Therapeutic activities of cefazolin, cefotaxime, and ceftazidime against experimentally induced Klebsiella pneumoniae pneumonia in rats

Bakker-Woudenberg, Irma A. J. M.; Berg, J C van den; Michel, M. F.

doi:10.1128/aac.22.6.1042

Cited by 40 publications

(17 citation statements)

References 19 publications

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“…A left-sided pneumonia was produced as previously described (2). In brief, rats were anesthetized with fluanisone and fentanyl citrate (Hypnorm) (Janssen, Animal Health, Saunderton, United Kingdom), followed by pentobarbital (Nembutal) (Sanofi Santé b.v., Maassluis, The Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Improved Efficacy of Ciprofloxacin Administered in Polyethylene Glycol-Coated Liposomes for Treatment of Klebsiella pneumoniae Pneumonia in Rats

Bakker-Woudenberg

Kate

Guo³

et al. 2001

Antimicrob Agents Chemother

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Animal and clinical data show that high ratios of the area under the concentration-time curve and the peak concentration in blood to the MIC of fluoroquinolones for a given pathogen are associated with a favorable outcome. The present study investigated whether improvement of the therapeutic potential of ciprofloxacin could be achieved by encapsulation in polyethylene glycol (PEG)-coated long-circulating sustained-release liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia (MIC ‫؍‬ 0.1 g/ml), antibiotic was administered at 12-or 24-h intervals at twofold-increasing doses. A treatment period of 3 days was started 24 h after inoculation of the left lung, when the bacterial count had increased 1,000-fold and some rats had positive blood cultures. The infection was fatal within 5 days in untreated rats. Administration of ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin clearance and increased and prolonged ciprofloxacin concentrations in blood and tissues. The ED 50 (dosage that results in 50% survival) of liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily, and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1 mg/kg/day twice daily. The ED 90 of liposomal ciprofloxacin was 15.0 mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin given once daily. In summary, the therapeutic efficacy of liposomal ciprofloxacin was superior to that of ciprofloxacin in the free form. PEG-coated liposomal ciprofloxacin was well tolerated in relatively high doses, permitting once daily administration with relatively low ciprofloxacin clearance and without compromising therapeutic efficacy.The pharmacodynamic and pharmacokinetic properties of antimicrobial agents have been intensively investigated in the recent past, years resulting in the optimization of dosage regimens. In vitro studies and dose-effect studies of experimental infections in animals have been performed with various classes of antibiotics to investigate which pharmacodynamic parameters determine therapeutic efficacy (9,24,26,28,42). Comparative studies of humans with different doses and dosage regimens have also been utilized to optimize antimicrobial treatment (9, 24).The fluoroquinolones are concentration dependent in their rates of bacterial killing. The area under the concentrationtime curve (AUC)/MIC ratio is the parameter that best correlates with the therapeutic efficacy of these agents. In addition, a sufficiently high peak concentration in serum/MIC ratio seems necessary to suppress the emergence of resistant mutants during treatment. This can be concluded from in vitro models that simulate human pharmacokinetics to study the effects of changing the concentrations of fluoroquinolones on a number of pathogens (6,12,13,15,23,29,32). For fluoroquinolones, a 24-h AUC/MIC ratio of Ͼ125 is needed for rapid bacterial eradication, whereas a peak serum drug concentration/MIC ratio of Ͼ8 is needed to preve...

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Section: Methodsmentioning

confidence: 99%

Improved Efficacy of Ciprofloxacin Administered in Polyethylene Glycol-Coated Liposomes for Treatment of Klebsiella pneumoniae Pneumonia in Rats

Bakker-Woudenberg

Kate

Guo³

et al. 2001

Antimicrob Agents Chemother

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“…A left-sided unilateral pneumonia was induced as described in detail elsewhere (2). In brief, rats were anesthetized, and the left primary bronchus was intubated.…”

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confidence: 99%

Therapeutic Efficacy of Liposome-Encapsulated Gentamicin in Rat Klebsiella pneumoniae Pneumonia in Relation to Impaired Host Defense and Low Bacterial Susceptibility to Gentamicin

