key: cord-0966765-j5n4n22z authors: Tanioka, H.; Tanioka, S. title: Risks and Benefits of Antibiotics vs. COVID-19 Morbidity and Mortality date: 2020-10-20 journal: nan DOI: 10.1101/2020.10.15.20213603 sha: f3723b2a53531db30ed630df33f9e28f5add78ae doc_id: 966765 cord_uid: j5n4n22z The purpose is to analyze the potential association of each antibiotic consumption rate and use ratio with COVID-19 morbidity and mortality, and to investigate the efficacy and safe use of antibiotics against COVID-19. Design Retrospective statistical analysis of antibiotic use compared with COVID-19 morbidity and mortality. Methods Each antibiotic defined daily dose per 1000 inhabitants per day as each antibiotic consumption rate was available in the official reports and each antibiotic use ratio data was calculated from them. Coronavirus disease data were obtained from the WHO Coronavirus Disease Dashboard. The relationships between the sum of defined daily dose, each antibiotic defined daily dose, each antibiotic use ratio, and COVID-19 morbidity and mortality were examined. The statistical correlation was calculated by univariate linear regression analysis and expressed by Pearson's correlation coefficient. Results Cephalosporins were a negative correlation with mortality and morbidity. Penicillin had a weak positive correlation with them. Macrolides, quinolone, and sulfonate showed a slightly negative correlation tendency with mortality. Conclusions Cephalosporins may affect less morbidity and mortality. Penicillin suggests to accelerate them. The combination of cephalosporins with macrolides or quinolones may be a helpful treatment. The World Health Organization (WHO) is very clear that antibiotics do not work against viruses but only bacteria, and yet health care providers are using antibiotics in some patients with COVID-19. Patients with viral pneumonia can develop a secondary bacterial infection that may need to be treated with antibiotics, although, this complication is reported to be uncommon early on in the course of COVID-19 pneumonia (1) . On the other hand, some antibiotics have demonstrated several antiviral activities. Azithromycin is a macrolide antibiotic that is being investigated as a potential treatment for people with COVID-19 (2, 3, 4, 5) . Clarithromycin suppresses virus growth (5, 6) . In in vitro laboratory studies, quinolones have demonstrated antiviral activity against human immunodeficiency virus (HIV). And their antiviral activity is identified by inhibition of viral RNA production in a dose-dependent manner (7, 8) . They also can be considered excellent candidates for the development of anti-Zika virus and anti-chikungunya virus (CHIKV) agents (9) . It seems that trimethoprim-sulfamethoxazole suppress human immunodeficiency viral load and provide an excellent clinical response to antiretroviral . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. . https://doi.org/10.1101/2020. 10.15.20213603 doi: medRxiv preprint 3 therapy for HIV (10) . Sulfonates can act on Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (11). Antibiotics have been already used for the treatment of community-acquired pneumonia caused by designated, susceptible bacteria, and for the treatment of other bacterial infections in daily practice. Cephalosporins that is more than 60% of them are third-generation, macrolides, and quinolones are frequently used in Japan, and penicillins are frequently used in EU/EEA countries (12, 13) . The antibiotic use trend is across in East Asia. The morbidity and mortality caused by COVID-19 in Japan and East Asia are less than in EU/EEA countries. Health care providers daily use several antibiotics to treat microbiological infectious patients under COVID-19 status. There are also differences between EU/EEA countries and Japan in how antibiotics are used. Therefore, it may be imagined that each antibiotic daily consumption rate and use ratio may influence COVID-19 morbidity and mortality. If they are associated with morbidity and mortality caused by COVID-19, antibiotics will be suggested to influence COVID-19. Little is known about the potential protective and promotive factors from antibiotics against COVID-19. It is necessary to investigate the protective factors of antiinfective agents that may protect against infection and the factors that improve or promote the outcome if physicians use antibiotics under the condition of COVID-19 epidemic. Therefore, the relationship between each daily antibiotic use and COVID-19 morbidity and mortality should be studied. This retrospective study aims to determine whether each antibiotic consumption rate and use ratio may have the potential affecting morbidity and mortality caused by and to investigate the effective and safe use of antibiotics against COVID-19. The retrospective statistical analysis study of antibiotic use compared with COVID-19 morbidity and mortality. This single-center study was obtained by the institutional ethics review board, and this study was the retrospective cohort study using public data. Data were collected for antibiotic consumption rate and use ratio, and COVID-19 morbidity and mortality. