{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:31:24Z","timestamp":1787027484678,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000774","name":"Defence Threat Reduction Agency","doi-asserted-by":"crossref","award":["HDTRA1-12-D-0003-0018"],"award-info":[{"award-number":["HDTRA1-12-D-0003-0018"]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Q fever, caused by Coxiella burnetii, is typically treated with doxycycline, but its efficacy is limited in chronic cases and may be poorly tolerated. Systemic ciprofloxacin shows limited activity for acute Q fever. However, inhaled liposomal formulations may provide therapeutic benefit. Methods: Two inhaled ciprofloxacin formulations (Lipoquin\u00ae and Apulmiq\u00ae) were evaluated in an A\/J mouse model of Q fever and compared with intraperitoneal ciprofloxacin and oral doxycycline. Initially, pharmacokinetic studies were performed to determine an appropriate dosing regimen for the inhaled ciprofloxacin formulations. A separate cohort of mice were then infected with C. burnetii and treated once daily via nebulisation with Lipoquin or Apulmiq, initiated at 24, 48, or 72 h post-challenge. Clinical signs, weight change, splenomegaly, bacterial burden, and lung histopathology were evaluated. Results: Pharmacokinetic analysis confirmed sustained lung concentrations of inhaled ciprofloxacin, supporting once-daily dosing. Inhaled Lipoquin and Apulmiq significantly reduced clinical signs, weight loss, splenomegaly, and pulmonary bacterial burden compared to untreated controls and doxycycline-treated mice. Histopathology revealed decreased lung inflammation and lesion severity following inhalational dosing. Systemic ciprofloxacin slightly reduced splenic bacterial burden but was less effective in controlling pulmonary infection. Conclusions: Inhaled liposomal ciprofloxacin demonstrated superior protection and reduced respiratory manifestations of Q fever compared to doxycycline and systemic ciprofloxacin. These findings suggest inhaled formulations may represent a viable alternative for the treatment of Q fever pneumonia. Further studies are needed to evaluate clinical applicability and long-term outcomes.<\/jats:p>","DOI":"10.3390\/antibiotics15030293","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T15:06:22Z","timestamp":1773414382000},"page":"293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhaled Ciprofloxacin as an Alternative Treatment for Infection with Coxiella burnetii"],"prefix":"10.3390","volume":"15","author":[{"given":"Rachel E.","family":"Ireland","sequence":"first","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9078-6734","authenticated-orcid":false,"given":"Kevin R.","family":"Bewley","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Salisbury SP4 0JG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7066-4767","authenticated-orcid":false,"given":"M. Gill","family":"Hartley","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karleigh A.","family":"Hamblin","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5628-0481","authenticated-orcid":false,"given":"Stuart J.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Nelson","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0142-9162","authenticated-orcid":false,"given":"Thomas R.","family":"Laws","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isobel H.","family":"Norville","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Salguero","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Salisbury SP4 0JG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6793-917X","authenticated-orcid":false,"given":"James D.","family":"Blanchard","sequence":"additional","affiliation":[{"name":"Aradigm Corporation, Hayward, CA 94545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Dayton","sequence":"additional","affiliation":[{"name":"Aradigm Corporation, Hayward, CA 94545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5206-794X","authenticated-orcid":false,"given":"Igor","family":"Gonda","sequence":"additional","affiliation":[{"name":"Aradigm Corporation, Hayward, CA 94545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen S.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah V.","family":"Harding","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, UK"},{"name":"Department of Respiratory Sciences, University of Leicester, Leicester LE1 7RH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1111\/j.1462-5822.2007.00901.x","article-title":"Lounging in a lysosome: The intracellular lifestyle of Coxiella burnetii","volume":"9","author":"Voth","year":"2007","journal-title":"Cell. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1128\/br.25.3.285-293.1961","article-title":"Airborne Q fever","volume":"25","author":"Tigertt","year":"1961","journal-title":"Bacteriol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0954-6111(93)90006-L","article-title":"A large Q fever outbreak in the West Midlands: Clinical aspects","volume":"87","author":"Smith","year":"1993","journal-title":"Respir. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s15010-010-0052-x","article-title":"One-year follow-up of patients of the ongoing Dutch Q fever outbreak: Clinical, serological and echocardiographic findings","volume":"38","author":"Limonard","year":"2010","journal-title":"Infection"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1016\/j.cmi.2018.11.023","article-title":"Chronic Q fever-related complications and mortality: Data from a nationwide cohort","volume":"25","author":"Wever","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1128\/JCM.03221-13","article-title":"Chronic Q fever in the Netherlands 5 years after the start of the Q fever epidemic: Results from the Dutch chronic Q fever database","volume":"52","author":"Kampschreur","year":"2014","journal-title":"J. Clin. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3276","DOI":"10.1128\/AAC.45.11.3276-3278.2001","article-title":"In vitro susceptibility of Coxiella burnetii to linezolid in comparison with its susceptibilities to quinolones, doxycycline, and clarithromycin","volume":"45","author":"Gikas","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1586\/14787210.2013.840534","article-title":"Antimicrobial therapies for Q fever","volume":"11","author":"Kersh","year":"2013","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1056\/NEJM199008303230916","article-title":"Ciprofloxacin in a case of Q fever endocarditis","volume":"323","author":"Yebra","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.ijantimicag.2017.08.006","article-title":"Use of axenic media to determine antibiotic efficacy against Coxiella burnetii","volume":"51","author":"Clay","year":"2018","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hartley, M.G., Norville, I.H., Richards, M.I., Barnes, K.B., Bewley, K.R., Vipond, J., Rayner, E., Vente, A., Armstrong, S.J., and Harding, S.V. (2021). Finafloxacin, a Novel Fluoroquinolone, Reduces the Clinical Signs of Infection and Pathology in a Mouse Model of Q Fever. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.760698"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5510","DOI":"10.1128\/AAC.03443-14","article-title":"Efficacy of liposome-encapsulated ciprofloxacin in a murine model of Q fever","volume":"58","author":"Norville","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1067\/mpd.2003.197","article-title":"Improved survival among young patients with cystic fibrosis","volume":"142","author":"Kulich","year":"2003","journal-title":"J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1128\/CMR.00101-15","article-title":"Inhaled Antibiotics for Gram-Negative Respiratory Infections","volume":"29","author":"Wenzler","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cipolla, D., Blanchard, J., and Gonda, I. (2016). Development of Liposomal Ciprofloxacin to Treat Lung Infections. Pharmaceutics, 8.","DOI":"10.3390\/pharmaceutics8010006"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1128\/AAC.38.3.547","article-title":"Treatment of severe pneumonia in hospitalized patients: Results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group","volume":"38","author":"Fink","year":"1994","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1001\/archinte.1989.00390100083020","article-title":"Evaluation of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections. Impact of plasma concentrations, organism, minimum inhibitory concentration, and clinical condition on bacterial eradication","volume":"149","author":"Peloquin","year":"1989","journal-title":"Arch. Intern. Med."},{"key":"ref_18","first-page":"2732017","article-title":"Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes","volume":"2018","author":"Borghardt","year":"2018","journal-title":"Can. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/jps.23795","article-title":"Development and Characterization of an In Vitro Release Assay for Liposomal Ciprofloxacin for Inhalation","volume":"103","author":"Cipolla","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_20","first-page":"73","article-title":"Inhaled liposomal ciprofloxacin: Once a day management of respiratory infections","volume":"1","author":"Bruinenberg","year":"2010","journal-title":"Respir. Drug Deliv."},{"key":"ref_21","unstructured":"Cipolla, D., Gonda, I., Serisier, D., and Bruinenberg, P. (2011). Dual Release Ciprofloxacin for Inhalation (DRCFI) improves time to first exacerbation in Bronchiectasis. J. Aerosol Med. Pulm. Drug Deliv., 24."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1136\/thoraxjnl-2013-203207","article-title":"Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): A randomised, double-blind, placebo-controlled trial","volume":"68","author":"Serisier","year":"2013","journal-title":"Thorax"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1111\/imj.15210","article-title":"Meta-analysis of efficacy and safety of inhaled ciprofloxacin in non-cystic fibrosis bronchiectasis patients","volume":"51","author":"Wang","year":"2021","journal-title":"Intern. Med. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S2213-2600(18)30427-2","article-title":"Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): Two phase 3, randomised controlled trials","volume":"7","author":"Haworth","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1128\/AAC.02555-13","article-title":"Liposome encapsulation of ciprofloxacin improves protection against highly virulent Francisella tularensis strain Schu S4","volume":"58","author":"Hamblin","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hamblin, K.A., Armstrong, S.J., Barnes, K.B., Davies, C., Laws, T., Blanchard, J.D., Harding, S.V., and Atkins, H.S. (2017). Inhaled Liposomal Ciprofloxacin Protects against a Lethal Infection in a Murine Model of Pneumonic Plague. