ANCONA, ITALY—Critical care specialists may soon turn to innate peptide antibiotics with which animals have fought gram-negative bacteria for eons: Cecropins derived from insects and mammals rescue rats from experimentally induced septic shock.[1] They offer an advantage over conventional antibiotics: Besides killing bacteria, cecropins reduce plasma levels of endotoxin and thereby mitigate its dangerous inflammatory effects.

One major complication of septic shock resulting from gram-negative bacterial infection is inflammation induced by endotoxin. This bacterial-membrane–associated lipopolysaccharide triggers release of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. “High amounts of TNF-alpha are toxic for the host,” explained Andrea Giacometti, MD, Associate Professor of Infectious Diseases at the University of Ancona, to PULMONARY REVIEWS. Further, he pointed out, “In animal models, … small doses of purified [endotoxin], in the absence of bacterial growth, can kill the animals and reproduce the symptoms of sepsis.”

Paradoxically, antibiotics may briefly worsen sepsis by causing gram-negative organisms to release endotoxin. Therefore, a goal of new sepsis treatments is to lower levels of endotoxin, as well as the bacteria that produce it.

Because cecropins isolated from silk moth (cecropins A and B) and pig intestine (cecropin P1) possess activities against both, Dr. Giacometti and colleagues tested their ability to reduce bacterial counts, endotoxin levels, and mortality in rats inoculated intraperitoneally with Escherichia coli. Each group of 15 rats was injected with either saline, E coli alone, or E coli plus either 1 mg/kg of cecropin A, B, or P1 or the antibiotics imipenem or piperacillin (20 mg/kg and 60 mg/kg, respectively). All five drug treatments significantly reduced mortality. All but two rats (86.7%) injected with bacteria alone died within 36 hours, whereas none of the rats receiving cecropin B, and only one rat (6.7%) in each of the cecropin A and P1 groups, died. Further, cecropins compared favorably with ß-lactams: Piperacillin failed to rescue five rats (33.3%) and imipenem failed to rescue three (20%); the difference in mortality between the cecropin B and piperacillin groups was statistically significant.

CECROPINS REDUCE BACTERIA, ENDOTOXINS

Dr. Giacometti and colleagues also obtained blood and abdominal fluid samples from the rats 48 hours after inoculation. All drug treatments significantly reduced bacterial counts in both fluids. Examination of plasma levels of endotoxin and TNF-alpha, however, revealed a dramatic difference: While all three cecropins significantly reduced these levels, both ß-lactams significantly increased them. “I believe that the high anti-endotoxin activity of cecropin B produced higher survival in the cecropin B–treated rats compared with the piperacillin-treated an-imals,” Dr. Giacometti said. “[C]ecropins are positively charged molecules that bind and inactivate endotoxins.” “Cecropins (and many polycationic peptides) … have a broad spectrum of activity, kill bacteria rapidly, are unaffected by classical antibiotic resistance mutations … and possess anti-endotoxic activity,” added Dr. Giacometti. “For this reason, it could be reasonable to use them in combination with classical antibiotics to increase killing, and at the same time, neutralize [endotoxin].”

—Mimi Zucker, PhD

Reference
Giacometti A, Cirioni O, Ghiselli R, et al. Effect of mono-dose intraperitoneal cecropins in experimental septic shock. Crit Care Med. 2001;29:1666-1669.

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