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. . https://doi.org/10.1101/2020. 10.15.20213603 doi: medRxiv preprint The antibiotic consumption data from the annual epidemiological report for 2019 that contained the consumption of antibacterials for systemic use by EU/EEA countries in 2018 expressed as DDD per 1000 inhabitants per day was used (12) . Japan data was obtained from the antimicrobial selling data in 2019 (13) . That is, these data represented each antibiotic consumption rate. Each antibacterial use ratio was calculated from these data. COVID-19 morbidity per 0. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. The antibiotic consumption dose for systemic use by EU/EEA countries in 2018 was expressed as DDD per 1000 inhabitants per day. Therefore, the relationship between each DDD per 1000 inhabitants per day, and COVID-19 morbidity and mortality represented whether each antibiotic consumption rate is related to COVID-19. The relationship between the antibiotic use ratio and COVID-19 morbidity and mortality indicated whether the antibiotic use trend affects COVID-19. The sum of DDD suggests no affect morbidity and mortality caused by COVID-19. However, each antibiotic analysis represents various analytical results. Cephalosporins suggest decreasing morbidity and mortality caused by COVID-19. Penicillins may have the potential to accelerate them. Quinolones suggest the potential to reduce morbidity, and the weak potential against mortality. Macrolides may have the potential for reducing morbidity and mortality. Therefore, macrolides and quinolones may suggest working against COVID-19. Sulfonates and trimethoprim have almost the same mortality affect as quinolones. However, they may suggest increasing morbidity. Tetracyclines may increase morbidity, but may not affect mortality. The results of these analyses were similar to those of EU/EEA countries alone. Therefore, cephalosporins, macrolides, and quinolones may be potentially effective against COVID-19 (SARS-CoV-2). And, sulfonates and is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. . https://doi.org/10.1101/2020.10.15.20213603 doi: medRxiv preprint trimethoprim may have the potential reducing mortality. Cephalosporins, macrolides, and quinolones are frequently used in Japan, but penicillins are frequently used in European countries (12, 13) . The different antibiotic use trends may suggest an explanation for less morbidity and mortality caused by COVID-19 in Japan rather than in EU/EEA countries. The antibiotic use trend in Japan is across East Asia. Although the analytical data is from 2018 and is not the latest, the antibiotic consumption rate and use trend from the previous report are not so different. Therefore, the results of this study will appear to fit in with the latest. The results imply that it is prudent to avoid penicillins use in the current status of the COVID-19 epidemic, as penicillins may suggest increasing morbidity and mortality caused by COVID-19. Penicillins may appear to create an environment for COVID-19 proliferation or may help the virus spread rapidly through cells. Macrolides have been shown to be active in vitro against RNA viruses. Azithromycin is thought to have antiviral and anti-inflammatory activity and may work synergistically with other antiviral treatments. Azithromycin has demonstrated antiviral activity against Zika virus and against rhinoviruses from in vitro studies. Azithromycin is a macrolide antibiotic that is being investigated as a potential treatment for people with COVID-19 caused by the new coronavirus (SARS-CoV-2) (2, 3, 4, 5) . Clarithromycin decreases interferon (IFN)-γ and increases IL-10 levels. Clarithromycin promotes the expansion of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides (6) . Clarithromycin suppresses virus growth (5, 6) . Ivermectin is a cyclic lactone oral anthelmintic that belongs to the macrolides group. Ivermectin is anti-parasitic previously shown to have broad-spectrum antiviral activity in vitro, and it is an inhibitor of SARS-CoV-2 (14) . Indeed, it seems that the mortality rate caused by COVID-19 is low in Onchocerciasis endemic areas of Africa (1). However, from an action point of view, these drugs seem to be effective only in the early stages. