Pharmacokinetic Considerations regarding Tigecycline for Multidrug-Resistant (MDR) Klebsiella pneumoniae or MDR Acinetobacter baumannii Urosepsis

I read with interest Dr. Curcio's letter arguing against tigecycline for urosepsis. Since tigecycline is one of the few antibiotics highly active against multidrug-resistant (MDR) Klebsiella pneumoniae and MDR Acinetobacter baumannii (MDR KP/AB), optimal dosing is critical for maximal therapeutic effectiveness. MICs of most of these pathogens are usually ≤0.5 (2, 5). Tigecycline's pharmacokinetic parameters include a serum half-life (t1/2) of 42 h, a volume of distribution (Vd) of 8 liters/kg, and hepatobiliary excretion with ∼20% excreted into urine. After a 100-mg (intravenous [i.v.]) dose, tigecycline serum concentrations are ∼1.5 μg/ml, and urinary concentrations are ∼0.3 μg/ml (3, 8, 10). However, for MDR KP/AB urosepsis/bacteremias resistant to other antibiotics, we have used “high-dose” tigecycline, since higher peak serum concentrations result in higher urinary concentrations. Using “high-dose” tigecycline, i.e., an initial dose of 200 mg (i.v.) one time followed by 100 mg (i.v.) every 24 h (q24h), we have successfully treated several cases of MDR KP/AB without any side effects. Even at the usual dose, if tigecycline is given too rapidly or in an inadequate volume, nausea/vomiting may result (3). Using a 200-mg (i.v.) initial dose, given in 400 ml, followed by a 200-mg (i.v.) dose q24h given in 200 ml, we have not had nausea/vomiting. If MDR KP/AB urinary tract infection (UTI)/urosepsis does not respond to a regimen of 200 mg (i.v.) one time followed by 100 mg (i.v.) q24h, we have used 400 mg (i.v.) one time followed by 200 mg (i.v.) q24h. The 400-mg (i.v.) initial dose is given in 500 ml, and the 200-mg daily maintenance dose given in 300 ml also has not been associated with nausea/vomiting. Given the emergence of MDR KP/AB UTI/urosepsis, tigecycline is one of few antibiotics effective against these pathogens (2, 7, 12). Concern regarding tigecycline for treating UTI/urosepsis due to MDR KP/AB is based on relatively low urinary concentrations. However, “high-dose” tigecycline (initial i.v. dose of 200 mg to 400 mg) is effective if the MIC is less than or equal to achievable urinary concentrations (Table ​(Table11). TABLE 1. Tigecycline: dose-related serum and urinary concentrations Most strains of MDR KP/AB will be effectively eradicated using the regimen of 200 mg (i.v.) one time followed by 100 mg (i.v.) q24h. However, with MDR KP/AB isolates with relatively high MICs, tigecycline given as an initial dose of 400 mg (i.v.) one time followed by 200 mg (i.v.) q24h has been effective. At high doses, tigecycline appears to resemble doxycycline's concentration-dependent kinetics at high doses (4). For MDR aerobic gram-negative bacteremias, “high-dose” tigecycline may optimize concentration-dependent killing (1). For UTIs, “high-dose” tigecycline provides higher urinary concentrations (2, 5). Tigecycline is a valuable addition to the therapeutic armamentarium to treat MDR KP/AB UTI/urosepsis not susceptible to other antibiotics. Our experience suggests that if urinary concentrations are above the uropathogen's MIC, “high-dose” tigecycline can be used effectively to treat MDR KP/AB UTI/urosepsis resistant to other antibiotics.