JAC Advance Access originally published online on February 25, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 1025-1028
© 2003 The British Society for Antimicrobial Chemotherapy
Microbiological efficacy of ABT-773 (cethromycin) for the treatment of community-acquired pneumonia due to Chlamydia pneumoniae
1 Departments of Pediatrics and Medicine, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York, NY 11203-2098; 2 Department of Medicine, University of Louisville, Louisville, KY; 3 Abbott Laboratories, 200 Abbott Park Road, Abbott Park, IL, USA
Received 22 October 2002; returned 13 December 2002; revised 24 December 2002; accepted 15 January 2003
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Abstract |
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Nasopharyngeal specimens for culture of Chlamydia pneumoniae were obtained from patients with community-acquired pneumonia enrolled in a randomized study comparing the novel ketolide antibiotic ABT-773 at a dose of 150 mg once a day to 150 mg twice a day, by mouth for 10 days. C. pneumoniae was eradicated from the nasopharynx of 10 of 10 (100%) microbiologically evaluable patients. MICs and MBCs for 13 isolates of C. pneumoniae from 12 patients obtained before and after therapy were performed against ABT-773. The MIC90 and MBC90 of ABT-773 were 0.015 mg/L.
Keywords: chlamydia, C. pneumoniae, ketolide
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Introduction |
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Chlamydia pneumoniae is a frequent cause of community-acquired respiratory tract infection, including pneumonia and bronchitis.1 However, data on treatment of respiratory infection due to C. pneumoniae are limited. The majority of previously published studies evaluating new macrolides/azalides and quinolones for the treatment of pneumonia have used serology alone for diagnosis, thereby limiting the evaluation of therapy. There are only three pneumonia treatment studies evaluating macrolides/azalides published to date that have utilized C. pneumoniae culture and assessed microbiological efficacy.2,3 We previously reported that ABT-773 (cethromycin), a new ketolide antibiotic, was the most active agent tested against C. pneumoniae with an MIC90 and MBC90 of 0.015 mg/L (range 0.008–0.015 mg/L).4 ABT-773 was at least four-fold more active in vitro against C. pneumoniae than telithromycin, clarithromycin and azithromycin. As part of a multicentre treatment study of community-acquired pneumonia (CAP) in adults evaluating two dosage regimens of ABT-773, we obtained nasopharyngeal swabs for C. pneumoniae culture and performed in vitro susceptibility testing against ABT-773 of isolates obtained from these patients.
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Materials and methods |
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Patients
Subjects aged 18 years or older and presenting with CAP were enrolled in a Phase 3, double-blind randomized study evaluating the efficacy of ABT-773, 150 mg by mouth once a day to 150 mg by mouth twice a day for 10 days. Inclusion criteria included radiographic evidence of pneumonia, and no history of allergy to macrolide antibiotics or serious underlying disease. In addition, a purulent sputum sample was obtained within 48 h before treatment, qualified by a Gram stain and submitted for routine bacterial culture with susceptibility testing. To qualify, the sputum sample had to have <10 squamous epithelial cells and >25 leucocytes per low-power (x100) field.
Subjects with lung diseases that were chronic or those with complications of CAP (e.g. empyema, lung abscess, pulmonary embolism, lung oedema, cystic fibrosis, primary or metastatic tumour involving the lung, bronchial obstruction, a history of post-obstructive pneumonia, or known or suspected Pneumocystis carinii pneumonia) were excluded, as were subjects known to be immunocompromised or suffering from HIV. Subjects were also excluded if suffering from any other significant disease such as cardiovascular, pulmonary, metabolic, gastrointestinal, neurological or endocrine disease, malignancy or any other abnormality other than CAP. Furthermore, subjects needed to be assessed as suitable for outpatient therapy such that subjects with the Fine Criteria5 requiring the need for possible hospitalization were excluded. Subjects with prior hospitalization and on antibiotics or other drugs likely to interact with ketolides or with a history of allergy were also excluded. Posterior nasopharyngeal (NP) specimens were obtained for C. pneumoniae culture at baseline, and 19–24 days after enrolment using wire-shafted, Dacron-tipped swabs (Puritan Quality Medical Products, Guilford, ME, USA), as described previously.2,3 The swabs were immersed in 2 mL of transport medium (sucrose-phosphate buffer with 20% fetal calf serum, 10 mg/L gentamicin, 10 mg/L vancomycin and 1 mg/L amphotericin B). An oropharyngeal swab was also obtained for detection of C. pneumoniae DNA by PCR at baseline. Sera were obtained at baseline and 19–24 days after enrolment for C. pneumoniae serology.
