initiated early during TB treatment. Interactions of rifampin with protease inhibitors or non-nucleoside reverse transcriptase inhibitors are significant and require close monitoring and dose adjustments. The TB immune reconstitution inflammatory syndrome (IRIS) may appear as early as 1 week after initiation of ART and manifests as paradoxical worsening or unmasking of existing TB infection. Conservative management consists of continued administration of ART and TB medications. However, severe or debilitating IRIS has been anecdotally treated with varying doses of glucocorticoids. Intermittent therapy in patients co-infected with HIV and M. tuberculosis has been associated with low plasma levels of several key TB drugs and with higher rates of treatment failure or relapse; therefore, intermittent


InternalMed_Harrison

InternalMed_Harrison. in patients co-infected with HIV and M. tuberculosis has been associated with low plasma levels of several key TB drugs and with higher rates of treatment failure or relapse; therefore, intermittent twice-weekly therapy for TB in HIV-co-infected individuals is not recommended.


InternalMed_Harrison

InternalMed_Harrison. Adherence to medications is critical in achieving a cure with antimycobacterial therapy. Consequently, directly observed therapy (DOT) by trained staff, either in the clinic or at home, is recommended to ensure adherence. In addition, monthly dispensing of TB medicines is recommended because monthly clinical monitoring for hepatotoxicity due to these medications is essential for all patients. Discontinuation of suspected offending agents at the onset of hepatitis symptoms reduces the risk of progression to fatal hepatitis. Clinical monitoring includes at least monthly assessment for symptoms (nausea, vomiting, abdominal discomfort, and unexplained fatigue) and signs (jaundice, dark urine, light stools, diffuse pruritus) of hepatotoxicity, although the latter represent comparatively late manifestations (Table 205e-3). The presence of such symptoms and signs mandates provisional discontinuation of potentially hepatotoxic agents. Biochemical testing of at least serum alanine


InternalMed_Harrison

InternalMed_Harrison. late manifestations (Table 205e-3). The presence of such symptoms and signs mandates provisional discontinuation of potentially hepatotoxic agents. Biochemical testing of at least serum alanine aminotransferase and total bilirubin levels and exclusion of other causes of these abnormalities are also indicated during treatment for those at risk for hepatotoxicity (Table 205e-3). For patients with active TB, monthly mycobacterial cultures of sputum are recommended until it is certain that the organisms have been cleared and the patient has responded to therapy or until no sputum is available for culture.


InternalMed_Harrison

InternalMed_Harrison. If significant clinical improvement does not occur or the patient’s condition deteriorates over the course of therapy, possibilities include treatment failure due to nonadherence, poor medication absorption, or the development of resistance. For patients co-infected with HIV and M. tuberculosis, IRIS, which is a diagnosis of exclusion, should also be a consideration. Drug susceptibility testing should be repeated at this point. If resistance is documented or strongly suspected, at least two efficacious drugs to which the isolate is susceptible or which the patient has not already taken should be added to the therapeutic regimen.


InternalMed_Harrison

InternalMed_Harrison. Multidrug-resistant TB (MDR-TB) is defined as disease caused by a strain of M. tuberculosis that is resistant to both isoniazid and rifampin—the most efficacious of the first-line TB drugs. The risk of MDR-TB is elevated in patients presenting from geographic areas in which ≥5% of incident cases are MDR-TB and in patients previously treated for TB. Treatment regimens for MDR-TB generally include a late-generation fluoroquinolone and an injectable second-line agent (such as capreomycin, amikacin, or kanamycin). Regimens of at least five drugs are recommended for the treatment of MDR-TB. Both standardized and optimized/customized regimens are in use around the world. Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB with additional resistance to any fluoroquinolone and at least one of the second-line injectable agents. Treatment of XDR-TB is individualized Culture Results Intensive Phase Continuation Phase Extension of Total Treatment


InternalMed_Harrison

InternalMed_Harrison. Culture Results Intensive Phase Continuation Phase Extension of Total Treatment Culture positive HRZE for 2 months, daily or intermit-HR for 4 months, daily or 5 d/wk To 9 months, if 2 months of Z is not completed or culture tent (with dose adjustment) or conversion is prolonged and cavitation is evident on plain radiographa HR for 4 months, intermittent (with dose adjustment) Culture negative HRZE for 2 months 2 months To 6 months, if patient is infected with HIV Extrapulmonary HRZE for 2 months HR for 4–7 months, daily or 5 d/wkb To 9–12 months in TB meningitis. Some recommend 9 months for bone/joint TB. Resistant to H QRZEc or, less often, RZES for 6 months … Prolonged culture conversion, cavitation Resistant to R HZEQc (IAd) for 2 months HEQ(S) for 10–16 months Prolonged culture conversion, delayed response


InternalMed_Harrison

InternalMed_Harrison. Resistant to HRe ZEQc (IAd) ± alternative agentsf for … Prolonged culture conversion 18–24 months a Culture conversion is prolonged if it occurs beyond 2 months. Some providers extend the continuation phase to 7 months if there is either prolonged culture conversion or cavitation. bMany experts recommend a continuation phase of 7 months for all extrapulmonary TB, including miliary disease. For TB pericarditis and meningitis, the addition of glucocorticoids is recommended. cLevofloxacin and moxifloxacin are the preferred fluoroquinolones. Gatifloxacin is associated with dysglycemia but may be an acceptable alternative; in a recent trial of TB treatment, this drug did not cause dysglycemia in patients who received it thrice weekly for 4 months. Ofloxacin and ciprofloxacin should generally be avoided because of resistance. dInjectable agents: streptomycin, amikacin, kanamycin, and capreomycin. eMultidrug-resistant TB should be managed by or in close consultation with an expert TB


InternalMed_Harrison

InternalMed_Harrison. be avoided because of resistance. dInjectable agents: streptomycin, amikacin, kanamycin, and capreomycin. eMultidrug-resistant TB should be managed by or in close consultation with an expert TB clinician. Surgical management should be considered. fAlternative agents: cycloserine, ethionamide, para-aminosalicylic acid, clarithromycin, linezolid, and amoxicillin-clavulanate.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: E, ethambutol; H, isoniazid; IA, injectable agent; Q, fluoroquinolone; R, rifampin; S, streptomycin; Z, pyrazinamide. Sources: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Am J Respir Crit Care Med 167:603, 2003; C Mitnick et al: N Engl J Med 359:563, 2008; World Health Organization 2011 update: Guidelines for the programmatic management of drug-resistant tuberculosis (www.who.int/tb/challenges/mdr/programmatic _guidelines_for_mdrtb/en/index.html). on the basis of complete phenotypic and, if possible, genotypic antimi-actively investigated during the current remarkable period of drug crobial susceptibility testing. Therapeutic regimens for either MDR-TB development for TB treatment. or XDR-TB should be constructed with input from experienced clini- Isoniazid Isoniazid is a critical drug for treatment of both TB discians who should continue the management of the disease.


InternalMed_Harrison

InternalMed_Harrison. Isoniazid Isoniazid is a critical drug for treatment of both TB discians who should continue the management of the disease. ease and LTBI. Isoniazid has excellent bactericidal activity against both intracellular M. tuberculosis and extracellular, actively dividing FIRST-LINE ANTITUBERCULOSIS DRUGS organisms. This drug is bacteriostatic against slowly dividing organ-The following discussion of individual anti-TB agents focuses on treat-isms. In treatment of LTBI, isoniazid is considered the first-line agent ment of TB in adults, unless otherwise noted. Several agents are being because it is generally well tolerated, has well-established efficacy, and With hepatic risk factorsb, check ALT and bilirubin at baseline. If ALT is ≥3 × ULN or total bilirubin is >2 × ULN, defer treatment and reevaluate. Check ALT, bilirubin, platelets, creatinine, and hepatitis panel for all patients at baseline. If hepatic risk factors are present, check ALT and bilirubin monthly.


InternalMed_Harrison

InternalMed_Harrison. Check ALT, bilirubin, platelets, creatinine, and hepatitis panel for all patients at baseline. If hepatic risk factors are present, check ALT and bilirubin monthly. aAll regimens require monthly clinical monitoring. bHepatic risk factors: chronic alcohol use, viral hepatitis, preexisting liver disease, pregnancy or ≤3 months postpartum, hepatotoxic medications. cRelevant manifestations include nausea, vomiting, abdominal pain, jaundice, or unexplained fatigue. Abbreviations: ALT, alanine aminotransferase; BUN, blood urea nitrogen; ECG, electrocardiogram; ENT, ear, nose, and throat; LTBI, latent tuberculosis infection; MDR-TB, multidrug-resistant tuberculosis; ULN, upper limit of normal. Sources: JJ Saukkonen et al: Am J Respir Crit Care Med 174:935, 2006; American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Am J Respir Crit Care Med 167:603, 2003.


