The potential role of Fluoroquinolones in the management of Covid-19 a rapid review
Zoheir A. Damanhouri1, Huda M. Alkreathy1, Ahmed S. Ali1, Shahid Karim1*
1Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Correspondence: Shahid Karim, Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. [email protected]
COVID-19 is a pandemic viral pneumonia caused by β-coronavirus SARS-CoV-2. It is associated with many complications including extreme systemic inflammatory response which eventually causes acute respiratory distress syndrome (ARDS), hypercoagulability, cytokine storm, failure of vital organs, and a high incidence of death. Bacterial secondary infection is possibly involved, in such cases, the role of antibiotics is justified. However, some antibiotics may have a role beyond the management of secondary infection. The current review discussed the potential antiviral effects of certain Fluoroquinolones (FQs) against SARS CoV-2 viruses. Several mechanisms such as targeting Main proteases and acting as zinc ionophore are discussed. Also explained their unique features, good access to lung tissues for suppression of inflammatory response via modulation of matrix metallopeptidases (MMPs) are explored. Their role in secondary infections, pharmacokinetics, and safety issues was briefly explored. The promising favorable features of FQs along with their efficacy in the management of secondary infections, highlights the need to consider these important antibiotics for more research as well as clinical trials in the management of COVID-19.
Keywords: FQ, Covid-19, Viral pneumonia, SARS-COV-2, ARDS, Matrix metallopeptidases
COVID-19 is a complicated infectious viral pneumonia caused by β-coronavirus SARS-CoV-2 [1-3]. There are many risk factors for Severe illness & complications including advanced age, comorbidities such as heart disease, hypertension, prior stroke, diabetes, etc [4, 5]. Complications also include ARDS . The most frequently observed histopathologic changes linked to critical cases of COVID-19 was Diffuse Alveolar Damage (DAD), with the focal organization, intra-alveolar fibrinous exudates containing inflammatory cells, hyaline membrane formation, proliferating fibroblasts surrounded by neutrophils, and dilated pulmonary capillaries with micro thrombus formation [7-10].
Moreover, complications may include hypoxia and coagulation disorders [11, 12]. Data were accumulated which documented the association between the novel virus infection and “cytokine storm” [13-15] which eventually cause acute respiratory distress syndrome (ARDS); organ failure, and high incidence of death .
SARS-CoV-2 genomics and drug targets
SARS-CoV-2 has a single- positive-sense stranded RNA associated with a nucleoprotein protein (Figure 1). In all coronaviruses, the genomic proteins are Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N) . Many target sites for drugs against the virus were suggested . Most repurposed drugs act against the virus by one or more of the following: (1) inhibition of viral binding to its host cell receptors, (2) preventing membrane fusion, (3) prevent viral endocytosis, and release of viral RNA, (4) suppressing replication and translation by interfering with many of viral-specific protease/helicase [17-26].
Figure 1. Simplified genomic structure of SARS-CoV-2
Secondary infection among hospitalized COVID-19 patients
Bacterial co-infection was recognized with previous pandemic viral pneumonia and possibly raise disease-associated mortality [27, 28].
Data are accumulated regarding secondary infections in covid-19 patients [29-40]. These findings can be summarized as follows:
- Severely ill hospitalized patients, especially those admitted to ICU commonly suffer secondary bacterial lung infections. The fungal or secondary viral infection is less common.
- Prolonged disease/intubation was associated with nosocomial infection with Gram-negative multidrug-resistant bacteria.
- Incidence of secondary infection among the elderly and those with chronic diseases such as chronic obstructive pulmonary disease (COPD) .
- Co-infection with various viruses was also possible; e.g. influenza A virus  and Cytomegalovirus .
Limited publications suggested the role of FQs in COVID-19 , therefore this review aimed to highlight the potential benefit of judicious use of these antibiotics in this pandemic disease.
COVID 19 and expanding use of antibiotics
Repurposing of available FDA approved drugs seemed a realistic approach for the management of the novel virus [45, 46]. These drugs were usually suggested by computational approaches . A list of these drugs was published [3, 48- 51]. Many are candidates for further in vivo testing or clinical trials . One drug may have multiple targets and additional effects. Among these repurposed drugs are antibiotics especially those with documented efficacy against secondary infections for example macrolides, tetracycline, fluoroquinolones (FQs) among others [53-56].
