key: cord-0271941-recze2y1
authors: Bogdanic, N.; Mocibob, L.; Vidovic, T.; Soldo, A.; Begovac, J.
title: Azithromycin consumption during the COVID-19 pandemic in Croatia, 2020
date: 2021-11-01
journal: nan
DOI: 10.1101/2021.10.31.21265714
sha: f87996ea53dac5a0b1d76dec0ba0836ac7680bc2
doc_id: 271941
cord_uid: recze2y1

Background. During the initial phase of the COVID-19 pandemic, there was great enthusiasm for the use of azithromycin with or without hydroxychloroquine. Objectives. We analyzed azithromycin consumption in Croatia in 2020 and compared this to the period 2017-2019. Methods. Azithromycin consumption was evaluated using the IQVIA Adriatic d.o.o. database which collects data on azithromycin distribution from wholesale pharmacies to hospital and non-hospital pharmacies in Croatia. We analyzed data for the period from January 2017 to December 2020. Azithromycin distribution was measured as days of therapy (DOT) and reported as per 1000 inhabitants or per 1000 inhabitant-days. Results. In the period 2017-2020, total azithromycin DOT in Croatia increased in 2017, 2018, 2019, and 2020 (1.76, 1.91, 1.91 and 2.01/1000 inhabitant-days, respectively). Non-hospital pharmacies received 2.18 times and hospital pharmacies 4.39 times more DOT units/1000 inhabitants of azithromycin in March 2020 compared to the average distribution rate in March 2017-2019. During the peak of the COVID-19 epidemic (November and December 2020) azithromycin distribution increased considerably in hospital (3.62 and 3.19 times, respectively) and non-hospital pharmacies (1.93 and 1.84 times, respectively) compared to the average consumption in the same months in 2017-2019. Conclusions. Our data showed increased azithromycin distribution in the period 2017-2020 which indicates azithromycin overuse. Preliminary information on COVID-19 treatments with a desire to offer and try what is available even in the absence of strong scientific evidence may have influenced practices of antimicrobial prescriptions.

Since the beginning of the COVID-19 pandemic concerns about the potential consequences of antimicrobial overuse have been raised [1] . At first, increased patient exposure to antimicrobials was caused by the lack of rapid diagnostic tools, decision tools, and concerns of bacterial coinfection [1] . An international survey among physicians involved in the treatment of COVID-19 patients on antibiotic prescribing practices conducted in April 2020 revealed that the decision on antibiotic use was mostly based on clinical presentation, with the need for coverage of atypical pathogens and more than half of the participants reported use of a combination of β lactams and macrolides or fluoroquinolones [2] .

Azithromycin has antibacterial activity, an immunomodulating effect, and perhaps even some antiviral activity [3] . The use of azithromycin with hydroxychloroquine gained much attention when preliminary observational reports and non-randomized pilot studies indicated favorable outcomes in patients treated with this combination [4, 5] . In vitro experiments suggested a synergistic effect with hydroxychloroquine on inhibition of viral replication [6] .

Preliminary information on COVID-19 treatments with a desire to offer and try what is available even in the absence of strong scientific evidence might have influenced practices of antimicrobial prescriptions. We investigated azithromycin consumption in Croatia in 2020 and compared this to the period 2017 to 2019.

The data on azithromycin distribution to hospital and non-hospital pharmacies in Croatia (population 4.058 million in 2020) served as a proxy to consumption and were extracted from the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) We analyzed data on azithromycin distribution for the period from 1 st January 2017 to 31 st December 2020. Azithromycin consumption was measured as days of therapy (DOT) which represents a ratio of the total dose of azithromycin in one package divided by the defined daily Spearman's rank-order correlation test was used to measure the association between quantities of azithromycin distribution and the number of COVID-19 cases. The study was approved by the Ethical Committee of the University Hospital for Infectious Diseases, Zagreb, Croatia.

In the period from 2017 to 2020, total azithromycin DOT distribution per calendar year increased in 2017, 2018, 2019, and 2020 (1.76, 1.91, 1.91, and 2.01/1000 inhabitant-days, respectively). This was a 5.2% increase from 2019 to 2020 and an 8.1% increase from the average of 2017-2019 to 2020. This 8.1% increase corresponds to a total of 37224 5-day courses of azithromycin prescriptions. Azithromycin was distributed to non-hospital pharmacies in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The monthly pattern of azithromycin distribution was quite different in 2020 compared to the previous three years (Fig 1) . Azithromycin distribution to both hospital and non-hospital pharmacies in 2020 was highest in March, followed by November and December. The number of COVID-19 cases in Croatia started to increase exponentially from September 2020 and the epidemic reached its peak in November and December 2020 with 79126 and 82395 cases, respectively (Fig 1) . There was a positive correlation between the number of COVID-19 cases and the total azithromycin consumption from July to December 2020 (Spearman's test, Fig 2) . In April-August 2020 the distributed DOT of azithromycin was not only lower than in other months of 2020, but also . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

The pattern of azithromycin monthly distribution in 2020 was different in comparison to previous years, probably due to various reasons. Azithromycin distribution to hospital and retail pharmacies was largest in March when the first small study of French authors on its efficacy in COVID-19 was published on a preprint server [7] . Also, the era of social media and its high impact on people's perception of disease-related themes created an infodemic. Galotti et al. [9] . It thus seems that fear of a great epidemic and uncertainty due to the absence of the treatment with proven efficacy can influence consumption of antimicrobials with assumed or unproven benefits.