InternalMed_Harrison

InternalMed_Harrison. is inexpensive. In this setting, the drug is taken daily or intermittently (i.e., twice weekly) as DOT for 9 months. The 9-month course is more efficacious than the 6-month course (75–90% vs ≤65%), but extension of treatment to 12 months is not likely to provide further protection. A 6-month course of daily or intermittent isoniazid is considered second-line, but acceptable, therapy. A recent large open-label, multicenter, randomized, controlled trial showed that weekly DOT with isoniazid and rifapentine, administered over 3 months, was not inferior to daily isoniazid given for 9 months and had a higher treatment completion rate than the single-drug regimen.


InternalMed_Harrison

InternalMed_Harrison. For treatment of TB disease, isoniazid is used in combination with other agents to ensure killing of both actively dividing M. tuberculosis and slowly growing "persister" organisms. Unless the organism is resistant, the standard regimen includes isoniazid, rifampin, ethambutol, and pyrazinamide (Table 205e-2). Isoniazid is often given together with 25–50 mg of pyridoxine daily to prevent drug-related peripheral neuropathy.


InternalMed_Harrison

InternalMed_Harrison. MechanisM of action Isoniazid is a prodrug activated by the mycobacterial KatG catalase-peroxidase; isoniazid is coupled with reduced nicotinamide adenine dinucleotide (NADH). The resulting isonicotinic acyl–NADH complex blocks the mycobacterial ketoenoylreductase known as InhA, binding to its substrate and inhibiting fatty acid synthase and ultimately mycolic acid synthesis. Mycolic acids are essential components of the mycobacterial cell wall. KatG activation of isoniazid also results in the release of free radicals that have antimycobacterial activity, including nitric oxide. The minimal inhibitory concentrations (MICs) of isoniazid for wild-type (untreated) susceptible strains are <0.1 μg/mL for M. tuberculosis and 0.5–2 μg/mL for Mycobacterium kansasii.


InternalMed_Harrison

InternalMed_Harrison. The minimal inhibitory concentrations (MICs) of isoniazid for wild-type (untreated) susceptible strains are <0.1 μg/mL for M. tuberculosis and 0.5–2 μg/mL for Mycobacterium kansasii. PharMacology Isoniazid is the hydrazide of isonicotinic acid, a small, water-soluble molecule. The usual adult oral daily dose of 300 mg results in peak serum levels of 3–5 μg/mL within 30 min to 2 h after ingestion—well in excess of the MICs for most susceptible strains of M. tuberculosis. Both oral and IM preparations of isoniazid reach effective levels in the body, although antacids and high-carbohydrate meals may interfere with oral absorption. Isoniazid diffuses well throughout the body, reaching therapeutic concentrations in body cavities and fluids, with concentrations in cerebrospinal fluid (CSF) comparable to those in serum.


InternalMed_Harrison

InternalMed_Harrison. Isoniazid is metabolized in the liver via acetylation by N-acetyltransferase 2 (NAT2) and hydrolysis. Both fastand slowacetylation phenotypes occur; patients who are “fast acetylators” may have lower serum levels of isoniazid, whereas “slow acetylators” may have higher levels and experience more toxicity. Satisfactory isoniazid levels are attained in the majority of homozygous fast NAT2 acetylators given a dose of 6 mg/kg and in the majority of homozygous slow acetylators given only 3 mg/kg. Genotyping is increasingly being used to characterize isoniazid-related pharmacogenomic responses. Isoniazid’s interactions with other drugs are due primarily to its inhibition of the cytochrome P450 system. Among the drugs with significant isoniazid interactions are warfarin, carbamazepine, benzodiazepines, acetaminophen, clopidogrel, maraviroc, dronedarone, salmeterol, tamoxifen, eplerenone, and phenytoin.


InternalMed_Harrison

InternalMed_Harrison. Dosing The recommended daily dose for the treatment of TB in the United States is 5 mg/kg for adults and 10–20 mg/kg for children, with a maximal daily dose of 300 mg for both. For intermittent therapy in adults (usually twice per week), the dose is 15 mg/kg, with a maximal daily dose of 900 mg. Isoniazid does not require dosage adjustment in patients with renal disease. When the 12-dose, 3-month weekly LTBI regimen is used, the dose of isoniazid is 15 mg/kg, with a maximal dose of 900 mg, and the drug is coadministered with rifapentine.


InternalMed_Harrison

InternalMed_Harrison. resistance Although isoniazid, along with rifampin, is the mainstay of TB treatment regimens, ~7% of clinical M. tuberculosis isolates in the United States are resistant. Rates of primary isoniazid resistance among untreated patients are significantly higher in many populations born outside the United States. Five separate pathways for isoniazid resistance have been elucidated. Most strains have amino acid changes in either the catalase-peroxidase gene (katG) or the mycobacterial ketoenoylreductase gene (inhA). Less frequently, alterations in kasA, the gene for an enzyme involved in mycolic acid elongation, and loss of NADH dehydrogenase 2 activity confer isoniazid resistance. In 20–30% of isoniazid-resistant M. tuberculosis isolates, increased expression of efflux pump genes, such as efpA, mmpL7, mmr, p55, and the Tap-like gene Rv1258c, has been implicated as the underlying mechanism of resistance.


InternalMed_Harrison

InternalMed_Harrison. aDverse effects Although isoniazid is generally well tolerated, drug-induced liver injury and peripheral neuropathy are significant adverse effects associated with this agent. Isoniazid may cause asymptomatic transient elevation of aminotransferase levels (often termed hepatic adaptation) in up to 20% of recipients. Other adverse reactions include rash (2%), fever (1.2%), anemia, acne, arthritic symptoms, a systemic lupus erythematosus–like syndrome, optic atrophy, seizures, and psychiatric symptoms. Symptomatic hepatitis occurs in fewer than 0.1% of persons treated with isoniazid alone for LTBI, and fulminant hepatitis with hepatic failure occurs in fewer than 0.01%. Isoniazid-associated hepatitis is idiosyncratic, but its incidence increases with age, with daily alcohol consumption, and in women who are within 3 months postpartum.


InternalMed_Harrison

InternalMed_Harrison. In patients who have liver disorders or HIV infection, who are pregnant or in the 3-month postpartum period, who have a history of liver disease (e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis), who use alcohol regularly, who have multiple medical problems, or who have other risk factors for chronic liver disease, the risks and benefits of treatment for LTBI should be weighed. If treatment is undertaken, these patients should have serum concentrations of alanine aminotransferase (ALT) determined at baseline. Routine baseline hepatic ALT testing based solely on an age of >35 years is optional and depends on individual concerns. Monthly biochemical monitoring during isoniazid treatment is indicated for patients whose baseline liver function tests yield abnormal results and for persons at risk for hepatic disease, including the groups just mentioned. Guidelines recommend that isoniazid be discontinued in the presence of hepatitis symptoms or jaundice and an ALT level three


InternalMed_Harrison

InternalMed_Harrison. persons at risk for hepatic disease, including the groups just mentioned. Guidelines recommend that isoniazid be discontinued in the presence of hepatitis symptoms or jaundice and an ALT level three times the upper limit of normal or in the absence of symptoms with an ALT level five times the upper limit of normal (Table 205e-3).


InternalMed_Harrison

InternalMed_Harrison. Peripheral neuropathy associated with isoniazid occurs in up to 2% of patients given 5 mg/kg. Isoniazid appears to interfere with pyridoxine (vitamin B6) metabolism. The risk of isoniazid-related neurotoxicity is greatest for patients with preexisting disorders that also pose a risk of neuropathy, such as HIV infection; for those with diabetes mellitus, alcohol abuse, or malnutrition; and for those simultaneously receiving other potentially neuropathic medications, such as stavudine. These patients should be given prophylactic pyridoxine (25–50 mg/d).


InternalMed_Harrison

InternalMed_Harrison. Rifampin Rifampin is a semisynthetic derivative of Amycolatopsis rifamycinica (formerly known as Streptomyces mediterranei). The most active antimycobacterial agent available, rifampin is the keystone of first-line treatment for TB. Introduced in 1968, this drug eventually permitted dramatic shortening of the TB treatment course. Rifampin has both sterilizing and bactericidal activity against dividing and nondividing M. tuberculosis. The drug is also active against an array of other organisms, including some gram-positive and gram-negative bacteria, Legionella, M. kansasii, and Mycobacterium marinum.