Materials and Methods
PubMed, Google Scholar, search. using appropriate Keywords, e.g., COVID-19, SARS-CoV-2, FQ, more detailed pharmacology of these drugs was retrieved from web-based drug information resources and textbooks
Quinolones and FQs are bactericidal, broad-spectrum antibiotics indicated for the management of, respiratory tract infections (RTI) among many other indications [57, 58]. FQs inhibit bacterial DNA synthesis . Currently, four generations of FQs are available, all are active against many gram-negative bacteria. The 4th generation e.g. gatifloxacin, clinafloxacin retains the gram-positive and gram-negative bactericidal activity and inhibits anaerobic bacteria .
Role in the management of pneumonia?
FQs have a clear role in the management of pneumonia. Levofloxacin and Oseltamivir were successfully used to treat Severe Pneumonia . The 4th generation gatifloxacin, moxifloxacin showed broad activity against Gram-positive organisms, as S. pneumoniae and Enterobacteriaceae, atypical and anaerobic, also showed a lower incidence of resistance and longer half-life allowing once-daily dosing . However, several reports highlighted the important rational use of FQs should be implemented to minimize the development of bacterial resistance [60, 61].
Antiviral activity of FQs
FQs were demonstrated to be active against certain viruses in cultured mammalian cells. Ofloxacin had inhibitory activity against the vaccinia virus (VV) and it prevents the pox tail lesion formation in mice infected with VV . Moreover, FQ derivatives inhibited the replication of HIV-1, HIV-2 , and African swine . The efficacy of some FQs e.g. ciprofloxacin was reported for Hepatitis C Virus (HCV) and the BK polyomavirus (BKV) [65, 66], Ofloxacin was active against rhinovirus (RV) .
Suggested mechanism for antiviral activity
Among the identified drug target for coronaviruses is the main protease (Mpro, or 3CLpro)  and papain-like protease(s) (PLpro), which are essential contributors in the viral replication cycle. These enzymes are not available in human cells so that drugs targeting these enzymes will be specific with a minor impact on human cells. Silico studies demonstrated that FQ (e.g. moxifloxacin), binds to and inhibits SARS-CoV-2 Mpro, consequently prevent its replication . Interestingly the interaction of FQs with Mpro suggested being stronger compared to other protease inhibitors namely nelfinavir and chloroquine.
An illustration of this suggested mechanism is presented in (Figure 2). In the same context, ofloxacin was observed to inhibit topoisomerases/helicases in the vaccinia virus . It also inhibited reverse transcriptase in human immunodeficiency virus (HIV) activity [70-73].
Figure 2. Proposed Cellular Effect of FQ on SARS-CoV-2
Immune modulation/ anti-inflammatory effect
Umbro et al. (2013) demonstrated the benefits of ciprofloxacin in kidney transplant patients in preventing acute rejection and attributed these findings to the activity of the drug against BKV . Also, Enoki et al. (2015) reported that levofloxacin attenuated various acute inflammatory conditions associated with viral pneumonia . Poor distribution of the HCQ due to lung pathological changes was suggested as a reason for lower efficacy in severe cases of covid-19 . Recall that viral lung infections, induce a state of oxidative stress due to reactive oxygen species (ROS) and nitric oxide (NO) . FQs show anti-oxidant activity against these events and suppress lung inflammation associated with pneumonia . Fluoroquinolones suppress the production of pro-inflammatory cytokine Il-1 and TNF . Phase 3 clinical trial proved its efficacy of IL-1 antagonist in the management of sepsis .
The diagram (Figure 2) shows, the viral entry, the release of its RNA from endosomes, FQs, accumulate intracellularly bind to Mpro and inhibit its activity, Mpro is involved in the production of Nsps which are essential for viral replication and assembly. Adapted from Mengist 2020 .
Favorable PK characteristics of FQs allowing efficacy in respiratory infections
FQ shows excellent access to lung tissue, including bronchial mucosa, so that its level excessed that, in serum at a steady state . An in vitro study showed that ciprofloxacin is actively transported across bronchial lung epithelial cells .
