The most serious complication of BCG therapy is generalized sepsis secondary to intravascular absorption of mycobacteria or other urinary pathogens. Traumatic catheterization, identified in more than two-thirds of such cases, is the most common etiologic factor (Lamm 1992). Severe cystitis and recent transurethral surgery (within 1 week) are other potential routes for dissemination. Fever is the most common presenting sign and typically occurs within 12 h ofBCG instillation (Pater-son and Patel 1998). High-grade fever within 2 h of BCG instillation is especially worrisome, as is hemodynamic instability and other signs of multisystem organ failure (Dalbagni and O'Donnell 2006). Blood and urine cultures are typically negative. The mortality rate of BCG sepsis approaches 50%; therefore empiric triple-drug therapy is indicated in any patient with persistent fever and evidence of sepsis in temporal association with BCG administration (Malkowicz 2002; Paterson and Patel 1998). A 6-month course of INH, rifampin, and ethambutol is the current standard of care (Table 13.3). Ethambutol may be discontinued after 2 months depending upon organism susceptibility and clinical resolution (Blumberg et al. 2003). Since the treatment response to antitubercular medications is delayed by 2-7 days, traditional guidelines recommended concurrent therapy with cycloserine, an antibiotic capable of controlling mycobacteria within 24 h (Lamm et al. 1992; Lotte et al. 1984). Recent susceptibility studies, however, have demonstrated that commercially available BCG strains are highly resistant to cycloserine. In contrast, fluoroquinolones, gentamicin, and all antitubercular drugs, except pyrazinamide, retain activity against BCG (Durek et al. 2000). As such, contemporary guidelines recommend the addition of a fluoroquinolo-ne or ampicillin plus gentamicin combination to standard antitubercular therapy in cases ofBCG sepsis (Durek et al. 2000; Paterson and Patel 1998). This allows rapid inhibition of mycobacterial growth while also providing adequate empiric coverage for possible Gram-negative sepsis. The duration of treatment with supplementary antibiotics, determined by the results of
Table 13.3. Treatment ofBCG sepsis
Isoniazid plus Rifampin plus Ethambutol plus Ampicillin plus Gentamicin2 Or ciprofloxacin
300 mg p.o. daily 600 mg p.o. daily 1,200 mgp.o. daily 1 g i.v. every 6 h 7 mg/kg i.v. every 24 h 500 mg p.o. twice daily or 400 mg i.v. every 12h
Based on potential nephrotoxicity, gentamicin dosing requires assessment of renal function standard blood and urine cultures, need only be short-term in true BCG sepsis. One caveat is the development of intolerance or systemic complication to any of the standard antitubercular drugs, in which case a fluoroquinolone maybe used in substitution.
The use of corticosteroids in BCG sepsis is somewhat controversial. Severe type IV hypersensitivity is an important diagnosis to consider in any patient with suspected BCG sepsis. Since the two diagnoses are often difficult to differentiate, most authorities recommend the addition of corticosteroids (prednisolone 40 mg p.o. daily) or hydrocortisone 100 mg i.v. four times daily (Lamm 1992; Paterson and Patel 1998) to standard treatment in the short term. Animal studies have shown that prednisolone in combination with standard antitubercular therapy is more effective than standard therapy alone (DeHaven et al. 1992). Exacerbation of true BCG sepsis secondary to immunosup-pression remains a concern; therefore the decision to continue steroid therapy should be made relatively soon, based on clinical and laboratory parameters.
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