Culture of C. pneumoniae
C. pneumoniae culture was performed at SUNY Downstate Medical Center utilizing cycloheximide-treated HEp-2 cells grown in 96-well microtitre plates.2,3 After 72 h incubation all specimens were passed once. Cultures were confirmed by fluorescent antibody staining with a Chlamydia-specific monoclonal antibody. Patient isolates were then passed five to six times in cell culture in antibiotic-free medium.
PCR for C. pneumoniae was performed at the University of Louisville, as described previously.6
Detection of anti-C. pneumoniae antibody was performed by microimmunofluorescence (MIF) assay using a commercial kit (Focus Technologies, Cypress, CA, USA). The serological diagnosis of acute C. pneumoniae infection required a four-fold increase in IgG and/or IgM in paired sera or a single IgM 
32.
ABT-773 (Abbott Laboratories) was supplied as a powder and solubilized according to the manufacturer’s instructions.
Susceptibility studies
Susceptibility testing of C. pneumoniae was performed in cell culture using HEp-2 cells grown in 96-well microtitre plates, as described previously.4 Each well was inoculated with 0.2 mL of the organism diluted to yield 103 inclusion-forming units (IFU)/mL, and centrifuged at 2000g for 1 h. The wells were then aspirated and overlaid with 0.2 mL of medium containing 1 mg/L cycloheximide and serial two-fold dilutions of the test drug. After incubation at 35°C for 72 h, cultures were fixed and stained for inclusions with fluorescein-conjugated antibody to the lipopolysaccharide genus antigen (Pathfinder Chlamydia Culture Confirmation System, Bio-Rad). The MIC was the lowest antibiotic concentration at which no inclusions were seen. The MBC was determined by freezing the cultures at –70°C, then thawing, passing the disrupted cell monolayers onto new cells, incubating for 72 h, then fixing and staining as above. The MBC was the lowest antibiotic concentration that resulted in no inclusions after passage. All tests were run in triplicate.
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Results |
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Nasopharyngeal specimens for C. pneumoniae were obtained from 335 patients, 12 (3.6 %) were culture positive for C. pneumoniae. The mean age of the C. pneumoniae-positive patients was 49 ± 13.8 years (range 34–70); seven were male and five were female. Two culture-positive patients were excluded from the final analysis because they were negative at baseline, but positive at the third follow-up visit, 19–24 days after the initiation of treatment. One of these patients, a 52-year-old man, was found to have pulmonary tuberculosis. The other patient, a 70-year-old man, had serological evidence of acute Legionella pneumophila infection. He initially responded to treatment and was felt to have a new respiratory infection at the time of evaluation 23 days after enrolment, when he was found to have a positive C. pneumoniae culture. Both these patients had stable anti-C. pneumoniae IgG titres and no detectable anti-C. pneumoniae IgM.
C. pneumoniae was eradicated from the nasopharynx of all 10 (100%) microbiologically evaluable patients; all were clinical cures. Five patients each were treated with either the once a day or twice a day dosing schedule. Eight of the C. pneumoniae-positive patients had other pathogens iso lated from sputum, including Haemophilus influenzae (one), H. parainfluenzae (seven) and Moraxella catarrhalis (one). C. pneumoniae DNA was detected by PCR in only two of the 10 patients who were culture positive at baseline. Of the 10 evaluable patients, two had anti-C. pneumoniae IgM 32; five had a four-fold rise in IgM with no detectable or stable IgG, two had a four-fold rise in IgG and one patient had a four-fold rise in IgM and IgG.