InternalMed_Harrison

InternalMed_Harrison. Rifampin, administered for 4 months, is also an alternative agent to isoniazid for the treatment of LTBI, although efficacy data are scant at this time. A 3-month course of rifampin alone has been found to be similar in efficacy to a 6-month course of isoniazid. Although the efficacy of the 4-month regimen of rifampin is under study, comparison of this regimen with 9 months of isoniazid in randomized safety and tolerability studies suggests fewer adverse events, including hepatotoxicity; less treatment interruption; a higher completion rate; and greater cost-effectiveness. MechanisM of action Rifampin exerts both intracellular and extracellular bactericidal activity. Like other rifamycins, rifampin specifically binds to and inhibits mycobacterial DNA-dependent RNA polymerase, blocking RNA synthesis. Susceptible strains of M. tuberculosis as well as M. kansasii and M. marinum are inhibited by rifampin concentrations of 1 μg/mL.


InternalMed_Harrison

InternalMed_Harrison. PharMacology Rifampin is a fat-soluble, complex macrocyclic molecule readily absorbed after oral administration. Serum levels of 10–20 μg/mL are achieved 2.5 h after the usual adult oral dose of 10 mg/kg (given without food). Rifampin has a half-life of 1.5–5 h. The drug distributes well throughout most body tissues, including CSF. Rifampin turns body fluids such as urine, saliva, sputum, and tears a reddish-orange color—an effect that offers a simple means of assessing patients’ adherence to this medication. Rifampin is excreted primarily through the bile and enters the enterohepatic circulation; <30% of a dose is renally excreted.


InternalMed_Harrison

InternalMed_Harrison. As a potent inducer of the hepatic cytochrome P450 system, rifampin can decrease the half-life of some drugs, such as digoxin, warfarin, phenytoin, prednisone, cyclosporine, methadone, oral contraceptives, clarithromycin, azole antifungal agents, quinidine, antiretroviral protease inhibitors, and non-nucleoside reverse transcriptase inhibitors. The Centers for Disease Control and Prevention has issued guidelines for the management of drug interactions during treatment of HIV and M. tuberculosis co-infection (www.cdc.gov/tb/publications/ guidelines/TB_HIV_Drugs/default.htm). Dosing The daily dosage of rifampin is 10 mg/kg for adults and 10–20 mg/kg for children, with a maximum of 600 mg/d for both. The drug is given once daily, twice weekly, or three times weekly. No adjustments of dose or frequency are necessary in patients with renal insufficiency.


InternalMed_Harrison

InternalMed_Harrison. resistance Resistance to rifampin in M. tuberculosis, Mycobacterium leprae, and other organisms is the consequence of spontaneous, mostly missense point mutations in a core region of the bacterial gene coding for the β subunit of RNA polymerase (rpoB). RNA polymerase altered in this manner is no longer subject to inhibition by rifampin. Most rapidly and slowly growing NTM harbor intrinsic resistance to rifampin, for which the mechanism has yet to be determined.


InternalMed_Harrison

InternalMed_Harrison. aDverse effects Adverse events associated with rifampin are infrequent and generally mild. Hepatotoxicity due to rifampin alone is uncommon in the absence of preexisting liver disease and often consists of isolated hyperbilirubinemia rather than aminotransferase elevation. Other adverse reactions include rash, pruritus, gastrointestinal symptoms, and pancytopenia. Rarely, a hypersensitivity reaction may occur with intermittent therapy, manifesting as fever, chills, malaise, rash, and—in some instances—renal and hepatic failure.


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InternalMed_Harrison. Ethambutol Ethambutol is a bacteriostatic antimycobacterial agent first synthesized in 1961. A component of the standard first-line regimen, ethambutol provides synergy with the other drugs in the regimen and is generally well tolerated. Susceptible species include M. tuberculosis, M. marinum, M. kansasii, and organisms of the Mycobacterium avium complex (MAC); however, among first-line drugs, ethambutol is the least potent against M. tuberculosis. This agent is also used in combination with other agents in the continuation phase of treatment when patients cannot tolerate isoniazid or rifampin or are infected with organisms resistant to either of the latter drugs.


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InternalMed_Harrison. MechanisM of action Ethambutol is bacteriostatic against M. tuberculosis. Its primary mechanism of action is the inhibition of the arabinosyltransferases involved in cell wall synthesis, which probably inhibits the formation of arabinogalactan and lipoarabinomannan. The MIC of ethambutol for susceptible strains of M. tuberculosis is 0.5–2 μg/mL. PharMacology anD Dosing From a single dose of ethambutol, 75–80% is absorbed within 2–4 h of administration. Serum levels peak at 2–4 μg/mL after the standard adult daily dose of 15 mg/kg. Ethambutol is well distributed throughout the body except in the CSF; a dosage of 25 mg/kg is necessary for attainment of a CSF level half of that in serum. For intermittent therapy, the dosage is 50 mg/kg twice weekly. To prevent toxicity, the dosage must be lowered and the frequency of administration reduced for patients with renal insufficiency.


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InternalMed_Harrison. aDverse effects Ethambutol is usually well tolerated and has no significant interactions with other drugs. Optic neuritis, the most serious adverse effect reported, typically presents as reduced visual acuity, central scotoma, and loss of the ability to see green (or, less commonly, red). The cause of this neuritis is unknown, but it may be due to an effect of ethambutol on the amacrine and bipolar cells of the retina. Symptoms typically develop several months after initiation of therapy, but ocular toxicity soon after initiation of ethambutol has been described. The risk of ocular toxicity is dose dependent, occurring in 1–5% of patients, and can be increased by renal insufficiency. The routine use of ethambutol in younger children is not recommended because monitoring for visual complications can be difficult. If drug-resistant TB is suspected, ethambutol can be used for treatment of children.


InternalMed_Harrison

InternalMed_Harrison. All patients starting therapy with ethambutol should have a baseline test for visual acuity, visual fields, and color vision and should undergo an examination of the optic fundus. Visual acuity and color vision should be monitored monthly or less often as needed. Cessation of ethambutol in response to early symptoms of ocular toxicity usually results in reversal of the deficit within several months. Recovery of all visual function may take up to 1 year. In the elderly and in patients whose symptoms are not recognized early, deficits may be permanent. Some experts think that supplementation with hydroxocobalamin (vitamin B12) is beneficial for patients with ethambutol-related ocular toxicity. Other adverse effects of ethambutol are rare. Peripheral sensory neuropathy occurs in rare instances.


InternalMed_Harrison

InternalMed_Harrison. resistance Ethambutol resistance in M. tuberculosis and NTM is associated primarily with missense mutations in the embB gene that encodes for arabinosyltransferase. Mutations have been found in resistant strains at codon 306 in 50–70% of cases. Mutations at embB306 can cause significantly increased MICs of ethambutol, resulting in clinical resistance. Pyrazinamide A nicotinamide analog, pyrazinamide is an important bactericidal drug used in the initial phase of TB treatment. Its administration for the first 2 months of therapy with rifampin and isoniazid allows treatment duration to be shortened from 9 months to 6 months and decreases rates of relapse.


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InternalMed_Harrison. MechanisM of action Pyrazinamide’s antimycobacterial activity is essentially limited to M. tuberculosis. The drug is more active against slowly replicating organisms than against actively replicating organisms. Pyrazinamide is a prodrug that is converted by the mycobacterial pyrimidase to the active form, pyrazinoic acid (POA). This agent is active only in acidic environments (pH <6.0), as are found within phagocytes or granulomas. The exact mechanism of action of POA is unclear, but fatty acid synthetase I may be the primary target in M. tuberculosis. Susceptible strains of M. tuberculosis are inhibited by pyrazinamide concentrations of 16–50 μg/mL at pH 5.5.


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InternalMed_Harrison. M. tuberculosis. Susceptible strains of M. tuberculosis are inhibited by pyrazinamide concentrations of 16–50 μg/mL at pH 5.5. PharMacology anD Dosing Pyrazinamide is well absorbed after oral administration, with peak serum concentrations of 20–60 μg/mL at 1–2 h after ingestion of the recommended adult daily dose of 15–30 mg/kg (maximum, 2 g/d). It distributes well to various body compartments, including CSF, and is an important component of treatment for tuberculous meningitis. The serum half-life of the drug is 9–11 h with normal renal and hepatic function. Pyrazinamide is metabolized in the liver to POA, 5-hydroxypyrazinamide, and 5-hydroxy-POA. A high proportion of pyrazinamide and its metabolites (~70%) is excreted in the urine. The dosage must be adjusted according to the level of renal function in patients with reduced creatinine clearance.


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InternalMed_Harrison. aDverse effects At the higher dosages used previously, hepatotoxicity was seen in as many as 15% of patients treated with pyrazinamide. However, at the currently recommended dosages, hepatotoxicity now occurs less commonly when this drug is administered with isoniazid and rifampin during the treatment of TB. Older age, active liver disease, HIV infection, and low albumin levels may increase the risk of hepatotoxicity. The use of pyrazinamide with rifampin for the treatment of LTBI is no longer recommended because of unacceptable rates of hepatotoxicity and death in this setting. Hyperuricemia is a common adverse effect of pyrazinamide therapy that usually can be managed conservatively. Clinical gout is rare. Although pyrazinamide is recommended by international TB organizations for routine use in pregnancy, it is not recom mended in the United States because of inadequate teratogenicity data.