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.00091"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1097\/00007435-200209000-00001","article-title":"Azithromycin versus doxycycline for genital chlamydial infections: A meta-analysis of randomized clinical trials","volume":"29","author":"Lau","year":"2002","journal-title":"Sex. Transm. Dis."},{"key":"ref_28","first-page":"469","article-title":"Animal models of Q fever (Coxiella burnetii)","volume":"63","author":"Bewley","year":"2013","journal-title":"Comp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e0067321","DOI":"10.1128\/AAC.00673-21","article-title":"Evaluation of the Efficacy of Doxycycline, Ciprofloxacin, Levofloxacin, and Co-trimoxazole Using In Vitro and In Vivo Models of Q Fever","volume":"65","author":"Clay","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1128\/AAC.43.5.1298","article-title":"In vitro activities of antibiotics alone and in combination against Brucella melitensis at neutral and acidic pHs","volume":"43","author":"Akova","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Barnes, K.B., Zumbrun, S.D., Halasohoris, S.A., Desai, P.D., Miller, L.L., Richards, M.I., Russell, P., Bentley, C., and Harding, S.V. (2019). Demonstration of the broad spectrum in vitro activity of finafloxacin against pathogens of biodefence interest. Antimicrob. Agents Chemother., 63.","DOI":"10.1128\/AAC.01470-19"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"415","DOI":"10.3109\/10731190009118586","article-title":"Effects of liposome-encapsulated ciprofloxacin on phagocytosis, nitric oxide and intracellular killing of Staphylcoccus aureus by murine macrophages","volume":"28","author":"Wong","year":"2000","journal-title":"Artif. Cells Blood Substit. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1002\/eji.200738067","article-title":"Coxiella burnetii, the agent of Q fever, stimulates an atypical M2 activation program in human macrophages","volume":"38","author":"Benoit","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Morroy, G., Keijmel, S.P., Delsing, C.E., Bleijenberg, G., Langendam, M., Timen, A., and Bleeker-Rovers, C.P. (2016). Fatigue following Acute Q-Fever: A Systematic Literature Review. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155884"},{"key":"ref_35","first-page":"98","article-title":"Studies on Q fever in man","volume":"69","author":"Benenson","year":"1956","journal-title":"Trans. Assoc. Am. Physicians"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Blanchard, J.D., Elias, V., Cipolla, D., Gonda, I., and Bermudez, L.E. (2018). Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin. Antimicrob. Agents Chemother., 62.","DOI":"10.1128\/AAC.00440-18"},{"key":"ref_37","first-page":"656","article-title":"Splenomegaly, sex, and other characteristics of laboratory animals used for primary isolations of Coxiella burnetii","volume":"24","author":"Franti","year":"1974","journal-title":"Lab. Anim. Sci."},{"key":"ref_38","first-page":"65","article-title":"Induction of splenomegaly in mice by killed Coxiella burnetii cells","volume":"27","author":"Schramek","year":"1983","journal-title":"Acta Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1128\/IAI.00108-16","article-title":"Mouse Model of Coxiella burnetii Aerosolization","volume":"84","author":"Melenotte","year":"2016","journal-title":"Infect. Immun."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bechah, Y., Verneau, J., Ben Amara, A., Barry, A.O., L\u00e9polard, C., Achard, V., Panicot-Dubois, L., Textoris, J., Capo, C., and Ghigo, E. (2014). Persistence of Coxiella burnetii, the agent of Q fever, in murine adipose tissue. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097503"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/j.1476-5381.2009.00267.x","article-title":"To scale or not to scale: The principles of dose extrapolation","volume":"157","author":"Sharma","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1152\/ajplegacy.1947.150.1.70","article-title":"Measurement of the respiratory volumes of laboratory animals","volume":"150","author":"Guyton","year":"1947","journal-title":"Am. J. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1017\/S0022172400015801","article-title":"The respiratory retention of bacterial aerosols: Experiments with radioactive spores","volume":"51","author":"Harper","year":"1953","journal-title":"J. Hyg."},{"key":"ref_44","unstructured":"Collett, D. (2003). Modelling Survival Data in Medical Research, Chapman & Hall\/CRC. [2nd ed.]."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/3\/293\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T05:14:44Z","timestamp":1773551684000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/3\/293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["antibiotics15030293"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics15030293","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,13]]}}}