Schiffelers

Storm

Kate

et al. 2001

Antimicrob Agents Chemother

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Long-circulating liposomes (LCL) may be used as targeted antimicrobial drug carriers as they localize at sites of infection. As a result, LCL-encapsulated gentamicin (LE-GEN) has demonstrated superior antibacterial activity over the free drug in a single-dose study of immunocompetent rats with Klebsiella pneumoniae pneumonia. In the present study, the therapeutic efficacy of LE-GEN was evaluated by monitoring rat survival and bacterial counts in blood and lung tissue in clinically relevant models, addressing the issue of impaired host defense and low bacterial antibiotic susceptibility. The results show that in immunocompetent rats infected with the high-GEN-susceptibility K. pneumoniae strain, a single dose of LE-GEN is clearly superior to an equivalent dose of free GEN. Yet complete survival can also be obtained with multiple doses of free GEN. In leukopenic rats infected with the high-GEN-susceptible K. pneumoniae strain, free GEN at the maximum tolerated dose (MTD) was needed to obtain survival. However, with the addition of a single dose of LE-GEN to free-GEN treatment, complete survival can be obtained using a sevenfold-lower cumulative amount of GEN than with free-GEN treatment alone. In leukopenic rats infected with low-GEN-susceptible K. pneumoniae cells, free GEN at the MTD did not result in survival. The use of LE-GEN is needed for therapeutic success. Increasing LE-GEN bilayer fluidity resulted in an increased GEN release from the liposomes and hence improved rat survival, thus showing the importance of the liposome lipid composition for therapeutic efficacy. These results warrant further clinical studies of liposomal formulations of aminoglycosides in immunocompromised patients with severe infections.

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“…There are only a few reports on models of chronic respiratory tract infection with K. pneumoniae (3, 8, 1 1), though many models concerned with acute infection have been reported (1,2,4,5,15,18). A mouse model of chronic respiratory tract infection caused by K. pneumoniae 27 which we have reported previously (11) is useful not only for evaluation of antibiotics or immunological drugs (12) but also for a fundamental study of the immunology and pathology of a chronic respiratory tract infection.…”

Section: Discussionmentioning

confidence: 99%

Examination of Host Defense Factors Responsible for Experimental Chronic Respiratory Tract Infection Caused by Klebsiella pneumoniae in Mice

Iizawa

Nishi

Kondo

et al. 1991

Microbiology and Immunology

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We have studied the host defense factors that operate during the course of chronic respiratory tract infection caused by Klebsiella pneumoniae 27 in CBA/J mice. A large number of polymorphonuclear leukocytes (PMNs) rapidly infiltrated the alveolar spaces after infection.Treatment with cyclophosphamide (CY) before infection greatly reduced the infiltration of PMNs and caused an increase in bacterial counts.CY treatment of mice in the chronic phase also caused bacterial proliferation in the lungs. The administration of a high titer immune serum efficiently reduced the bacterial counts in the lungs during the early phase but not during the chronic phase.The proliferation of bacteria induced by CY treatment was not suppressed by the administration of the immune serum in either phase. When the mice were exposed to an aerosol containing Pseudomonas aeruginosa P9 in the chronic phase, the organisms from the secondary infection were eliminated from the lungs in the same manner as in the case of primary infection with P. aeruginosa. Thus, PMNs seem to play an important role in the suppression of bacterial proliferation in the early and chronic phases, and the specific antibody might have a supplementary effect on the defensive action of PMNs in the chronic phase.It is also presumed that the bacteria in the chronic phase of infection are sequestered at sites hardly accessible to PMNs.Although many antimicrobial agents are now available, chronic infections are still difficult to cure. Chronic infection models are therefore required to examine the host-parasite relationship in the chronic phase.We have previously established a model of chronic respiratory tract infection in mice caused by Klebsiella pneumoniae (11). The course of infection in this model is highly reproducible, and the bacterial counts in the lungs after infection change with time, showing four different phases. In the first phase, the bacterial counts decrease for 4 days. In the second phase, the bacterial counts increase starting day 4 and reaching the initial level 1 week after infection. The third phase lasts from 1 week to 4 weeks after infection, during which time the bacterial counts remain relatively unchanged. The fourth phase starts 4 weeks after infection, and thereafter the bacterial counts gradually increase. This model is useful for analyzing 615

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Therapeutic activities of cefazolin, cefotaxime, and ceftazidime against experimentally induced Klebsiella pneumoniae pneumonia in rats

Cited by 40 publications

References 19 publications

Improved Efficacy of Ciprofloxacin Administered in Polyethylene Glycol-Coated Liposomes for Treatment of Klebsiella pneumoniae Pneumonia in Rats

Improved Efficacy of Ciprofloxacin Administered in Polyethylene Glycol-Coated Liposomes for Treatment of Klebsiella pneumoniae Pneumonia in Rats

Therapeutic Efficacy of Liposome-Encapsulated Gentamicin in Rat Klebsiella pneumoniae Pneumonia in Relation to Impaired Host Defense and Low Bacterial Susceptibility to Gentamicin

Examination of Host Defense Factors Responsible for Experimental Chronic Respiratory Tract Infection Caused by Klebsiella pneumoniae in Mice

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