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InternalMed_Harrison. Although pyrazinamide is recommended by international TB organizations for routine use in pregnancy, it is not recom mended in the United States because of inadequate teratogenicity data. resistance The basis of pyrazinamide resistance in M. tuberculosis is a mutation in the pncA gene coding for pyrazinamidase, the enzyme that converts the prodrug to active POA. Resistance to pyrazinamide is associated with loss of pyrazinamidase activity, which prevents conversion of pyrazinamide to POA. Of pyrazinamide-resistant M. tuberculosis isolates, 72–98% have mutations in pncA. Conventional methods of testing for susceptibility to pyrazinamide may produce both false-negative and false-positive results because the high-acidity environment required for the drug's activation also inhibits the growth of M. tuberculosis. There is some controversy as to the clinical significance of in vitro pyrazinamide resistance.


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InternalMed_Harrison. OTHER FIRST-LINE DRUGS Rifabutin Rifabutin, a semisynthetic derivative of rifamycin S, inhibits mycobacterial DNA-dependent RNA polymerase. Rifabutin is recommended in place of rifampin for the treatment of HIV-co-infected individuals who are taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors, particularly nevirapine. Rifabutin’s effect on hepatic enzyme induction is less pronounced than that of rifampin. Protease inhibitors may cause significant increases in rifabutin levels through inhibition of hepatic metabolism. Rifabutin is more active in vitro than rifampin against MAC organisms and other NTM, but its clinical superiority has not been established.


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InternalMed_Harrison. PharMacology Like rifampin, rifabutin is lipophilic and is absorbed rapidly after oral administration, reaching peak serum levels 2–4 h after ingestion. Rifabutin distributes best to tissues, reaching levels 5–10 times higher than those in plasma. Unlike rifampin, rifabutin and its metabolites are partially cleared by the hepatic microsomal system. Rifabutin’s slow clearance results in a mean serum half-life of 45 h— much longer than the 3to 5-h half-life of rifampin. Clarithromycin (but not azithromycin) and fluconazole appear to increase rifabutin levels by inhibiting hepatic metabolism.


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InternalMed_Harrison. aDverse effects Rifabutin is generally well tolerated, with adverse effects occurring at higher doses. The most common adverse events are gastrointestinal; other reactions include rash, headache, asthenia, chest pain, myalgia, and insomnia. Less common adverse reactions include fever, chills, a flulike syndrome, anterior uveitis, hepatitis, Clostridium difficile– associated diarrhea, a diffuse polymyalgia syndrome, and yellow skin discoloration (“pseudo-jaundice”). Laboratory abnormalities include neutropenia, leukopenia, thrombocytopenia, and increased levels of liver enzymes. Approximately 80% of patients who develop rifampin-related adverse events are able to complete TB treatment with rifabutin. resistance Similar to rifampin resistance, resistance to rifabutin is mediated by some mutations in rpoB.


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InternalMed_Harrison. Rifapentine Rifapentine is a semisynthetic cyclopentyl rifamycin, sharing a mechanism of action with rifampin. Rifapentine is lipophilic and has a prolonged half-life that permits weekly or twice-weekly dosing. Therefore, this drug is the subject of intensive clinical investigation aimed at determining optimal dosing and frequency of administration. Currently, rifapentine is an alternative to rifampin in the continuation phase of treatment for noncavitary drug-susceptible pulmonary TB in HIV-seronegative patients who have negative sputum smears at completion of the initial phase of treatment. When administered in these specific circumstances, rifapentine (10 mg/kg, up to 600 mg) is given once weekly with isoniazid. Because of higher rates of relapse, this regimen is not recommended for patients with TB disease and HIV co-infection. A large randomized controlled trial recently demonstrated that, for latent TB, a 12-dose (3-month) regimen of weekly DOT with a weight-based dose of


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InternalMed_Harrison. for patients with TB disease and HIV co-infection. A large randomized controlled trial recently demonstrated that, for latent TB, a 12-dose (3-month) regimen of weekly DOT with a weight-based dose of isoniazid and rifapentine was noninferior to daily isoniazid for 9 months. Although the rate of permanent drug discontinuation due to adverse events was higher with rifapentine/ isoniazid, this regimen had a higher treatment completion rate than daily isoniazid in this study. The efficacy of this combination regimen in HIV-infected individuals not receiving ART and in children <12 years of age is under study. The regimen is not recommended for pregnant women, for persons with hypersensitivity reactions to isoniazid or rifampin, or for HIV-infected individuals taking ART.


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InternalMed_Harrison. PharMacology Rifapentine’s absorption is improved when the drug is taken with food. After oral administration, rifapentine reaches peak serum concentrations in 5–6 h and achieves a steady state in 10 days. The half-life of rifapentine and its active metabolite, 25-desacetyl rifapentine, is ~13 h. The administered dose is excreted via the liver (70%). aDverse effects The adverse-effects profile of rifapentine is similar to that of other rifamycins. Rifapentine is teratogenic in animal models and is relatively contraindicated in pregnancy. resistance Rifapentine resistance is mediated by mutations in rpoB. Mutations that cause resistance to rifampin also cause resistance to rifapentine.


InternalMed_Harrison

InternalMed_Harrison. resistance Rifapentine resistance is mediated by mutations in rpoB. Mutations that cause resistance to rifampin also cause resistance to rifapentine. Streptomycin Streptomycin was the first antimycobacterial agent used for the treatment of TB. Derived from Streptomyces griseus, streptomycin is bactericidal against dividing M. tuberculosis organisms but has only low-level early bactericidal activity. This drug is administered only by the IM and IV routes. In developed nations, streptomycin is used infrequently because of its toxicity, the inconvenience of injections, and drug resistance. In developing countries, however, streptomycin is used because of its low cost. MechanisM of action Streptomycin inhibits protein synthesis by binding at a site on the 30S mycobacterial ribosome.


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InternalMed_Harrison. MechanisM of action Streptomycin inhibits protein synthesis by binding at a site on the 30S mycobacterial ribosome. PharMacology anD Dosing Serum levels of streptomycin peak at 25–45 μg/mL after a 1-g dose. This agent penetrates poorly into the CSF, reaching levels that are only 20% of serum levels. The usual daily dose of streptomycin (given IM either daily or 5 days per week) is 15 mg/kg for adults and 20–40 mg/kg for children, with a maximum of 1 g/d for both. For patients ≥60 years of age, 10 mg/kg is the recommended daily dose, with a maximum of 750 mg/d. Because streptomycin is eliminated almost exclusively by the kidneys, its use in patients with renal impairment should be avoided or implemented with caution, with lower doses and less frequent administration.


InternalMed_Harrison

InternalMed_Harrison. aDverse effects Adverse reactions occur frequently with streptomycin (10–20% of patients). Ototoxicity (primarily vestibulotoxicity), neuropathy, and renal toxicity are the most common and the most serious. Renal toxicity, usually manifested as nonoliguric renal failure, is less common with streptomycin than with other frequently used aminoglycosides, such as gentamicin. Manifestations of vestibular toxicity include loss of balance, vertigo, and tinnitus. Patients receiving streptomycin must be monitored carefully for these adverse effects, undergoing audiometry at baseline and monthly thereafter.


InternalMed_Harrison

InternalMed_Harrison. resistance Spontaneous mutations conferring resistance to streptomycin are relatively common, occurring in 1 in 106 organisms. In the two-thirds of streptomycin-resistant M. tuberculosis strains exhibiting high-level resistance, mutations have been identified in one of two genes: a 16S rRNA gene (rrs) or the gene encoding ribosomal protein S12 (rpsL). Both targets are believed to be involved in streptomycin ribosomal binding. However, low-level resistance, which is seen in about one-third of resistant isolates, has no associated resistance mutation. A gene (gidB) that confers low-level resistance to streptomycin has recently been identified. Strains of M. tuberculosis resistant to streptomycin generally are not cross-resistant to capreomycin or amikacin. Streptomycin is not used for the treatment of MDR-TB or XDR-TB because of (1) the high prevalence of streptomycin resistance among strains resistant to isoniazid and (2) the unreliability of drug susceptibility testing.


InternalMed_Harrison

InternalMed_Harrison. Second-line antituberculosis agents are indicated for treatment of drug-resistant TB, for patients who are intolerant or allergic to first-line agents, and when first-line supplemental agents are unavailable.