In vitro susceptibility testing of 13 isolates of C. pneumoniae from the 12 patients in this study, obtained before and after therapy, was performed against ABT-773 (one subject had two samples sent). The MIC90 and MBC90 were 0.015 mg/L (range 0.008–0.015 mg/L).
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Discussion |
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ABT-773 was very efficacious in the eradication of C. pneumoniae from the nasopharynx of adults with pneumonia. Both dosage regimens were equally effective; however, the numbers were too small for a meaningful statistical analysis. These results compare very favourably with prior experience of macrolides/azalides.2,3 Results of several treatment studies that performed C. pneumoniae culture demonstrated that 10–14 days of treatment with erythromycin and clarithromycin or 5 days of azithromycin has
80% efficacy in the eradication of C. pneumoniae from the respiratory tract of children and adults with pneumonia.2,3 The C. pneumoniae isolates obtained from the patients in this study were highly susceptible to ABT-773, with a MIC90 and MBC90 of 0.015 mg/L, which was identical to our earlier report.5 ABT-773 also appears to be more active than telithromycin, another ketolide. We previously reported a MIC90 and MBC90 of telithromycin for 19 isolates of C. pneumoniae of 0.25 mg/L.4 Unlike ABT-773, there was wide inter-isolate variation in the MICs and MBCs, which ranged from 0.031 to 2.0 mg/L. Similar data were reported by Miyashita et al.,7 who tested 20 isolates of C. pneumonaie and found a MIC90 and MBC90 of 0.125 mg/L (range 0.031–0.25 mg/L). There are no data on the efficacy of telithromycin for the eradication of C. pneumoniae from the respiratory tract of patients with pneumonia. However, in vitro activity may not always predict in vivo efficacy. For example, clarithromycin is 10- to 100-fold more active than erythromycin, but it was not more effective in the eradication of C. pneumoniae.2
As access to culture is limited and there are no Food and Drug Administration-approved, commercially available, standardized nucleic amplification tests for C. pneumoniae, diagnosis in many treatment studies has been based on serology.1,8 Unfortunately, use of serology provides only a clinical endpoint and does not allow for the assessment of microbiological efficacy. In addition, C. pneumoniae serology is also not standardized and there are problems with both inter- and intra-laboratory reproducibility, especially with the MIF assay.8 Studies in children, and to a lesser extent in adults, have often found a poor correlation between serology and the identification of the organism by culture and/or PCR.2,3,9,10 Two studies in children found that >70% culture-positive patients with pneumonia were seronegative.2,3 Although the 10 evaluable culture-positive patients in this study met the study criteria for serological diagnosis of acute C. pneumoniae infection, the Centers for Disease Control and Prevention (CDC) recently proposed several modifications of these criteria.8 They include a single IgM 16 and/or a four-fold rise in IgG only. However, the use of a single IgM could be misleading as 10–18% of asymptomatic, culture-negative adults may have anti-C. pneumoniae IgM 16.8 Results of two adult treatment studies found that only 30–40% of patients with culture-documented C. pneumoniae infection met the serological definition for acute infection with the MIF test recently proposed by the CDC. The remaining patients had either no detectable antibody or stable IgG titres.9,10
In addition to having excellent activity against a wide range of bacteria involved in respiratory infection, including erythromycin-resistant Streptococcus pneumoniae,11 ABT-773 has also been demonstrated to have excellent in vitro activity against extracellular and intracellular L. pneumophila.12 The results of this initial study support further studies of the clinical and microbiological effectiveness of ABT-773 for the treatment of CAP, including infections due to C. pneumoniae.
