LETTER
Nafithromycin (WCK 4873) is a novel lactone ketolide under clinical development as an orally administered antibiotic for treatment of community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and methicillin-susceptible Staphylococcus aureus. A recent worldwide antibiotic resistance surveillance study found that nafithromycin had an MIC90 of 0.12 mg/liter against macrolide-resistant and telithromycin-nonsusceptible S. pneumoniae isolates (1). However, there are no published data on the activity of nafithromycin against atypical respiratory pathogens, including Chlamydia pneumoniae and Mycoplasma pneumoniae, which are important causatives agents of CAP (2). We tested the in vitro activity of nafithromycin compared to azithromycin, doxycycline, and levofloxacin against 10 clinical isolates of C. pneumoniae from patients with community-acquired pneumonia.
The antibiotics were provided as powders and solubilized according to the manufacturers’ instructions. Susceptibility testing of C. pneumoniae was performed in cell culture using HEp-2 cells grown in 96-well microtiter plates as previously described (3). Each well was inoculated with 0.2 ml of the C. pneumoniae isolate diluted to yield 104 inclusion-forming units per ml; the plates were centrifuged at 1,700 × g for 1 h and incubated at 35°C for 1 h. Wells were then aspirated and overlaid with medium containing 1 μg/ml of cycloheximide and serial 2-fold dilutions of the test drugs. After incubation at 35°C for 72 h, cultures were fixed and stained for inclusions with fluorescein-conjugated antibody to the chlamydial lipopolysaccharide genus-specific antigen (Pathfinder Chlamydia Culture Confirmation System). The MIC was the lowest antibiotic concentration at which no inclusions were seen. The activity of nafithromycin and comparators against individual isolates of C. pneumoniae is shown in Table 1. The MICs of nafithromycin ranged from 0.03 to 1 mg/liter, the MIC50 was 0.03 mg/liter, and the MIC90 was 0.25 mg/liter. The MIC ranges of azithromycin were from 0.03 to 0.125 mg/liter with an MIC50 of 0.03 mg/liter and MIC90 of 0.06 mg/liter. The MIC range for doxycycline was 0.03 to 0.25 mg/liter, with MIC50 and MIC90 of 0.125 mg/liter. The MIC range of levofloxacin was 0.25 to 0.5 mg/liter; MIC50 and MIC90 were 0.5 mg/liter.
TABLE 1.
MICs of individual C. pneumoniae isolates to nafithromycin and comparators
| C. pneumoniae isolate | MIC (mg/liter) of: |
|||
|---|---|---|---|---|
| Nafithromycin | Azithromycin | Doxycycline | Levofloxacin | |
| BAL13 | 1 | 0.03 | 0.25 | 0.5 |
| BAL15 | 0.03 | 0.03 | 0.125 | 0.5 |
| BAL16 | 0.25 | 0.06 | 0.125 | 0.5 |
| BAL19 | 0.03 | 0.06 | 0.06 | 0.5 |
| BAL37 | 0.03 | 0.06 | 0.125 | 0.25 |
| BAL62 | 0.03 | 0.06 | 0.06 | 0.25 |
| TW2040 | 0.25 | 0.03 | 0.03 | 0.5 |
| TW183 | 0.03 | 0.03 | 0.125 | 0.5 |
| CM-1 | 0.25 | 0.03 | 0.125 | 0.25 |
| AR39 | 0.25 | 0.125 | 0.125 | 0.25 |
| MIC50 | 0.03 | 0.03 | 0.125 | 0.5 |
| MIC90 | 0.25 | 0.06 | 0.125 | 0.5 |
The in vitro activity of nafithromycin against C. pneumoniae was comparable to the other antibiotics tested. Recent pharmacokinetic studies have demonstrated good absorption after oral dosing with nafithromycin maximum concentration of drug in serum (Cmax) ranging from 1.34 to 2.987 mg/liter after 7 days, which is significantly above the MIC90 for C. pneumoniae (0.25 mg/liter) reported here (4). Nafithromycin has also demonstrated sustained levels in epithelial lining fluid (ELF) and alveolar macrophages (AM) with ratios of ELF to plasma concentrations based on the median area under the concentration-time curve from 0 to 24 h (AUC0–24) values of >10 and >350, respectively (5). A phase II, randomized placebo-controlled study has compared oral nafithromycin to moxifloxacin for treatment of CAP in adults; preliminary results showed clinical equivalence, but no microbiologic data were reported (https://clinicaltrials.gov/ct2/show/results/NCT02903836). The in vitro susceptibility methods used to perform this study have been shown to correlate with microbiological eradication of C. pneumoniae from the respiratory tract by other antibiotics, including azithromycin, clarithromycin, levofloxacin, and moxifloxacin (2, 3, 6). The role of nafithromycin in the treatment of C. pneumoniae infection will depend on the results of clinical studies that assess microbiological efficacy.
ACKNOWLEDGMENTS
This work was supported in part by a grant from Wockhardt Pharmaceuticals.
We have no competing interests to declare.
REFERENCES
- 1.Flamm RK, Rhomberg PR, Sader HS. 2017. In vitro activity of the novel lactone ketolide nafithromycin (WCK 4873) against contemporary clinical bacteria from a global surveillance program. Antimicrob Agents Chemother 61:e01230-17. doi: 10.1128/AAC.01230-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hammerschlag MR, Kohlhoff SA, Gaydos CA. 2020. Chlamydia pneumoniae, p 2323–2331. In Bennett JE, Dolin R, Blaser MJ (ed), Mandell, Douglas and Bennett’s principles and practice of infectious diseases, 9th ed. Elsevier, Inc., Philadelphia, PA. [Google Scholar]
- 3.Roblin PM, Hammerschlag MR. 1998. Microbiologic efficacy of azithromycin and susceptibility to azithromycin of isolates of Chlamydia pneumoniae from adults and children with community acquired pneumonia. Antimicrob Agents Chemother 42:194–196. doi: 10.1128/AAC.42.1.194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Iwanowski P, Bhatia A, Gupta M, Patel A, Chavan R, Yeole R, Friedland D. 2019. Safety, tolerability and pharmacokinetics of oral nafithromycin (WCK 4873) after single or multiple doses and effect of food on single dose-bioavailability in healthy adult subjects. Antimicrob Agents Chemother 63:e01253-19. doi: 10.1128/AAC.01253-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Rodvold KA, Gotfried MH, Chugh R, Gupta M, Friedland HD, Bhatia A. 2017. Comparison of plasma concentrations of nafithromycin (WCK 4873) in healthy adult subjects. Antimicrob Agents Chemother 61:e01096-17. doi: 10.1128/AAC.01096-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kohlhoff SA, Hammerschlag MR. 2014. Treatment of chlamydial infections: 2014 update. Expert Opin Pharmacother 16:2015–2202. doi: 10.1517/14656566.2015.999041. [DOI] [PubMed] [Google Scholar]