InternalMed_Harrison

InternalMed_Harrison. Fluoroquinolones Fluoroquinolones inhibit mycobacterial DNA gyrase and topoisomerase IV, preventing cell replication and protein synthesis, and are bactericidal. The later-generation fluoroquinolones levofloxacin and moxifloxacin are the most active against M. tuberculosis and are recommended for the treatment of MDR-TB. They are also being investigated for their potential to shorten the course of treatment for TB. In a recent trial, gatifloxacin, which had been withdrawn from the market because of significant dysglycemia, was assessed for treatment shortening; although its inclusion in the TB treatment regimen did not shorten the duration of therapy from 6 to 4 months, the drug did not cause dysglycemia in TB patients who took it thrice weekly for 4 months. Ciprofloxacin and ofloxacin are no longer recommended for the treatment of TB because of poor efficacy. Despite the documented resistance of the infecting strains to these and other early-generation fluoroquinolones, use of a


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InternalMed_Harrison. are no longer recommended for the treatment of TB because of poor efficacy. Despite the documented resistance of the infecting strains to these and other early-generation fluoroquinolones, use of a later-generation fluoroquinolone in patients with XDR-TB has been associated with favorable outcomes. Fluoroquinolones are also considered safe alternatives for patients who develop treatment-limiting adverse effects due to first-line agents. Levofloxacin and moxifloxacin have both been used effectively in the treatment of MDR-TB. The optimal dose of levofloxacin for this indication is being actively studied, but doses of at least 750 mg are commonly used.


InternalMed_Harrison

InternalMed_Harrison. The fluoroquinolones are well absorbed orally, reach high serum levels, and distribute well into body tissues and fluids. Their absorption is decreased by co-ingestion with products containing multivalent cations, such as antacids. Adverse effects are relatively infrequent (0.5–10% of patients) and include gastrointestinal intolerance, rashes, dizziness, and headache. Most studies of fluoroquinolone side effects have been based on relatively short-term administration for bacterial infections, but trials have now shown the relative safety and tolerability of fluoroquinolones administered for months during TB treatment in adults. Although the potential to prolong the QTc interval, leading to cardiac arrhythmias, has been a source of concern with fluoroquinolones, cessation of treatment due to this adverse effect is rare. There is increasing interest in the use of fluoroquinolones in children, which has traditionally been avoided because of the risks of tendon rupture and cartilage


InternalMed_Harrison

InternalMed_Harrison. due to this adverse effect is rare. There is increasing interest in the use of fluoroquinolones in children, which has traditionally been avoided because of the risks of tendon rupture and cartilage damage, because the benefits in treatment of drug-resistant TB may outweigh the risks.


InternalMed_Harrison

InternalMed_Harrison. Mycobacterial resistance can develop rapidly when a fluoroquinolone is inadvertently administered alone. Empirical fluoroquinolone therapy for presumed community-acquired pneumonia is associated with increased fluoroquinolone resistance in M. tuberculosis. Mutations in the genes encoding for DNA gyrase (gyrA and gyrB) are implicated in the majority of cases—but not all cases—of clinical resistance to fluoroquinolones.


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InternalMed_Harrison. Injectable Agents • caPreoMycin Capreomycin, a cyclic peptide antibiotic derived from Streptomyces capreolus, is an important first-choice second-line agent used for treatment of MDR-TB, particularly when additional resistance to aminoglycosides is documented. Capreomycin is administered by the IM route; an inhaled preparation is under study. A dose of 15 mg/kg per day is given five to seven times per week (maximal daily dose, 1 g) and results in peak blood levels of 20–40 μg/mL. The dosage may be reduced to 1 g two or three times per week 2–4 months after mycobacterial cultures become negative. For individuals ≥60 years of age, the dose should be reduced to 10 mg/kg per day (maximal daily dose, 750 mg). For patients with renal insufficiency, the drug should be given intermittently and at lower dosage (12–15 mg/kg two or three times per week). A minimal duration of 3 months is recommended for MDR-TB treatment. Penetration of capreomycin into the CSF is believed to be poor.


InternalMed_Harrison

InternalMed_Harrison. The mechanism of capreomycin’s action is not well understood but involves interference with the mycobacterial ribosome and inhibition of protein synthesis. Resistance to capreomycin is associated with mutations that inactivate a ribosomal methylase (tlyA) or that encode genes for the 16S ribosomal subunit (rrs). Cross-resistance to kanamycin and amikacin is common with rrs but not always with tylA mutations. However, some strains that are resistant to streptomycin, kanamycin, and amikacin generally remain susceptible to capreomycin. Adverse effects of capreomycin are relatively common. Significant hypokalemia and hypomagnesemia as well as otoand renal toxicity have been reported.


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InternalMed_Harrison. aMikacin anD kanaMycin Amikacin and kanamycin are aminoglycosides that exert mycobactericidal activity by binding to the 16S ribosomal subunit. The spectrum of antibiotic activity for amikacin and kanamycin includes M. tuberculosis, several NTM species, and aerobic gram-negative and gram-positive bacteria. Although amikacin is highly active against M. tuberculosis, it is used only infrequently because of its significant side effects. The usual daily adult dosage of both amikacin and kanamycin is 15–30 mg/kg given IM or IV (maximal daily dose, 1 g), with a reduction to 10 mg/kg for patients ≥60 years old. For patients with renal insufficiency, the dose and frequency should be reduced (12–15 mg/kg two or three times per week). Mycobacterial resistance is due to mutations in the genes encoding the 16S ribosomal RNA gene. Cross-resistance among kanamycin, amikacin, and capreomycin is common. Isolates resistant to streptomycin are frequently susceptible to amikacin or kanamycin. Adverse


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InternalMed_Harrison. the 16S ribosomal RNA gene. Cross-resistance among kanamycin, amikacin, and capreomycin is common. Isolates resistant to streptomycin are frequently susceptible to amikacin or kanamycin. Adverse effects of amikacin include ototoxicity (in up to 10% of recipients, with auditory dysfunction occurring more commonly than vestibulotoxicity), nephrotoxicity, and neurotoxicity. Kanamycin has a similar side-effects profile, but adverse reactions are thought to be less frequent and less severe.


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InternalMed_Harrison. Other Second-Line Agents • ethionaMiDe Ethionamide is a derivative of isonicotinic acid. Its mechanism of action is through inhibition of the inhA gene product enoyl–acyl carrier protein (acp) reductase, which is involved in mycolic acid synthesis. Ethionamide is bacteriostatic against metabolically active M. tuberculosis and some NTM. It is used in the treatment of drug-resistant TB, but its use is limited by severe gastrointestinal reactions (including abdominal pain, nausea, and vomiting) as well as significant central and peripheral neurologic side effects, reversible hepatitis (in ~5% of recipients), hypersensitivity reactions, and hypothyroidism. Ethionamide should be taken with food to reduce gastrointestinal effects and with pyridoxine (50–100 mg/d) to limit neuropathic side effects.


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InternalMed_Harrison. cycloserine Cycloserine is an analog of the amino acid d-alanine and prevents cell wall synthesis. It inhibits the action of enzymes, including alanine racemase, that are involved in the production of peptidoglycans. Cycloserine is active against a range of bacteria, including


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InternalMed_Harrison. M. tuberculosis. Mechanisms of mycobacterial resistance are not well understood, but overexpression of alanine racemase can confer resistance in Mycobacterium smegmatis. Cycloserine is well absorbed after oral administration and is widely distributed throughout body fluids, including CSF. The usual adult dosage is 250 mg two or three times per day. Serious potential side effects include seizures and psychosis (with suicide in some cases), peripheral neuropathy, headache, somnolence, and allergic reactions. Drug levels are monitored to achieve optimal dosing and to reduce the risk of adverse effects, especially in patients with renal failure. Cycloserine should be administered as DOT only with caution and with support from experienced TB physicians to patients with epilepsy, active alcohol abuse, severe renal insufficiency, or a history of depression or psychosis.


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InternalMed_Harrison. Para-aMinosalicylic aciD Para-aminosalicylic acid (PAS, 4-aminosalicylic acid) is an oral agent used in the treatment of MDRand XDR-TB. Its bacteriostatic activity is due to inhibition of folate synthesis and of iron uptake. PAS has relatively little activity as an anti-TB agent. Adverse effects may include high-level nausea, vomiting, and diarrhea. PAS may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. The drug should be taken with acidic foods to improve absorption. Enteric-coated PAS granules (4 g orally every 8 h) appear to be better tolerated than other formulations and produce higher therapeutic blood levels. PAS has a short half-life (1 h), and 80% of the dose is excreted in the urine.


