Comparative Effects of Carbapenems on Bacterial Load and Host Immune Response in aKlebsiella pneumoniaeMurine Pneumonia Model

Abstract

Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum ␤-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log 10 CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log 10 CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log 10 CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem-and imipenemtreated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7-and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.Bacterial infections of the lower respiratory tract continue to be a major cause of morbidity and mortality despite the development of broad-spectrum antibiotics (11). Infections originating in the lung more frequently lead to sepsis than those originating in the abdomen or the urinary tract, with community-acquired pneumonia (CAP) emerging as one of the leading causes of death worldwide (4). Klebsiella pneumoniae is an increasingly important CAP pathogen, particularly in individuals with impaired pulmonary defenses, and is also a key pathogen in nosocomial pneumonia (42). Pulmonary infections caused by K. pneumoniae are often characterized by a rapid clinical course that includes multilobar involvement, formation of abscesses, and dissemination of bacteria from the pulmonary air space into the bloodstream, leading to widespread systemic effects and death (27,31,43). Treatment of K. pneumoniae infections can be complicated by the presence of extended-spectrum ␤-lactamases (ESBLs), which confer resistance to many broad-spectrum penicillin and cephalosporin antibiotics. K. pneumoniae i...

An audit of colistin use in neonatal sepsis from a tertiary care centre of a resource-limited country

“…An in vitro study 21 has concluded that the addition of doripenem with colistin is synergistic and suppresses those Klebsiella organisms that were resistant to colistin. A study conducted using a murine model for K. pneumoniae showed more rapid resolution with enhanced antibacterial activity of doripenem as compared to other carbapenems 22 . These studies including the present study warrant continuous surveillance of infection with Klebsiella organisms including the use of combination therapy with colistin.…”

Evaluation of the Efficacy of a Bacteriophage in the Treatment of Pneumonia Induced by Multidrug ResistanceKlebsiella pneumoniaein Mice

“…In addition, treating Klebsiella pneumoniae has become more difficult due to the worldwide increase in multidrug resistant strains, leaving only limited clinical treatment options [ 4 – 8 ]. In effect, about 80% of the nosocomial infections caused by K. pneumoniae are due to these multidrug-resistant strains; the incidence of ESBLs (extended-spectrum beta-lactamase) isolates ranges from 8% to 44% [ 9 , 10 ].…”

Use of Carbapenems against Clinical, Nontyphoid Salmonella Isolates: Results from In Vitro and In Vivo Animal Studies

“…In preliminary studies, the 50% lethal dose (LD 50 ) of S129-42 for healthy female BALB/c mice was less than 30 CFU by intraperitoneal infection (data not shown), indicating that female BALB/c mice are susceptible to Salmonella infection. To determine the serum concentrations of ceftriaxone, ertapenem, doripenem, and meropenem in these mice, each drug was subcutaneously administered to healthy mice as a single dose as previously described: 100 mg/kg of body weight for ceftriaxone (1) and 50 mg/kg for ertapenem (34), doripenem (12), and meropenem (15). At 0.5, 1, 2, 4, 6, and 8 h postinjection, blood samples from six anesthetized mice per treatment group were collected by cardiac puncture.…”