March 2020 was similar to that in 2017-2019 [10] . In our study, it seems that the huge supplies acquired by hospitals and retail pharmacies in March 2020 have been dispensed to patients over the following months because the distribution of azithromycin was several times lower in the period from April to August 2020 compared to 2017-2019 (Fig 2) . Data from the US showed that the number of patients dispensed azithromycin in May 2020 was 62% lower than the historic average, and this was assumed to be related to mitigation measures undertaken to curb the higher [11] .

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 1, 2021. ; https://doi.org/10.1101/2021.10.31.21265714 doi: medRxiv preprint 9

The monthly pattern of azithromycin distribution was similar in 2017, 2018 and 2019 with higher distribution during winter months. It is known that every influenza season leads to increased use of antibiotics in the winter months [12] . Isolation measures and social distancing during 2020 probably contributed to fewer acute respiratory infections including post-influenza pneumococcal infection and atypical pneumonia which is a common reason for azithromycin use during the influenza season. In the 2020/2021 season the influenza epidemic was at a very low level in the whole European Region and it could not have had a significant impact on antimicrobials prescription in Croatia in 2020 [13] . So, the facts that there was no significant influenza epidemic would indicate that the increase in azithromycin distribution was mainly due to COVID-19 and suggests that the true overconsumption was higher than the 8.1% increase found in our study. and/or M. pneumoniae [17] . However, PCR-based assays are preferred for diagnosis of both C.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Azithromycin consumption gradually increased from July and peaked in November and December 2020 (Figs 1 and 2) . In September 2020 the results of a randomized study showed no benefit on clinical outcome of adding azithromycin to standard of care treatment and this has been confirmed in the RECOVERY randomized trial [18, 19] . Despite these findings and low occurrence of bacterial coinfections [15] , azithromycin distribution to hospital pharmacies increased about 3 times in November and December 2020 in comparison to the average of the same months in 2017-2019. The increase was less pronounced in non-hospital pharmacies; however, it was almost 2 times higher when compared to 2017-2019 (Fig 2) .

Our study has limitations. The data on individual patients were not available and we could not follow up dispensed azithromycin from pharmacies to patients. However, it is quite certain that all quantities of distributed azithromycin have been dispensed to patients. We were also not able to report more standard measures of antibiotic usage such as defined daily dose or DOT per 1000 patient-days. Nevertheless, we did provide data on azithromycin overuse during the COVID-19 epidemic in Croatia.

Even though an increase of 8.1% of total azithromycin DOT from the average of 2017-2019 compared to 2020 seems modest, we should highlight the fact that Croatia is already one of the countries with highest percentage of macrolide resistant isolates among EU/EEA countries [20] . Macrolides were the second most common used antibiotics with azithromycin accounting for most of the use in Croatia in 2014 -2019 with daily defined doses (DDD)/1000 inhabitants . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 1, 2021. [20] . Resistance data collected from 38 centers in Croatia in 2019 showed 31% resistant S. pneumoniae to macrolides with a range of local results from 0 to 53% and 9% of macrolide resistant Streptococcus pyogenes with a range of local results from 0 to 25% [23]. While widespread use of antimicrobials leads to more bacterial resistance which is of great public health concern, it also exposes patients to possible side effects. Azithromycin is generally a well tolerated and safe drug, however, when combined with other QT-prolonging drugs (such as hydroxychloroquine) it may increase the risk for serious toxicities and requires careful monitoring.

In conclusion, we provided national data on overuse of azithromycin during the COVID-19 epidemic in Croatia. Antibiotic stewardship principles should not vanish during the challenging times of the COVID-19 pandemic. To preserve the effectiveness of existing antimicrobials such as azithromycin, antibiotic stewardship principles should be followed and carefully applied in times of crisis.

Antimicrobial use, drugresistant infections and COVID-19

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We thank IQVIA Adriatic d.o.o. for providing the data on azithromycin distribution.

Antibiotic resistance in Croatia, 2019. 1st ed. Croatia: The Croatian Academy of Medical Sciences; 2020.. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 1, 2021. ; https://doi.org/10.1101/2021.10.31.21265714 doi: medRxiv preprint 15 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 1, 2021. ; https://doi.org/10.1101/2021.10.31.21265714 doi: medRxiv preprint