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InternalMed_Harrison. clofaziMine Clofazimine is a fat-soluble riminophenazine dye used primarily in the treatment of leprosy worldwide. It is currently gaining popularity in the management of MDRand XDR-TB because of its low cost and intracellular and extracellular activity. By increasing reactive oxygen species and causing membrane destabilization, clofazimine may promote killing of antibiotic-tolerant M. tuberculosis persister organisms. In addition to antimicrobial activity, the drug has other pharmacologic properties—e.g., anti-inflammatory, pro-oxidative, and immunopharmacologic. Clofazimine has a half-life of ~70 days in humans, and average steady-state concentrations are achieved at ~1 month. Ingestion with fatty meals can improve its low and variable rates of absorption (45–62%). Common side effects include gastrointestinal intolerance and reversible orange-to-brownish discoloration of the skin, bodily fluids, and secretions. Dose adjustment may be necessary in patients with severe hepatic


InternalMed_Harrison

InternalMed_Harrison. include gastrointestinal intolerance and reversible orange-to-brownish discoloration of the skin, bodily fluids, and secretions. Dose adjustment may be necessary in patients with severe hepatic impairment. Clofazimine is being studied as part of a regimen developed in Bangladesh for potential shortening of the MDR-TB treatment course. A recent meta-analysis suggested that inclusion of clofazimine in a multidrug regimen for treatment of MDR-TB was associated with a favorable outcome. Newer analogues with improved pharmacokinetics and alternative formulations of clofazimine (liposomal, nanosuspension, inhalational) are being studied.


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InternalMed_Harrison. NEWER ANTITUBERCULOSIS DRUGS Oxazolidinones Linezolid is an oxazolidinone used primarily for the treatment of drug-resistant gram-positive bacterial infections. However, this drug is active in vitro against M. tuberculosis and NTM. Several case series have suggested that linezolid may help clear mycobacteria relatively rapidly when included in a regimen for the treatment of complex cases of MDRand XDR-TB. Linezolid’s mechanism of action is disruption of protein synthesis by binding to the 50S bacterial ribosome. Linezolid has nearly 100% oral bioavailability, with good penetration into tissues and fluids, including CSF. Clinical resistance to linezolid has been reported, but the mechanism is unclear. Adverse effects may include optic and peripheral neuropathy, pancytopenia, and lactic acidosis. Linezolid is a weak monoamine oxidase inhibitor and can be associated with the serotonin syndrome when given concomitantly with serotonergic drugs (primarily antidepressants such as selective


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InternalMed_Harrison. Linezolid is a weak monoamine oxidase inhibitor and can be associated with the serotonin syndrome when given concomitantly with serotonergic drugs (primarily antidepressants such as selective serotonin-reuptake inhibitors). A recent meta-analysis showed that ~80% of patients with MDRor XDR-TB can be successfully treated with linezolid-containing anti-TB regimens; however, significant adverse events attributed to linezolid were reported. For MDR-TB treatment, linezolid is usually administered at a dose of 600 mg (or less in some cases) once daily, which appears to be effective. The single daily dose is associated with fewer adverse events than twice-a-day dosing.


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InternalMed_Harrison. PNU 100480 and AZD 5847, modified versions of oxazolidinones and protein synthesis inhibitors, are undergoing phase 1 trials and appear to have greater efficacy than linezolid against M. tuberculosis. However, the adverse effect profiles of these compounds compared with that of linezolid need further investigation.


InternalMed_Harrison

InternalMed_Harrison. Amoxicillin-Clavulanate and Carbapenems β-Lactam agents are largely ineffective for the treatment of M. tuberculosis because of resistance conferred by a hydrolyzing class A β-lactamase. Because clavulanate may theoretically inhibit the β-lactamase, amoxicillin-clavulanate has been used in the treatment of MDR-TB; however, it is a comparatively weak agent. Carbapenems are poor substrates for class A β-lactamases found in M. tuberculosis. Accordingly, meropenem and imipenem have in vitro activity against M. tuberculosis, and their use to treat MDRand XDR-TB has been reported anecdotally. Nevertheless, the need to administer carbapenems by the IV route and lack of information on the drugs' long-term side effects have restricted their use to certain severe cases only.


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InternalMed_Harrison. Diarylquinolines Bedaquiline (TMC207 or R207910) is a new diarylquinoline with a novel mechanism of action: inhibition of the mycobacterial ATP synthetase proton pump. TMC207 is bactericidal for drug-susceptible and MDR strains of M. tuberculosis. Resistance has been reported and is due to point mutations in the atpE gene encoding for subunit c of ATP synthetase. A phase 2 randomized controlled clinical trial in MDR-TB patients demonstrated substantial improvement in 2-month culture-conversion rates as well as a reduction in acquired resistance to companion drugs. This drug is metabolized by the hepatic cytochrome CYP3A4. Rifampin lowers TMC207 levels by 50%, and protease inhibitors also interact significantly with this drug. The oral bioavailability of TMC207 appears to be excellent. The dosage is 400 mg/d for the first 2 weeks and then 200 mg thrice weekly. The elimination half-life is long (>14 days). A single dose of this drug can inhibit the growth of M. tuberculosis for up to 1


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InternalMed_Harrison. dosage is 400 mg/d for the first 2 weeks and then 200 mg thrice weekly. The elimination half-life is long (>14 days). A single dose of this drug can inhibit the growth of M. tuberculosis for up to 1 week through a combination of long plasma half-life, high-level tissue penetration, and long tissue half-life. Bedaquiline added to a background regimen improved the 2-month sputum culture conversion rate in multicenter, randomized placebo-controlled trials, and these results led to approval by the U.S. Food and Drug Administration (FDA). However, a higher death rate in one trial was observed in the bedaquiline arm than in the control arm (11.4% vs 2.5%); the result was a “black box” warning from the FDA, which also included QT prolongation. The Centers for Disease Control and Prevention has made a provisional recommendation for the use of bedaquiline for 24 weeks in adults with laboratory-confirmed pulmonary MDR-TB when no other effective treatment regimen can be provided.


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InternalMed_Harrison. Nitroimidazoles The prodrugs delamanid (OPC-67683) and PA 824 are novel nitro-dihydro-imidazooxazole derivatives that are activated by M. tuberculosis–specific flavin-dependent nitroreductases whose antimycobacterial activity is attributable to inhibition of mycolic acid biosynthesis. These drugs are currently in phase 2 clinical trials and show potential in shortening treatment duration through their activity against nonreplicating drug-susceptible and drug-resistant mycobacteria. Delamanid was shown in a randomized, placebo-controlled, multinational clinical trial to significantly improve the culture conversion rate at 2 months. QT prolongation occurred significantly more often in delamanid-treated patients, but no clinically relevant events were reported.


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InternalMed_Harrison. Diamines SQ109, an ethambutol analogue with a 1,2-diamine pharmacophore, is the most promising of the diamines for TB treatment. It is activated by mycobacterial cytochrome enzymes and inhibits mycobacterial cell-wall synthesis by an unknown mechanism. It has a high tissue protein-binding capacity with a very long half-life (~61 h) in humans. In vitro studies have demonstrated that SQ109 has low MICs against both susceptible and resistant M. tuberculosis strains as well as a synergistic effect when administered with isoniazid and rifampin. The drug is under study in clinical trials for TB treatment. Pyrroles LL3858, a pyrrole derivative, has entered clinical trials examining its utility in the treatment of drug-susceptible and drug-resistant TB. The drug’s mechanism of action is unknown. However, because it is active against M. tuberculosis strains that are resistant to available anti-TB drugs, its target is thought to differ from those of currently used agents.


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InternalMed_Harrison. More than 150 species of NTM have been identified. Only a minority of these environmental organisms, which are found in soil and water, are important human pathogens. NTM cause extensive disease, primarily in persons with preexisting pulmonary disease or immunocompromise, but also can cause nodular/bronchiectatic disease in otherwise seemingly healthy hosts. NTM are also important causes of infections in surgical settings. The two major classes of NTM are the slow-growing and rapidly growing species; subcultures of the latter grow within 1 week. The growth characteristics of NTM have diagnostic, therapeutic, and prognostic implications. The rate of growth can provide useful preliminary information within a specific clinical context, in that growth within 2–3 weeks is much more likely to indicate an NTM than M. tuberculosis. When NTM do grow from cultures, colonization should be distinguished from active disease in order to optimize the risk and benefit of prolonged treatment with


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InternalMed_Harrison. to indicate an NTM than M. tuberculosis. When NTM do grow from cultures, colonization should be distinguished from active disease in order to optimize the risk and benefit of prolonged treatment with multiple medications. According to the recommendations of the American Thoracic Society and the Infectious Diseases Society of America, significant clinical manifestations and/or sputum radiographic evidence of progressive disease consistent with NTM infection as well as either reproducible sputum culture results or a single positive culture are required for the diagnosis of NTM pulmonary disease. Isolation of NTM from blood or from an infected-appearing extrapulmonary site, such as soft tissue or bone, is usually indicative of disseminated or local NTM infection (Chap. 204). Treatment of NTM disease is prolonged and requires multiple medications. Side effects of the regimens employed are common, and intermittent therapy is often used to mitigate these adverse events. Treatment regimens


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InternalMed_Harrison. disease is prolonged and requires multiple medications. Side effects of the regimens employed are common, and intermittent therapy is often used to mitigate these adverse events. Treatment regimens depend on the NTM species, the extent or type of disease, and—to some degree—drug susceptibility test results. The nodular bronchiectatic form of MAC infection is generally treated three times per week, whereas fibrocavitary or disseminated MAC infection is treated daily.


