Differential Efficacy of Clarithromycin in Lung versus Thigh Infection Models

Maglio, Dana; Capitano, Blair; Banevicius, Mary Anné; Geng, Qiuming; Nightingale, Charles H.; Nicolau, David P.

doi:10.1159/000077804

Cited by 17 publications

(28 citation statements)

References 7 publications

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“…In contrast, the mean R. equi CFU in the lungs were lower in mice receiving CLR monotherapy than in saline controls. The preferential activity of CLR in the lungs has been documented previously, presumably because of the high concentrations achieved in the pulmonary epithelial lining fluid (22).…”

supporting

confidence: 55%

Activity of Clarithromycin or Rifampin Alone or in Combination against Experimental Rhodococcus equi Infection in Mice

Burton

Giguère

Berghaus

et al. 2015

Antimicrob Agents Chemother

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Treatment of mice with the combination of clarithromycin with rifampin resulted in a significantly lower number of Rhodococcus equi CFU in the organs of mice than treatment with either drug alone or placebo. There was no significant difference in the number of R. equi CFU between mice treated with clarithromycin monotherapy, rifampin monotherapy, or placebo. The combination of clarithromycin with rifampin conferred a clear advantage over either drug as monotherapy in this model of chronic R. equi infection. Rhodococcus equi, a Gram-positive facultative intracellular pathogen, is one of the most important causes of disease in foals between 3 weeks and 5 months of age. R. equi has also emerged as a common opportunistic pathogen in immunocompromised people, especially those infected with HIV (1-3). Infection in both foals and people is most commonly characterized by life-threatening pyogranulomatous pneumonia, but extrapulmonary infections are also common (3,4).Although a wide variety of antimicrobial agents are active in vitro against R. equi (5, 6), many of these drugs are reported to be ineffective in vivo, presumably because of poor cellular uptake and the resulting low intracellular concentrations (7). The combination of a macrolide, such as erythromycin, clarithromycin (CLR), or azithromycin, with rifampin (RIF), the mainstay of therapy in foals infected with R. equi (8-10), is also used commonly for the treatment of infections caused by R. equi in people (3). The combination of a macrolide and RIF is synergistic in vitro (11,12), and the use of the 2 classes of drugs in combination reduces the likelihood of resistance to either drug developing in R. equi (13). CLR is often selected over other macrolides because of its greater in vitro activity against R. equi (6) and because a retrospective study in foals suggests that, in combination therapy with RIF, CLR is more effective than other macrolides (8). However, in both people and foals, concurrent administration of RIF considerably reduces CLR concentrations compared to concentrations achieved with CLR monotherapy (14-16). This has raised the question of whether administration of RIF in addition to CLR is necessary, or even advisable, for the treatment of infections caused by R. equi. The objective of this study was to compare the in vivo activity of CLR and RIF alone and in combination in a mouse model of R. equi infection.The virulent R. equi strain 103ϩ was used for infection of mice based on its documented ability to replicate in macrophages and in immunodeficient mice (17,18). The MICs of CLR and RIF were determined by broth macrodilution, as described previously (13), in accordance with the guidelines established by the Clinical and Laboratory Standards Institute (19).The animal efficacy studies were approved by the Institutional Animal Care and Use Committee of the University of Georgia. Six-to 8-week-old male athymic nude (nu/nu) mice (Harlan Laboratories, Inc., Indianapolis, IN, USA) were used in an R. equi infection model. In this model system, virul...