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Footnotes |
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* Corresponding author. Tel: +1-718-270-3097; Fax: +1-718-270-1985; E-mail: mhammerschlag{at}pol.net
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References |
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1 . File, T. M., Bartlett, J. G., Cassell, G. H., Gaydos, C. A., Grayston, J. T., Hammerschlag, M. R. et al. (1997). The importance of Chlamydia pneumoniae as a pathogen: the 1996 Consensus Conference on Chlamydia pneumoniae infections. Infectious Diseases in Clinical Practice 6, Suppl. 2, S28–31.
2 . Block, S. J., Hedrick, J., Hammerschlag, M. R., Cassell, G. H. & Craft, C. (1995). Mycoplasma pneumoniae and Chlamydia pneumoniae in pediatric community-acquired pneumonia: comparative efficacy and safety of clarithromycin vs erythromycin ethylsuccinate. Pediatric Infectious Disease Journal 14, 471–7.[Web of Science][Medline]
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Roblin, P. M. & Hammerschlag, M. R. (1998). Microbiologic efficacy of azithromycin and susceptibility to azithromycin of isolates of Chlamydia pneumoniae from adults and children with community acquired pneumonia. Antimicrobial Agents and Chemotherapy 42, 194–6.
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Strigl, S., Roblin, P. M., Reznik, T. & Hammerschlag, M. R. (2000). In vitro activity of ABT 773, a new ketolide antibiotic, against Chlamydia pneumoniae. Antimicrobial Agents and Chemotherapy 44, 1112–3.
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Fine, M. J., Auble, T. E., Yealy, D. M., Hanusa, B. H., Weissfeld, L. A., Singer, D. E. et al. (1997). A prediction rule to identify low-risk patients with community-acquired pneumonia. New England Journal of Medicine 336, 243–50.
6 . Ramirez, J. A., Ahkee, S., Tolentino, A., Miller, R. D. & Summersgill, J. T. (1996). Diagnosis of Legionella pneumophila, Mycoplasma pneumoniae or Chlamydia pneumoniae lower respiratory infection using the polymerase chain reaction on a single throat swab specimen. Diagnostic Microbiology and Infectious Disease 24, 7–14.[CrossRef][Web of Science][Medline]
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Miyashita, N., Fukano, H., Niki, Y. & Matsushima, T. (2001). In vitro activity of telithromycin, a new ketolide, against Chlamydia pneumoniae. Journal of Antimicrobial Chemotherapy 48, 403–5.
8 . Dowell, S. F., Peeling, R. W., Boman, J., Carlone, G. M., Fields, B. S., Guarner, J. et al. (2001). Standardizing Chlamydia pneumoniae assays: recommendations from the Centers for Disease Control and Prevention (USA) and the Laboratory Centre for Disease Control (Canada). Clinical Infectious Diseases 33, 492–503.[CrossRef][Web of Science][Medline]
9 . Hammerschlag, M. R. & Roblin, P. M. (2000). Microbiologic efficacy of moxifloxacin for the treatment of community-acquired pneumonia due to Chlamydia pneumoniae. International Journal of Antimicrobial Agents 15, 149–52.[CrossRef][Web of Science][Medline]
10 . Hammerschlag, M. R., Reznik, T. & Roblin, P. (2001). Microbiologic efficacy of levofloxacin for the treatment of serious community-acquired pneumonia due to Chlamydia pneumoniae. Journal of Antimicrobial Chemotherapy 47, Suppl. S1, Abstract P112, p. 45.
11 . Barry, A. L., Fuchs, P. C. & Brown, S. D. (2001). In vitro activity of the ketolide ABT-773. Antimicrobial Agents and Chemotherapy 45, 2922–4.
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Jung, R., Danziger, L. H. & Pendland, S. L. (2002). Intracellular activity of ABT-773 and other antimicrobial agents against Legionella pneumophila. Journal of Antimicrobial Chemotherapy 49, 857–61.
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