Date Published: April 26, 2019
Publisher: Public Library of Science
Author(s): Laura S. M. Kuula, Kati M. Viljemaa, Janne T. Backman, Marja Blom, Surbhi Leekha.
Adverse events (AEs) associated with the use of fluoroquinolone antimicrobials include Clostridium difficile associated diarrhea (CDAD), liver injury and seizures. Yet, the economic impact of these AEs is seldom acknowledged. The aim of this review was to identify health service use and subsequent costs associated with ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin and ofloxacin -related AEs.
A literature search covering Medline, SCOPUS, Cinahl, Web of Science and Cochrane Library was performed in April 2017. Two independent reviewers systematically extracted the data and assessed the quality of the included studies. All costs were converted to 2016 euro in order to improve comparability.
Of the 5,687 references found in the literature search, 19 observational studies, of which five were case-controlled, fulfilled the inclusion criteria. Hospitalization was an AE-related health service use outcome in 17 studies. Length of hospital stay associated with AEs varied between <5 and 45 days. The estimated cost of an AE episode ranged between 140 and 18,252 €. CDAD was associated with the longest stays in hospital. Ten studies reported AE-related length of stays and five evaluated costs associated with AEs. Due to the lack of published literature, health service use and costs associated with many high-risk FQ-related AEs could not be evaluated. Because of the wide clinical use of fluoroquinolones, in particular serious fluoroquinolone-related AEs can have substantial economic implications, in addition to imposing potentially devastating health complications for patients. Further measures are required to prevent and reduce health service use and costs associated with fluoroquinolone-related AEs. Equally, better-quality reporting and additional published data on health service use and costs associated with AEs are needed.
Fluoroquinolones (FQs) are counted among broad-spectrum antimicrobials and are used to treat genitourinary, respiratory, gastrointestinal, skin and soft tissue infections. FQs are generally well tolerated antimicrobials: the discontinuation of treatment due to AEs is required in fewer than five percent of consumption. Their mechanism of action is based on the drugs’ ability to inhibit DNA gyrase and topoisomerase IV, and thus, DNA synthesis. The most common AEs are mild and reversible, such as diarrhea, nausea and headaches. However, FQs are also associated with more serious AEs, including Clostridium difficile infections, prolonged QT interval, tendinitis and tendon rupture, dysglycemia, hepatic toxicity, phototoxicity, acute renal failure and serious AEs involving the central nervous system, such as seizures.   FQ-related AEs can be multisymptomatic, progressive and have long latency periods, which can make them difficult to detect. FQs have been in clinical use since the 1980s and are globally among the most consumed antimicrobials. Due to reported serious AEs associated with the use of FQs, the European Medicines Agency (EMA) recommended restrictions on their use in October 2018. The U.S. Food and Drugs Administration (FDA) has issued several “black box warnings” against FQs with the latest safety announcement dated in December 2018 warning about an increased risk of ruptures or tears in the aorta blood vessel in some patients. FDA-approved FQs are ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, gemifloxacin and recently, delafloxacin. FQs approved in Europe include ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, gemifloxacin, cinoxacin, enoxacin, flumequine, lomefloxacin, nalidixic acid, norfloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin.
The aim of this systematic review was to identify health service use and costs associated with FQ-related AEs. To date, research concentrating on costs associated with drug-related AEs remains scarce. As far as we know, the economic impacts of any FQ-related AEs have previously not been examined in a systematic review. Due to the substantial gap in published literature, we were unable to examine many serious and costly FQ-related AEs, such as neuropsychiatric AEs, QT interval prolongation, aortic aneurysm and tendinopathy in this review. There was considerable heterogeneity among the included studies. The most variation was associated with population sample sizes (n = 33–1,277,248) and study duration (4 weeks—22 years) as well as AEs considered. Although randomized controlled trials (RCTs) were not excluded from the literature search, all the included studies were observational. Observational studies may pick up on AEs not observed in RCTs, which might be due to several factors. RCTs frequently exclude patients who are most vulnerable to AEs, such as the elderly and patients with comorbidities. In addition, sample sizes are in many cases smaller and follow-up periods often shorter in RCTs than in observational studies. Of the 19 studies included in the review, five were case-controlled, in order to explicitly observe risk rates of AEs associated with FQs. Even then, the number of FQ-related AEs assessed in the included studies in proportion to the population size was small, which could mean that all FQ-related AEs were not assessed. In 13 studies--, only specific AEs were examined and many AEs may not have been reported or even recognized. Of the five FQs in this study, levofloxacin was associated with the most reported AEs, health service use, length of hospital stay and costs. Ciprofloxacin was associated with similar AEs, health service use, length of stay and costs as levofloxacin, but with smaller volume. Norfloxacin, on the other hand, was only linked to two cases of hepatitis. These data do not allow comparisons across FQs and drawing of definite conclusions relating to health service use and costs associated with levofloxacin, ciprofloxacin, moxifloxacin, norfloxacin and ofloxacin. Levofloxacin and ciprofloxacin were considered in 12 studies, including extremely large studies, and norfloxacin in only one. Therefore, the number of AEs associated with specific FQs reported in the studies is related to the utilization of the FQ and not necessarily to the toxicity. At present ciprofloxacin followed by levofloxacin are the most consumed FQs globally. Previous research has shown that the safety profiles of the FQs included in this systematic review are similar to each other.
Because of the wide clinical use of FQs, in particular serious FQ-related AEs can have substantial economic implications, in addition to imposing potentially long-lasting health complications for patients. Better-quality reporting and additional published data on health service use and costs associated with AEs are both necessary and overdue.