This was confirmed clinically in mechanically ventilated severely ill Patients with COPD. The drug demonstrated excellent penetration into bronchial secretions, In all patients, the target level (AUC0–24/MIC ≥125) was achieved . Moreover, a prospective open-label study documented the favorable pharmacokinetics and pharmacodynamics of moxifloxacin in COPD patients .
FQ as zinc ionophore
Ciprofloxacin can form a complex with Zn(II), (Figure 3) with enhanced antibacterial activity against bacteria compared to the parent noncomplex drug. This was explained because the fact chelation of the Zn ion reduces its polarity thus increases its lipophilicity and permeation through the membranes .
Figure 3. Ciprofloxacin Zinc complex
Recalling the role of zinc supplement against Covid-19 due to its potential immune stimulation, broad-spectrum antiviral activity [85-87]. It is supposed to enhance both innate and humoral immunity, especially in immunocompromised geriatric patients. Zinc shows the synergistic effect with some antiviral drugs. It may diminish the RNA-synthesis in coronavirus. Taken together, we speculate that FQ is likely to have (Zinc ionophore action), zinc supplement may enhance their activity against covid-19.
Safety concern of FQs
The pharmacology of FQs is detailed in several textbooks and web-based drug information resources . Fluoroquinolones, like most antibiotics, have a long list of adverse effects, drug interactions, and contraindications that should be considered before their use . The safety concern of FQs was a subject of several reviews . A Systematic Review and Meta-Analysis of Randomized Controlled Trials revealed FQs are associated with more CNS- and GI-related adverse effects compared with other types of antibiotics . However, regarding the management of life-threatening infections, it is logical to judge the risk to benefit ratio. Although potential FQs related disability was associated with their chronic use (120 days) . This concern is not likely to be relevant in the management of Covid-19 associated pneumonia. The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture was also reported .
Cardiac toxicity of FQs
Meta-analysis studies showed a positive association between FQs and the development of an aortic aneurysm. Some risk factors that appear to be related to these effects include prolonged FQ treatment and aging [94, 95]. FQs prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I(Kr), expressed by HERG (the human ether-a-go-go-related gene). Moxifloxacin carries the greatest risk. Ciprofloxacin has the lowest risk of QT prolongation. All FQs should also be used with caution in patients at risk for QT prolongation. The overall risk of fatal arrhythmia TdP is low, which can be minimized by a proper management plan including identifying high-risk patients and avoiding concomitant drugs with synergistic cardiotoxic effects [96, 97].
There are significant interactions between FQs and multivalent cations (calcium, aluminum, zinc) . FQs can increase the level of warfarin, cyclosporine, sirolimus, and digoxin . However, in a clinical setting, the extent of drug interaction may vary under fast and fed conditions .
It is imperative to suggest that FQs may have potential antiviral effects and can be effective in some patients affected by SARS CoV-2 viruses. It is suggested that these infected patients could be stratified according to certain criteria such as cardiac, diabetic, and old age patients, etc. Accordingly, various types of patients could benefit from the use of FQs in the present pandemic.
Conflict of interest: None
Financial support: None
Ethics statement: None
1. van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564-7.
2. Mackenzie JS, Smith DW. COVID-19: a novel zoonotic disease caused by a coronavirus from China: what we know and what we don't. Microbiol Aust. 2020:MA20013-MA.
3. Rabaan AA, Al-Ahmed SH, Haque S, Sah R, Tiwari R, Malik YS, et al. SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview. Infez Med. 2020;28(2):174-84.
4. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Jama. 2020;323(13):1239-42.
5. Livingston E, Bucher K. Coronavirus disease 2019 (COVID-19) in Italy. Jama. 2020;323(14):1335.
6. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420-2.
7. Shao C, Liu H, Meng L, Sun L, Wang Y, Yue Z, et al. Evolution of severe acute respiratory syndrome coronavirus 2 RNA test results in a patient with fatal coronavirus disease 2019: a case report. Hum Pathol. 2020:101:82-8.
8. Magomedova UG, Khadartseva ZA, Grechko VV, Polivanova MN, Mishvelov AE, Povetkin SN, et al. The Role of Covid-19 in the Acute Respiratory Pathology Formation in Children. Pharmacophore. 2020;11(5):61-5.