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InternalMed_Harrison. M. avium Complex Among the NTM, MAC organisms most commonly cause human disease. In immunocompetent hosts, MAC species are most often found in conjunction with underlying significant lung disease, such as chronic obstructive pulmonary disease or bronchiectasis. For patients with nodular or bronchiectatic MAC lung disease, an initial regimen consisting of clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol is given three times per week. Routine initial testing for macrolide resistance is recommended, as is testing at 6 months with a failing regimen (i.e., with cultures persistently positive for NTM).


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InternalMed_Harrison. In immunocompromised individuals, disseminated MAC infection is generally treated with clarithromycin, ethambutol, and rifabutin. Azithromycin may be substituted in patients unable to tolerate clarithromycin. Amikacin and fluoroquinolones are often used in salvage regimens. Treatment for disseminated MAC infection in AIDS patients may be lifelong in the absence of immune reconstitution. At least 12 months of MAC therapy and 6 months of effective immune reconstitution may be adequate. M. kansasii M. kansasii is the second most common NTM causing human disease. It is also the second most common cause of NTM pulmonary disease in the United States, where it is most often reported in the southeastern region. M. kansasii infection can be treated with isoniazid, rifampin, and ethambutol; therapy continues for 12 months after culture conversion. Rifampin-resistant M. kansasii has been treated with clarithromycin, trimethoprim-sulfamethoxazole, and streptomycin.


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InternalMed_Harrison. Rapidly Growing Mycobacteria Rapidly growing mycobacteria causing human disease include Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae. Treatment of these mycobacteria is complex and should be undertaken with input from experienced clinicians. Testing for macrolide resistance is recommended. However, in rapidly growing mycobacteria, an inducible erm gene may confer in vivo macrolide resistance to isolates that are susceptible in vitro. M. marinum M. marinum is an NTM found in salt water and freshwater, including swimming pools and fish tanks. It is a cause of localized soft-tissue infections, which may require surgical management. Combination regimens include clarithromycin and either ethambutol or rifampin. Other agents with activity against M. marinum include doxycycline, minocycline, and trimethoprim-sulfamethoxazole.


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InternalMed_Harrison. Clarithromycin is a macrolide antibiotic with broad activity against many gram-positive and gram-negative bacteria as well as NTM. This drug is active against MAC organisms and many other NTM species, inhibiting protein synthesis by binding to the 50S mycobacterial ribosomal subunit. NTM resistance to macrolides is probably caused by overexpression of the gene ermB, with consequent methylation of the binding site. Clarithromycin is well absorbed orally and distributes well to tissues. It is cleared both hepatically and renally; the dosage should be reduced in renal insufficiency. Clarithromycin is a substrate for and inhibits cytochrome 3A4 and should not be administered with cisapride, pimozide, or terfenadine because cardiac arrhythmias may occur. Numerous drugs interact with clarithromycin through the CYP3A4 metabolic pathway. Rifampin lowers clarithromycin levels; conversely, rifampin levels are increased by clarithromycin. However, the clinical relevance of this interaction does


InternalMed_Harrison

InternalMed_Harrison. through the CYP3A4 metabolic pathway. Rifampin lowers clarithromycin levels; conversely, rifampin levels are increased by clarithromycin. However, the clinical relevance of this interaction does not appear to be great.


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InternalMed_Harrison. For patients with nodular/bronchiectatic MAC infection, the dosage of clarithromycin is 500 mg, given morning and evening three times a week. For the treatment of fibrocavitary or severe nodular/ bronchiectatic MAC infection, a dose of 500–1000 mg is given daily. Disseminated MAC infection is treated with 1000 mg daily. Clarithromycin is used in combination regimens that typically include ethambutol and a rifamycin in order to avoid the development of macrolide resistance. Adverse effects include frequent gastrointestinal intolerance, hepatotoxicity, headache, rash, and rare instances of hypoglycemia. Clarithromycin is contraindicated during pregnancy because of its teratogenicity in animal models.


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InternalMed_Harrison. Azithromycin Azithromycin is a derivative of erythromycin. Although technically an azalide and not a macrolide, it works similarly to macrolides, inhibiting protein synthesis through binding to the 50S ribosomal subunit. Resistance to azithromycin is almost always associated with complete cross-resistance to clarithromycin. Azithromycin is well absorbed orally, with good tissue penetration and a prolonged half-life (~48 h). The usual dosage for treatment of MAC infection is 250 mg/d or 500 mg three times per week. Azithromycin is used in combination with other agents to avoid the development of resistance. For prophylaxis against disseminated MAC infection in immunocompromised individuals, a dose of 1200 mg once per week is given. Because azithromycin is not metabolized by cytochrome P450, it interacts with few drugs. Adjustment of the dosage on the basis of renal function is not necessary.


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InternalMed_Harrison. Cefoxitin Cefoxitin is a second-generation parenteral cephalosporin with activity against rapidly growing NTM, particularly M. abscessus, M. marinum, and M. chelonae. Its mechanism of action against NTM is unknown but may involve inactivation of cell wall synthesis enzymes. High doses are used for treatment of NTM: 200 mg/kg IV three or four times per day, with a maximal daily dose of 12 g. The half-life of cefoxitin is ~1 h, with primarily renal clearance that requires adjustment in renal insufficiency. Adverse effects are uncommon but include gastrointestinal manifestations, rash, eosinophilia, fever, and neutropenia.


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InternalMed_Harrison. Treatment of mycobacterial infections requires multiple-drug regimens that often exert significant side effects with the potential to limit tolerability. The prolonged duration of treatment has vastly improved results over those obtained in past decades, but drugs and regimens that will shorten treatment duration and limit adverse drug effects and interactions are needed.


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InternalMed_Harrison. syphilis Sheila A. Lukehart DEFINITION Syphilis, a chronic systemic infection caused by Treponema pallidum subspecies pallidum, is usually sexually transmitted and is characterized 206 sECTIOn 9 sPIROCHETAL dIsEAsEs by episodes of active disease interrupted by periods of latency. After an incubation period averaging 2–6 weeks, a primary lesion appears—often associated with regional lymphadenopathy—that resolves without treatment. The secondary stage, associated with generalized mucocutaneous lesions and generalized lymphadenopathy, is followed by a latent period of subclinical infection lasting years or decades. Central nervous system (CNS) involvement may occur early in infection and may be symptomatic or asymptomatic. In the preantibiotic era, about one-third of patients with untreated cases developed the tertiary stage, characterized by progressive destructive mucocutaneous, musculoskeletal, or parenchymal lesions; aortitis; or late CNS manifestations.


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InternalMed_Harrison. The Spirochaetales include four genera that are pathogenic for humans and for a variety of other animals: Leptospira species, which cause leptospirosis (Chap. 208); Borrelia species, which cause relapsing fever and Lyme disease (Chaps. 209 and 210); Brachyspira species, which cause intestinal infections; and Treponema species, which cause the diseases known collectively as treponematoses (see also Chap. 207e). The Treponema species include T. pallidum subspecies pallidum, which causes venereal syphilis; T. pallidum subspecies pertenue, which causes yaws; T. pallidum subspecies endemicum, which causes endemic syphilis or bejel; and T. carateum, which causes pinta. Until recently, the subspecies were distinguished primarily by the clinical syndromes they produce. Researchers have now identified molecular signatures sex with men (MSM), 20–70% of whom are co-infected with HIV 1133 (depending on geographic location). The number of primary and secondary cases among women in the United


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InternalMed_Harrison. molecular signatures sex with men (MSM), 20–70% of whom are co-infected with HIV 1133 (depending on geographic location). The number of primary and secondary cases among women in the United States increased from 2004 to 2008 but has since been declining in conjunction with a decline in congenital syphilis. Surveillance of the number of new cases of primary and secondary syphilis has revealed multiple 7to 10-year cycles, which may be attributed to herd immunity in at-risk populations, changing sexual behaviors, and changes in control efforts.


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InternalMed_Harrison. The populations at highest risk for acquiring syphilis have changed over time, with outbreaks among MSM in the pre-HIV era of the late 1970s and early 1980s as well as at present. It is speculated that recent increases in syphilis and other sexually transmitted infections in MSM may be due to unprotected sex between persons who are HIV concordant and to disinhibition caused by highly effective antiretroviral therapies. The syphilis epidemic that peaked in 1990 predominantly affected African-American heterosexual men and women and occurred largely in urban areas, where infectious syphilis was correlated with the exchange of sex for crack cocaine. The rate of primary and secondary syphilis among African Americans nearly doubled between 2003 and 2009, remains higher than rates for other racial/ethnic groups, but has since declined somewhat (Fig. 206-1).


