Tachyplesin III and granulocyte-colony stimulating factor enhance the efficacy of tazobactam/piperacillin in a neutropenic mouse model of polymicrobial peritonitis.
We investigated the efficacy of tazobactam/piperacillin (TZP), tachyplesin III and granulocyte-colony stimulating factor (G-CSF) in an experimental murine neutropenic intraabdominal infection. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 pre-infection. Septic shock was induced by cecal ligation and puncture. Animals received intravenously isotonic sodium chloride solution (control group C1), 1mg/kg of tachyplesin III, 120 mg/kg of TZP, 0.1mg/kg of G-CSF, tachyplesin III plus TZP, G-CSF plus TZP and finally tachyplesin III plus G-CSF plus TZP, respectively. Lethality, bacterial growth in blood, peritoneum, spleen, liver, and mesenteric lymph nodes, endotoxin, IL-6 and TNF-alpha concentrations in plasma were evaluated. All compounds reduced the lethality when compared to controls. Endotoxin and cytokine plasma levels were significantly higher in TZP-treated animals compared to tachyplesin III-treated animals. Finally, all drug combinations showed to be the most effective treatment in reducing all variables measured. Interestingly, the strongest results concerning the bacterial growth inhibition, lethality and endotoxemia were obtained when the three compounds were contemporaneously administered. The presence of their positive interaction makes tachyplesin III and G-CSF potentially valuable as an adjuvant for antimicrobial chemotherapy of sepsis.
Cirioni
Oscar
O
Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy. anconacmi@interfree.it <anconacmi@interfree.it>
Ghiselli
Roberto
R
Kamysz
Wojciech
W
Orlando
Fiorenza
F
Silvestri
Carmela
C
Mocchegiani
Federico
F
Di Matteo
Fabio
F
Kamysz
Elzbieta
E
Riva
Alessandra
A
Rocchi
Marco
M
Saba
Vittorio
V
Scalise
Giorgio
G
Giacometti
Andrea
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology; D010878:Piperacillin / Q000627:therapeutic use*; D015996:Survival Rate; D000078142:Tazobactam; D013997:Time Factors
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004268:DNA-Binding Proteins; D010456:Peptides, Cyclic; C057636:tachyplesin peptide, Tachypleus tridentatus; D016179:Granulocyte Colony-Stimulating Factor; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin