Continuous administration of PBP-2- and PBP-3-specific beta-lactams causes higher cytokine responses in murine Pseudomonas aeruginosa and Escherichia coli sepsis.
OBJECTIVE
Initial antibiotic treatment of severe infections can lead to clinical deterioration due to sudden endotoxin release and concomitant exaggerated inflammatory response. Antibiotic-induced morphological changes may contribute to this phenomenon. High-dose ceftazidime, which inhibits penicillin-binding protein (PBP)-1 in Gram-negative bacteria, causes quick bacteriolysis and low endotoxin release. Low-dose ceftazidime leads to PBP-3 inhibition, which causes bacterial filament formation, associated with high endotoxin releases. PBP-2-specific antibiotics induce spheroplasts, again associated with low endotoxin release. We hypothesized that antibiotic type, concentration and regimen influence bacterial morphology, endotoxin levels and inflammatory response.


METHODS
Neutropenic mice with Escherichia coli or Pseudomonas aeruginosa sepsis were treated with ceftazidime or meropenem 10-320 mg/kg as an intravenous bolus or as continuous tail vein infusions of 0.1 mL/h. Four hours later, bacterial counts, morphology, plasma endotoxin, pro-inflammatory cytokines [tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)] and antibiotic concentrations were measured.


RESULTS
Continuous infusion of 80 mg/kg ceftazidime was the lowest dose preventing filaments in E. coli infections. Bolus treatment resulted in filament formation, irrespective of the dose. During continuous treatment, IL-6 and TNF-alpha concentrations were higher compared with bolus treatment and controls for both antibiotics and both strains. A clear relationship between cfu counts in muscle and circulating IL-6 was shown (r=- 0.579, P=0.007), suggesting that plasma IL-6 is a valuable indicator of bacterial killing at the infection site.


CONCLUSIONS
Our findings show that not PBP affinity but the method of antibiotic administration is crucial during initial treatment of severe infections.
Buijs
Jacqueline
J
Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands. j.buijs@atriummc.nl/jacqbuijs@hotmail.com
Dofferhoff
Anthonius S M
AS
Mouton
Johan W
JW
van der Meer
Jos W M
JW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002442:Ceftazidime / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015169:Colony Count, Microbial; D016207:Cytokines / Q000276:immunology*; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D005260:Female; D000077731:Meropenem; D051379:Mice; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000166:cytology / Q000187:drug effects; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D013845:Thienamycins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004731:Endotoxins; D046915:Penicillin-Binding Proteins; D013845:Thienamycins; D002442:Ceftazidime; D000077731:Meropenem