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InternalMed_Harrison. The incidence of congenital syphilis roughly parallels that of infectious syphilis in women. In 2011, 360 cases in infants <1 year of age were reported, for a decline of 20% since 2008. The case definition for congenital syphilis was broadened in 1989 and now includes all live or stillborn infants delivered to women with untreated or inadequately treated syphilis. One-third to one-half of individuals named as sexual contacts of that can differentiate the three subspecies of T. pallidum by culture-independent methods based on polymerase chain reaction (PCR), but other sequence signatures cross subspecies boundaries in certain strains. Other Treponema species found in the human mouth, genital mucosa, and gastrointestinal tract have been associated with disease (e.g., periodontitis), but their role as primary etiologic agents is unclear.


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InternalMed_Harrison. T. pallidum subspecies pallidum (referred to hereafter as T. pallidum), a thin spiral organism, has a cell body surrounded by a trilaminar cytoplasmic membrane, a delicate peptidoglycan layer providing some structural rigidity, and a lipid-rich outer membrane containing relatively few integral membrane proteins. Endoflagella wind around the cell body in the periplasmic space and are responsible for motility.


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InternalMed_Harrison. T. pallidum cannot be cultured in vitro, and little was known about its metabolism until the genome was sequenced in 1998. This spirochete possesses severely limited metabolic capabilities, lacking the genes required for de novo synthesis of most amino acids, nucleotides, and lipids. In addition, T. pallidum lacks genes encoding the enzymes of the Krebs cycle and oxidative phosphorylation. The organism contains numerous compensatory genes predicted to encode transporters of amino acids, carbohydrates, and lipids. In addition, genome analyses and other studies have revealed the existence of a 12-member gene family (tpr) that bears similarities to variable outer-membrane antigens of other spirochetes. One member, TprK, has discrete variable (V) regions that undergo antigenic variation during infection, providing a mechanism for immune evasion.


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InternalMed_Harrison. The only known natural host for T. pallidum is the human. T. pallidum can infect many mammals, but only humans, higher apes, and a few laboratory animals regularly develop syphilitic lesions. Rabbits are used to propagate virulent strains of T. pallidum and serve as the animal model that best reflects human disease and immunopathology. Nearly all cases of syphilis are acquired by sexual contact with infectious lesions (i.e., the chancre, mucous patch, skin rash, or condylomata lata; see Fig. 25e-20). Less common modes of transmission include nonsexual personal contact, infection in utero, blood transfusion, and organ transplantation.


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InternalMed_Harrison. With the advent of penicillin therapy, the total number of cases of syphilis reported annually in the United States declined significantly to a low of 31,575 cases in 2000—a 95% decrease from 1943—with <6000 reported cases of infectious primary and secondary syphilis (the latter being a better indicator of disease activity than total syphilis cases). Since 2000, the number of cases of primary and secondary syphilis has more than doubled, with more than 14,000 cases reported in 2012 (Fig. 206-1). Approximately 70% of these cases were in men who have persons with infectious syphilis become infected. Many have already developed manifestations of syphilis when they are first seen, and ∼30% of asymptomatic contacts examined within 30 days of exposure actually have incubating infection and will later develop infectious syphilis if not treated. Thus, identification and treatment of all recently exposed sexual contacts continue to be important aspects of syphilis control.


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InternalMed_Harrison. Syphilis remains a significant health problem globally; the number of new infections is estimated at 11 million per year. The regions that are most affected include sub-Saharan Africa, South America, China, and Southeast Asia. During the past decade, the incidence rate in China has increased by approximately eightfold, and higher rates of infectious syphilis have been reported among MSM in many European countries. Worldwide, there are estimated to be 1.4 million cases of syphilis among pregnant women, with 500,000 adverse pregnancy outcomes annually (e.g., stillbirth, neonatal and early fetal death, prematurity/low birth weight, and infection in newborns). Congenital syphilis rates in China are ∼150 cases per 100,000 live births. FIGuRE 206-1 Primary and secondary syphilis in the United States, 1990–2012, by sex (A) and by race or ethnicity (B). (Data from the Centers for Disease Control and Prevention.) Number of cases 30,000 40,000


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InternalMed_Harrison. Number of cases 30,000 40,000 Number of cases 30,000 20,000 20,000 10,000 10,000 T. pallidum rapidly penetrates intact mucous membranes or microscopic abrasions in skin and, within a few hours, enters the lymphatics and blood to produce systemic infection and metastatic foci long before the appearance of a primary lesion. Blood from a patient with incubating or early syphilis is infectious. The generation time of T. pallidum during early active disease in vivo is estimated to be ∼30 h, and the incubation period of syphilis is inversely proportional to the number of organisms inoculated. The 50% infectious dose for intradermal inoculation in humans has been calculated to be 57 organisms, and the treponeme concentration generally reaches 107/g of tissue before a clinical lesion appears. The median incubation period in humans (∼21 days) suggests an average inoculum of 500–1000 infectious organisms for naturally acquired disease; the incubation period rarely exceeds 6 weeks.


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InternalMed_Harrison. The primary lesion appears at the site of inoculation, usually persists for 4–6 weeks, and then heals spontaneously. Histopathologic examination shows perivascular infiltration, chiefly by CD4+ and CD8+ T lymphocytes, plasma cells, and macrophages, with capillary endothelial proliferation and subsequent obliteration of small blood vessels. The cellular infiltration displays a TH1-type cytokine profile consistent with the activation of macrophages. Phagocytosis of opsonized organisms by activated macrophages ultimately causes their destruction, resulting in spontaneous resolution of the chancre.


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InternalMed_Harrison. The generalized parenchymal, constitutional, and mucocutaneous manifestations of secondary syphilis usually appear ∼6–8 weeks after the chancre heals, although primary and secondary manifestations may overlap. In contrast, some patients may enter the latent stage without ever recognizing secondary lesions. The histopathologic features of secondary maculopapular skin lesions include hyperkeratosis of the epidermis, capillary proliferation with endothelial swelling in the superficial dermis, dermal papillae with transmigration of polymorphonuclear leukocytes, and—in the deeper dermis—perivascular infiltration by CD8+ T lymphocytes, CD4+ T lymphocytes, macrophages, and plasma cells. Treponemes are found in many tissues, including the aqueous humor of the eye and the cerebrospinal fluid (CSF). T. pallidum invades the CNS during the first weeks or months of infection, and CSF abnormalities are detected in as many as 40% of patients during the secondary stage. Clinical hepatitis and immune


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InternalMed_Harrison. T. pallidum invades the CNS during the first weeks or months of infection, and CSF abnormalities are detected in as many as 40% of patients during the secondary stage. Clinical hepatitis and immune complex–induced glomerulonephritis are relatively rare but recognized manifestations of secondary syphilis; liver function tests may yield abnormal results in up to one-quarter of patients with early syphilis. Generalized non-tender lymphadenopathy is noted in 85% of patients with secondary syphilis. The paradoxical appearance of secondary manifestations despite high titers of antibody (including immobilizing antibody) to


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InternalMed_Harrison. T. pallidum may result from immune evasion due to antigenic variation or changes in expression of surface antigens. Secondary lesions generally subside within 2–6 weeks, and the infection enters the latent stage, which is detectable only by serologic testing. In the preantibiotic era, up to 25% of untreated patients experienced at least one generalized or localized mucocutaneous relapse, usually during the first year. Therefore, identification and examination of sexual contacts are most important for patients with syphilis of <1 year’s duration.


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InternalMed_Harrison. As stated earlier, about one-third of patients with untreated latent syphilis developed clinically apparent tertiary disease in the preantibiotic era, when the most common types of tertiary disease were the gumma (a usually benign granulomatous lesion); cardiovascular syphilis (usually involving the vasa vasorum of the ascending aorta and resulting in aneurysm); and late symptomatic neurosyphilis (tabes dorsalis and paresis). In Western countries today, specific treatment for early and latent syphilis and coincidental therapy (i.e., therapy with antibiotics that are given for other conditions but are active against treponemes) have nearly eliminated tertiary syphilis. Asymptomatic CNS involvement, however, is still demonstrable in up to 40% of persons with early syphilis and 25% of patients with late latent syphilis, and cases of general paresis and tabes dorsalis are being reported from China. The factors that contribute to the development and progression of tertiary disease are


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InternalMed_Harrison. with late latent syphilis, and cases of general paresis and tabes dorsalis are being reported from China. The factors that contribute to the development and progression of tertiary disease are unknown.