9. Albureikan MO. COVID-19 Outbreak in Terms of Viral Transmission and Disease Biocontrol by Healthy Microbiome. Int J Pharm Phytopharmacol Res. 2020;10(3):139-46.
10. Meconcelli G, Bazzoni G, Casu C. Auriculotherapy for Stress Management as Self-Help in Isolation Situations (COVID 19). Int J Pharm Phytopharmacol Res. 2020;10(3):1-2.
11. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020; 75(23):2950-73.
12. Cannegieter SC, Klok FA. COVID‐19 associated coagulopathy and thromboembolic disease: Commentary on an interim expert guidance. Res Pract Thromb Haemost. 2020;4(4):439-45.
13. Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, et al. On the alert for cytokine storm: Immunopathology in COVID‐19. Arthritis Rheumatol. 2020;72(7):1059-63.
14. Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S, Nabipour I. COVID-19 cytokine storm: The anger of inflammation. Cytokine. 2020:155151.
15. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
16. Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect. 2020;S1684-182(20):30082-7.
17. Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, et al. Drug targets for coronavirus: A systematic review. Indian J Pharmacol. 2020;52(1):56-65.
18. Wang X, Zou P, Wu F, Lu L, Jiang S. Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses. Front Med. 2017;11(4):449-61.
19. Yoshimoto FK. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. Protein J. 2020;39(3):198-216.
20. Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J. 2019;16(1):69.
21. van Hemert MJ, van den Worm SH, Knoops K, Mommaas AM, Gorbalenya AE, Snijder EJ. SARS-coronavirus replication/transcription complexes are membrane-protected and need a host factor for activity in vitro. PLoS Pathog. 2008;4(5):e1000054.
22. Ghosh AK, Xi K, Ratia K, Santarsiero BD, Fu W, Harcourt BH, et al. Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors. J Med Chem. 2005;48(22):6767-71.
23. Kumar S, Zhi K, Mukherji A, Gerth K. Repurposing Antiviral Protease Inhibitors Using Extracellular Vesicles for Potential Therapy of COVID-19. Viruses. 2020;12(5):486.
24. Liang J, Pitsillou E, Karagiannis C, Darmawan KK, Ng K, Hung A, et al. Interaction of the prototypical α-ketoamide inhibitor with the SARS-CoV-2 main protease active site in silico: Molecular dynamic simulations highlight the stability of the ligand-protein complex. Comput Biol Chem. 2020;87:107292.
25. Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ. Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution. Proc Natl Acad Sci U S A. 2008;105(26):9065-9.
26. Frick DN, Lam AM. Understanding helicases as a means of virus control. Curr Pharm Des. 2006;12(11):1315-38.
27. Morris DE, Cleary DW, Clarke SC. Secondary Bacterial Infections Associated with Influenza Pandemics. Front Microbiol. 2017;8:1041.
28. Kwon JW, Li G, Zheng M, Kaur H, Magbual N, Dalai S. Superinfections and Coinfections in COVID-19. MedPage Today. [Internet] 2020. Available from: https://www.medpagetoday.com/infectiousdisease/covid19/86192.
29. Garazzino S, Montagnani C, Donà D, Meini A, Felici E, Vergine G, et al. Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020. Euro Surveill. 2020;25(18):2000600.
30. Hendaus MA, Jomha FA. Covid-19 induced superimposed bacterial infection. J Biomol Struct Dyn. 2020:1-10.
31. Lai CC, Wang CY, Hsueh PR. Co-infections among patients with COVID-19: The need for combination therapy with non-anti-SARS-CoV-2 agents? J Microbiol Immunol Infect. 2020;53(4):505-12.
32. Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect. 2020.81(2):266-75.
33. Li ZT, Chen ZM, Chen LD, Zhan YQ, Li SQ, Cheng J, et al. Coinfection with SARS-CoV-2 and other respiratory pathogens in COVID-19 patients in Guangzhou, China. J Med Virol. 2020;92:2381-3.
34. Zhu X, Ge Y, Wu T, Zhao K, Chen Y, Wu B, et al. Co-infection with respiratory pathogens among COVID-2019 cases. Virus Res. 2020;285:198005.
35. Yang Y, Peng F, Wang R, Guan K, Jiang T, Xu G, et al. The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun. 2020;109:102434.
