INFLUENCE OF DRUG CLASS AND DOSE SIZE ON ANTIBIOTIC-INDUCED ENDOTOXINIL-6 RELEASE AND IMPACT ON EFFICACY OF ANTIENDOTOXIN ANTIBODY/

There are limited comparative data on antibiotic-mediated endotoxin re lease and cytokine liberation in septic hosts. To determine the effect of antimicrobial drug class and dose size on the relative concentrati on kinetics of free endotoxin and interleukin-6 (IL-6), CF-1 mice were made septic following a thermal injury and low-dose (10(3) CFU) subes char challenge with Klebsiella pneumoniae serotype K2. Single intraper itoneal (i.p.) doses (in mg/kg) of ceftazidime (TAZ, 25, 200), aztreon am (AZT, 200), piperacillin (PIP, 200), meropenem (MER, 200), imipenem (IMI, 25, 100, 200), ciprofloxacin (CIP, 25) and gentamicin (GEN, 25) were administered at 72 h post burn and infection, when mice were sep tic with organ dysfunction. AZT, TAZ, MER, PIP (each at 200 mg/kg) and IMI (100 mg/kg) resulted in fold-increases in median endotoxin levels of 15.3, 14.9, 13.1, 8.2 and 12.4, respectively. All were significant ly greater than predose baseline values (P <0.01), however differences among agents did not reach statistical significance. The increases in free endotoxin levels for all of the beta lactams (8.2-15.3-fold) and CIP (7.7-fold) were significantly greater than for GEN (3.9-fold, P < 0.01). The fold-rise in median IL-6 concentrations from baseline for t he beta lactams ranged from 3.0-7.7. All of the beta lactams resulted in statistically greater IL-6 release as compared with CIP (1.9-fold, P < 0.01) and GEN (1.4-fold, P <0.01). The median endotoxin concentrat ions were significantly higher for the 100 mg/kg (668 EU/ml) and 200 m g/kg (862 EU/ml) doses of IMI compared to the 25 mg/kg dose (378 EU/mL , P <0.05). There was also a significant increase in endotoxin levels with a dose increase of TAZ from 25 to 200 mg/kg (597 vs 1030 EU/ml, P =0.017). The addition of antiendotoxin monoclonal antibody (E5, 2 mg/k g i.p. four times daily [qid]) to AZT (75 mg/kg qid) or TAZ (10 mg/kg old) for 2 days significantly reduced the mortality by similar to 20-4 0% for a 2-3 day period (P <0.05) compared to ATT or TAZ alone. In con trast, the administration of E5 with either CIP (10 mg/kg) or GEN (10 mg/kg) by the same old dosing schedule did not improve survival (P >0. 05). In conclusion, data from the present study, generated in a physio logically relevant model of sepsis, found relatively greater release o f unbound endotoxin and IL-6 with the beta lactams, intermediate for C IP and lowest for GEN. The size of the dose of two beta lactams was al so found to be a potentially important variable, suggesting that dose optimization might be possible to minimize antibiotic-associated endot oxin release. Furthermore, under our experimental conditions, the effi cacy of E5 appears to be dependent upon the antibiotic with which it i s administered. In order to understand better the potential significan ce of antibiotic-induced endotoxin release, the pharmacologic variable s of the antimicrobial should be systematically evaluated in preclinic al and clinical trials.