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supporting

confidence: 55%

Activity of Clarithromycin or Rifampin Alone or in Combination against Experimental Rhodococcus equi Infection in Mice

Burton

Giguère

Berghaus

et al. 2015

Antimicrob Agents Chemother

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“…Agents Chemother., abstr. A-1097, 2001) conducted with clarithromycin and three S. pneumoniae strains, the doses of the antimicrobial used in that study (0.38 to 48 mg/kg administered every 6 h) were considerably different from the regimen of 200 mg/kg administered every 12 h used in our previous study (12). As a result of these murine studies, we must interpret the data that have been generated with the thigh infection model cautiously when assessing the magnitude of exposure required to ensure microbiologic eradication by treatment with telithromycin in humans, since this compound also displays the ability to accumulate in epithelial lining fluid, as the concentrations at this pulmonary site exceed the corresponding concentrations in plasma (10,13).…”

Section: Discussionmentioning

confidence: 74%

“…As a result, while the pharmacodynamic parameter most predictive of outcome (i.e., AUC/MIC) remains constant in the absence or the presence of neutrophils, the magnitude of drug exposure required to produce any given reduction in bacterial density is substantially reduced in the immunocompetent host. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]1998) evaluated the impacts of neutrophils on the bacteriostatic activity of telithromycin and a structurally related ketolide against S. pneumoniae strains with various macrolide susceptibilities in the murine thigh infection model and reported that the potencies of the ketolides are enhanced (1.8-to 24-fold) in the presence of neutrophils. Moreover, although neutropenic conditions were used in the present study, the enhanced in vivo potency of another ketolide, ABT-773, against pneumococci in immunocompetent hosts has also recently been demonstrated (5).…”

Section: Discussionmentioning

confidence: 99%

“…This issue has been raised with the macrolide clarithromycin in a study previously conducted by our group (24). Moreover, an additional study was conducted with clarithromycin to evaluate the differences in the dispositions and the resulting changes in bacterial density in murine pneumonia and thigh infection models (12). In that study the activity of the macrolide was evaluated against seven S. pneumoniae isolates with efflux-mediated resistance in both models.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

Tessier¹,

Mattoes²,

Dandekar³

et al. 2005

Antimicrob Agents Chemother

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The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were <0.5 g/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 10 5 to 10 6 CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.Telithromycin, the first of the new class of antimicrobials to be developed for clinical use, the ketolides, possesses potent activity against a variety of pathogenic gram-positive species, including penicillin-and macrolide-resistant Streptococcus pneumoniae strains (1, 2). Telithromycin is a semisynthetic derivative of the 14-membered-ring macrolide parent compound erythromycin A. As a consequence of chemical modifications made to the parent compound, telithromycin is highly acid stable, has an extended half-life, and lacks the ability to induce resistance to other macrolides (4). Additionally, these alterations allow telithromycin to retain activity against macrolide-resistant isolates due to the presence of the mefA and/or the ermB gene and against S. pneumoniae strains with 23S rRNA mutations (4, 14). Typical telithromycin MICs at which 90% of isolates are inhibited (MIC 90 ) for S. pneumoniae range from 0.125 to 0.5 g/ml for both susceptible and penicillinand/or macrolide-resistant S. pneumoniae isolates (1,7,11,22). Telithromycin is also efficacious against fluoroquinolone-resistant S. pneumoniae strains; the MIC 90 for these isolates remain at equally low levels of 0.25 to 0.5 g/ml (9, 15).While telithromycin has activity against pneumococc...

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“…Another factor playing a significant role is drug concentration at the site of infection. Antimicrobials such as macrolides and telithromycin have been shown to be sequestered in macrophages and in the epithelial lining fluid of the lungs [6][7][8].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of telithromycin against Streptococcus pneumoniae with ribosomal mutations utilizing in vitro time–kill methodology

Dandekar

Tessier

Farrell

et al. 2005

International Journal of Antimicrobial Agents

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Differential Efficacy of Clarithromycin in Lung versus Thigh Infection Models

Cited by 17 publications

References 7 publications

Activity of Clarithromycin or Rifampin Alone or in Combination against Experimental Rhodococcus equi Infection in Mice

Activity of Clarithromycin or Rifampin Alone or in Combination against Experimental Rhodococcus equi Infection in Mice

Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

Evaluation of telithromycin against Streptococcus pneumoniae with ribosomal mutations utilizing in vitro time–kill methodology

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