36. Lv Z, Cheng S, Le J, Huang J, Feng L, Zhang B, et al. Clinical characteristics and co-infections of 354 hospitalized patients with COVID-19 in Wuhan, China: a retrospective cohort study. Microbes Infect. 2020;22(4):195-9.
37. Rawson TM, Moore LS, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M, et al. Bacterial and fungal co-infection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis. 2020;.71(9):2459-68.
38. Tian S, Xiong Y, Liu H, Niu L, Guo J, Liao M, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020:1-8.
39. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatr. 2020;58(4):712-3.
40. Lim WS, Liang CK, Assantachai P, Auyeung TW, Kang L, Lee WJ, et al. COVID-19 and Older People in Asia: Geriatr Gerontol Int. 2020;20(6):547-58.
41. Hashemi SA, Safamanesh S, Ghafouri M, Taghavi MR, Mohajer Zadeh Heydari MS, Namdar Ahmadabad H, et al. Co-infection with COVID-19 and influenza A virus in two died patients with acute respiratory syndrome, Bojnurd, Iran. J Med Virol. 2020; 92(11):2319-21.
42. D’Ardes D, Boccatonda A, Schiavone C, Santilli F, Guagnano MT, Bucci M, et al. A Case of Coinfection with SARS-COV-2 and Cytomegalovirus in the Era of COVID-19. Eur J Case Rep Intern Med. 2020;7(5):001652.
43. Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020;6(1):1-18.
44. Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Burgstaller-Muehlbacher S, et al. A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals. bioRxiv. 2020:2020.04.16.044016.
45. Ciliberto G, Cardone L. Boosting the arsenal against COVID-19 through computational drug repurposing. Drug Discov Today. 2020:S1359-6446(20)30152-5.
46. COVID-19 Drug Repurposing Database made open-access Excelra; 2020 [updated 2020].
47. Sun P, Qie S, Liu Z, Ren J, Xi JJ. Clinical characteristics of 50466 patients with 2019-nCoV infection. medRxiv. 2020.
48. Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020;6:14.
49. Balfour H. (Drug Target Review): Excelra 2020. Available from: https://www.drugtargetreview.com/news/60109/covid-19-drug-repurposing-database-made-open-access-by-excelra/.
50. Rosa SG, Santos WC. Clinical trials on drug repositioning for COVID-19 treatment. Rev Panam Salud Publica. 2020;44:e40.
51. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020.
52. Tobaiqy M, Qashqary M, Al-Dahery S, Mujallad A, Hershan AA, Kamal MA, et al. Therapeutic management of COVID-19 patients: a systematic review. Infect Prev Pract. 2020:100061.
53. Ali AS, Abdel-Rahman MS, Almalikil RS, Mohamed AS, Alfaifi KA, Fadil AE, et al. Optimizing the Use of Hydroxychloroquine in the Management of COVID-19 Given Its Pharmacological Profile. J Pharm Res Int. 2020;32(8):29-43.
54. Ali AS, ASattar MA, Karim S, Kutbi D, Aljohani H, Bakhshwin D, et al. Pharmacological basis for the potential role of Azithromycin and Doxycycline in management of COVID-19. Arabian J Chem. 2021;14(3):102983.
55. Oliphant CM, Green G. Quinolones: a comprehensive review. Am Fam Physician. 2002;65(3):455.
56. Cho JC, Crotty MP, White BP, Worley MV. What is old is new again: delafloxacin, a modern fluoroquinolone. Pharmacother: J Hum Pharmacol Drug Ther. 2018;38(1):108-21.
57. Sood D, Kumar N, Singh A, Sakharkar MK, Tomar V, Chandra R. Antibacterial and pharmacological evaluation of fluoroquinolones: a chemoinformatics approach. Genomics Inform. 2018;16(3):44.
58. Kabalak PA, Esenkaya A. Severe Pneumonia Treated Successfully with Levofloxacin and Oseltamivir During Flu Epidemic. Turk Thorac J. 2016;17(2):84-7.
59. Ezelarab HA, Abbas SH, Hassan HA, Abuo‐Rahma GEDA. Recent updates of fluoroquinolones as antibacterial agents. Arch Pharm. 2018;351(9):1800141.