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. . https://doi.org/10.1101/2020. 10.15.20213603 doi: medRxiv preprint group into the piperazine moiety of fluoroquinolone changed its activity from antibacterial to antiviral, with specific effects on human immunodeficiency virus (HIV) (8) . Antiviral activity is confirmed by dose-dependently inhibiting viral RNA production (9) . Sulfonates and trimethoprim show almost the same mortality effect as quinolones. So, they may work against COVID-19 mortality. Trimethoprim-sulfamethoxazole appears to be effective in suppressing human immunodeficiency virus (HIV) load and antiretroviral therapy (10) . It has antimalarial and antibacterial properties. Since trimethoprimsulfamethoxazole is used in the current state of COVID-19, its function against RNA viruses may be due to its antimalarial properties. Because, in principle, antibacterial agents do not act on viruses. Sulfonates can also act on herpesvirus such as EBV and Kaposi sarcoma herpesvirus belonging to DNA virus (11). Hence, antimalarial properties may act on RNA and DNA viruses. Strangely, in this study, the higher cephalosporins consumption rate and use ratio will make lower morbidity and mortality caused by COVID-19 than other antibacterials. Cephalosporins have not been proven effective against viruses. β-lactam antibiotics including cephalosporins have a bacteriostatic effect. The bacteriostatic action means the action of suppressing the growth of bacteria. β-lactam antibiotics act by inhibiting peptidoglycan synthase, which is an enzyme required for synthesizing bacterial cell walls. However, cephalosporins suggest inhibiting SARS-CoV-2. There are four effective cases of cephalosporins (Ceftriaxone) combination therapy with minocycline (broad-spectrum tetracycline) in Japan (15) . Tetracyclines do not affect mortality caused by COVID-19 from this study. Therefore, the results of this study and these effective cases imply that cephalosporins may work against SARS-CoV-2. According to the previous report (16) for patients with MERS coronavirus (MERS-CoV) that is the same coronavirus of SARS-CoV-2, empirical treatment with neuraminidase inhibitors and an association of antibiotics effective against S. pneumoniae and L. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. The results of this study imply that penicillins should be avoided to use under the condition in COVID-19. Empirical treatment with neuraminidase inhibitors and the combination of cephalosporins and macrolides or quinolones are suggested to be an effective treatment for COVID-19. No source of funding was used. We declare that we have no conflict of interest. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted October 20, 2020. . https://doi.org/10.1101/2020. 10.15.20213603 doi: medRxiv preprint Coronavirus disease (COVID-19) advice for the public: Myth busters Zika virus cell tropism in the developing human brain and inhibition by azithromycin Evaluation of Ebola virus inhibitors for drug repurposing Azithromycin inhibits the replication of Zika virus Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia Broad-spectrum antiviral activity and mechanism of antiviral action of the fluoroquinolone derivative K-12 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted Antiviral Properties of Quinolone-based Drugs Quinolone-N-acylhyd.razone hybrids as potent Zika and Chikungunya virus inhibitors A community-based study of the incidence of trimethoprim-sulfamethoxazole-preventable infections in Malawian adults living with HIV European Centre for Disease Prevention and Control: European Surveillance Antimicrobial consumption in the EU/EEA Annual epidemiological report Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expectations Four case reports of coronavirus disease 2019 (COVID-19): Two Chinese visitors from Wuhan and two Chinese Canadian passengers on the cruise ship. The Japanese Association for Infectious Diseases Case report 2020 10_4.pdf. downloaded on 9 This retrospective study complies with ethical standards. All data generated or analyzed during this study are included in this article. This study was done by ourselves. We carried out the design of the study, performed the statistical analysis, and prepared the manuscript. HT wrote the final manuscript. It is made available under a perpetuity.is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted October 20, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted October 20, 2020. . https://doi.org/10.1101/2020. 10.15.20213603 doi: medRxiv preprint