60. Richards G, Brink A, Feldman C. Rational use of the fluoroquinolones. SAMJ: S Afr Med J. 2019;109(6):378-81.
61. Kabbani S, Hersh AL, Shapiro DJ, Fleming-Dutra KE, Pavia AT, Hicks LA. Opportunities to improve fluoroquinolone prescribing in the United States for adult ambulatory care visits. Clin Infect Dis. 2018;67(1):134-6.
62. Ikeda S, Yazawa M, Nishimura C. Antiviral activity and inhibition of topoisomerase by ofloxacin, a new quinolone derivative. Antivir Res. 1987;8(3):103-13.
63. Baba M, Okamoto M, Makino M, Kimura Y, Ikeuchi T, Sakaguchi T, et al. Potent and selective inhibition of human immunodeficiency virus type 1 transcription by piperazinyloxoquinoline derivatives. Antimicrob Agents Chemother. 1997;41(6):1250-5.
64. Mottola C, Freitas FB, Simões M, Martins C, Leitão A, Ferreira F. In vitro antiviral activity of fluoroquinolones against African swine fever virus. Vet Microbiol. 2013;165(1-2):86-94.
65. Sharma BN, Li R, Bernhoff E, Guttenberg TJ, Rinaldo CH. Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells. Antiviral Res. 2011;92(1):115-23.
66. Takada A, Takase S, Tsutsumi M, Sawada M. Effects of ofloxacin for type C hepatitis. Int Hepatol Commun. 1993;1(5):272-7.
67. Yamaya M, Nishimura H, Hatachi Y, Yasuda H, Deng X, Sasaki T, et al. Levofloxacin inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells. Antimicrob Agents Chemother. 2012;56(8):4052-61.
68. Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. Coronavirus Main Proteinase (3CL<sup>pro</sup>) Structure: Basis for Design of Anti-SARS Drugs. Science. 2003;300(5626):1763.
69. Marciniec K, Beberok A, Pęcak P, Boryczka S, Wrześniok D. Ciprofloxacin and moxifloxacin could interact with SARS-CoV-2 protease: preliminary in silico analysis. Pharmacol Rep. 2020;72(6):1553-61.
70. Dalhoff A. Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action? Eur J Clin Microbiol Infect Dis. 2015;34(4):661-8.
71. Ali SH, Chandraker A, DeCaprio JA. Inhibition of Simian virus 40 large T antigen helicase activity by fluoroquinolones. Antivir Ther. 2007;12(1):1.
72. Khan IA, Siddiqui S, Rehmani S, Kazmi SU, Ali SH. Fluoroquinolones inhibit HCV by targeting its helicase. Antivir Ther. 2012;17(3):467.
73. Umbro I, Anzivino E, Tinti F, Zavatto A, Bellizzi A, Rodio DM, et al. Possible antiviral effect of ciprofloxacin treatment on polyomavirus BK replication and analysis of non-coding control region sequences. Virol J. 2013;10(1):274.
74. Enoki Y, Ishima Y, Tanaka R, Sato K, Kimachi K, Shirai T, et al. Pleiotropic effects of levofloxacin, fluoroquinolone antibiotics, against influenza virus-induced lung injury. PloS one. 2015;10(6):e0130248.
75. Ali AS, Abdel-Rahman MS, Almalikil RS, Mohamed AS, Alfaifi KA, Fadil AE, et al. Optimizing the Use of Hydroxychloroquine in the Management of COVID-19 Given Its Pharmacological Profile. J Pharm Res Int. 2020:29-43.
76. Vlahos R, Stambas J, Selemidis S. Suppressing production of reactive oxygen species (ROS) for influenza A virus therapy. Trends Pharmacol Sci. 2012;33(1):3-8.
77. Dalhoff A. Immunomodulatory activities of fluoroquinolones. Infect. 2005;33(2):55-70.
78. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of the macrophage activation syndrome: Re-analysis of a prior Phase III trial. Crit Care Med. 2016;44(2):275.
79. Mengist HM, Fan X, Jin T. Designing of improved drugs for COVID-19: Crystal structure of SARS-CoV-2 main protease M pro. Signal Transduct Target Ther. 2020;5(1):1-2.
80. Wise R. Comparative penetration of selected fluoroquinolones into respiratory tract fluids and tissues. Am J Med. 1991;91(6a):67s-70s.
81. Ong HX, Traini D, Bebawy M, Young PM. Ciprofloxacin Is Actively Transported across Bronchial Lung Epithelial Cells Using a Calu-3 Air Interface Cell Model. Antimicrob Agents Chemother. 2013;57(6):2535.
82. Kontou P, Chatzika K, Pitsiou G, Stanopoulos I, Argyropoulou-Pataka P, Kioumis I. Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease. Antimicrob Agents Chemother. 2011;55(9):4149-53.
83. Sionidou M, Manika K, Pitsiou G, Kontou P, Chatzika K, Zarogoulidis P, et al. Moxifloxacin in Chronic Obstructive Pulmonary Disease: Pharmacokinetics and Penetration into Bronchial Secretions in Ward and Intensive Care Unit Patients. Antimicrob Agents Chemother. 2019;63(3):e01974-18.
84. Chohan ZH, Supuran CT, Scozzafava A. Metal binding and antibacterial activity of ciprofloxacin complexes. J Enzyme Inhib Med Chem. 2005;20(3):303-7.
85. Prasad AS. Zinc: role in immunity, oxidative stress, and chronic inflammation. Curr Opin Clin Nutr Metab Care. 2009;12(6):646-52.
86. Kumar A, Kubota Y, Chernov M, Kasuya H. Potential role of zinc supplementation in prophylaxis and treatment of COVID-19. Med Hypotheses. 2020;144:109848.
87. Skalny AV, Rink L, Ajsuvakova OP, Aschner M, Gritsenko VA, Alekseenko SI, et al. Zinc and respiratory tract infections: Perspectives for COVID‑19. Int J Mol Med. 2020;46(1):17-26.
88. David Hooper. Fluoroquinolone up to date UpToDate, Inc.; [Internet] 2020. Available from: https://www.uptodate.com/contents/fluoroquinolones?search=ciprofloxacin-drug&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1.
89. Ball P, Mandell L, Patou G, Dankner W, Tillotson G. A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context. Int J Antimicrob Agents. 2004;23(5):421-9.
90. Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolones. Ann Pharmacother. 2007;41(11):1859-66.
91. Tandan M, Cormican M, Vellinga A. Adverse events of fluoroquinolones vs. other antimicrobials prescribed in primary care: A systematic review and meta-analysis of randomized controlled trials. Int J Antimicrob Agents. 2018;52(5):529-40.
92. Wilcox MA, Villasis-Keever A, Sena AG, Knoll C, Fife D. Evaluation of disability in patients exposed to fluoroquinolones. BMC Pharmacol Toxicol. 2020;21(1):40.
93. Kim GK. The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know? J Clin Aesthet Dermatol. 2010;3(4):49-54.
94. Rawla P, El Helou ML, Vellipuram AR. Fluoroquinolones and the risk of aortic aneurysm or aortic dissection: a systematic review and meta-analysis. Cardiovasc Hematol Agents Med Chem (Formerly Current Medicinal Chemistry-Cardiovascular & Hematological Agents). 2019;17(1):3-10.
95. Noman AT, Qazi AH, Alqasrawi M, Ayinde H, Tleyjeh IM, Lindower P, et al. Fluoroquinolones and the risk of aortopathy: A systematic review and meta-analysis. Int J Cardiol. 2019;274:299-302.
96. Falagas ME, Rafailidis PI, Rosmarakis ES. Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents. 2007;29(4):374-9.
97. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120(2):103-10.
98. Douros A, Grabowski K, Stahlmann R. Safety issues and drug-drug interactions with commonly used quinolones. Expert Opin Drug Metab Toxicol. 2015;11(1):25-39.
99. Zhang L, WEI Mj, ZHAO Cy, QI Hm. Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes. Acta Pharmacol Sin. 2008;29(12):1507-14.
100. Imaoka A, Abiru K, Akiyoshi T, Ohtani H. Food intake attenuates the drug interaction between new quinolones and aluminum. J Pharm Health Care Sci. 2018;4(1):11.
Contact SPER Publications
SPER Publications and Solutions Pvt. Ltd.
HD - 236,
Near The Shri Ram Millenium School,
Noida-Greater Noida Expressway,
Noida-201301 [Delhi-NCR] India