Fluoroquinolone antibiotics: High-risk prescriptions in Germany

For years it has been reported worldwide that antibiotics from the fluoroquinolones group are associated with serious and sometimes irreversible risks for patients. In comparison, these antibiotics in particular are prescribed very frequently in Germany. According to calculations by the AOK Scientific Institute (WIdO) based on prescription data from AOK insured persons, these drugs were prescribed to 3.3 million patients in Germany in 2018 alone - still too often given the fact that fluoroquinolones are are reserve antibiotics. For many indications, highly effective and at the same time lower-risk substances are available. In the case of minor illnesses such as uncomplicated urinary tract or simple respiratory tract infections, the use of antibiotics can be avoided entirely. Fluoroquinolones are antibiotics whose active ingredient name ends in “-floxacin”, such as ciprofloxacin (trade name, e.g. “Ciprobay”) or levofloxacin (trade name, e.g. “Tavanic”). They have antibacterial properties and can cure serious, life-threatening infections. However, in a few cases they cause serious and long-lasting side effects such as tendon ruptures or psychological disorders such as depression and anxiety. Therefore, these reserve antibiotics should only be used after a thorough benefit-risk assessment and only as a last-line treatment option (so-called last-line use). Patients must be intensively informed about the dangers and alternatives of these medications and receive targeted support in the event of damage.

>> The Federal Institute for Drugs and Medical Devices (BfArM) announced at the beginning of April 2019 that doctors should only prescribe the antibiotics from the fluoroquinolones group, which are very frequently prescribed in Germany, in individual cases due to serious side effects (Federal Institute for Drugs and Medical Devices 2019). However, this warning came late. It has been known for more than ten years that fluoroquinolone antibiotics have serious side effects: However, it was only in February 2017 that a European risk assessment procedure was initiated at the European Medicines Agency (EMA) for these drugs (Federal Institute for Drugs and Medical Devices 2017). Delayed, because the American Medicines Agency (FDA) has been informing about serious side effects since 2008, the French Medicines Agency called for safety measures in 2015 and the FDA ordered in 2016 that these antibiotics should only be used as a last resort in numerous infections. The toxicity pattern of quinolones and fluoroquinolones is now referred to as a special FQAD syndrome (Fluoroquinolone-Associated Disability). Of the 16 fluoroquinolones that once existed, only five are currently on the market in Germany. The remaining eleven were taken off the market shortly after their introduction - mostly due to toxic complications or intolerances. In order to protect patients from the use of harmful medicines, reports of side effects in Germany are recorded by the BfArM, among others. Depending on the frequency of these reports and the severity of the reported side effects, the authority initiates a risk assessment process at the EMA.
The Drug Commission of the German Medical Association (AkdÄ) had repeatedly pointed out the risks of fluoroquinolone antibiotics to doctors and advocated for their moderate use. The pharmaceutical-independent pharma-telegram has also been reporting since 1989 on serious undesirable effects of this group of substances, including central nervous effects through to psychoses and tendon damage (arznei-telegramm 2019). However, it is only now - after the process, which lasted over two years, that the pharmaceutical manufacturers have to take action at the request of the BfArM and massively restrict the areas of application in the package inserts for their drugs. In a so-called Red Hand Letter on April 8, 2019, they informed about the risks of “quality of life-impairing, long-lasting and possibly irreversible side effects when using systemic and inhaled quinolone antibiotics”. In addition, manufacturers must include this warning in every package insert.
Decline in prescriptions for fluoroquinolones
More than one in four people insured with statutory health insurance received an antibiotic prescription from their doctor at least once in 2018. Of the 310 million daily doses of antibiotics prescribed in 2018, 8.2 percent (25.6 million daily doses) were from the group of fluoroquinolone antibiotics (Fig. 1, Table 1).
On average, in 2018, each person insured by the GKV received 4.3 prescribed daily doses of antibiotics, including 0.35 from the group of fluoroquinolone antibiotics, which corresponds to a share of 8.2 percent (Fig. 2). A regional comparison shows clear differences in the number of antibiotic prescriptions: While the outpatient statutory health insurance physicians in Berlin manage with 2.8 daily doses of antibiotics for the GKV insured people living there, the comparable value in Westphalia-Lippe is 4.8 daily doses per GKV insured person in 2018 was more than 40 percent higher. However, there is no connection between the number of antibiotic prescriptions and the proportion of fluoroquinolones: the fewest daily doses of fluoroquinolone per GKV insured person were prescribed in Hamburg (0.24 daily doses) and Bremen (0.25 daily doses) in 2018. The top spot here is taken by Saarland with 0.50 daily doses, which takes third place with a comparatively high number of antibiotic prescriptions.
Even though prescriptions have been declining since 2016, according to an estimate based on AOK data, around 7.1 million patients have still been treated since 2017 (3.8 million patients in 2017 and 3.3 million in 2018). patients) and thus around 5 percent of the more than 72 million people insured by statutory health insurance are treated with at least one fluoroquinolone therapy every year (Table 1). This is despite the fact that these active ingredients are considered reserve antibiotics worldwide and should only be used after other alternatives have failed. Above all, they should not be used for minor illnesses such as simple colds or bladder infections, which usually do not require antibiotic treatment at all. This could also counteract the development of resistance and maintain the effectiveness of the reserve antibiotics. However, the extent of the regulations in Germany suggests that fluoroquinolone antibiotics are not only used as a backup agent and not exclusively for serious and life-threatening infections. Ciprofloxacin is the leader among fluoroquinolones with almost two thirds of prescriptions (64 percent).
Risk for the fluoroquinolone patients
The WIdO, with the support of Prof. Dr. Winfried V. Kern from the Center for Infectious Diseases at the University Hospital of Freiburg made an estimate of how many patients in Germany were at risk of certain fluoroquinolone-associated side effects. Based on various epidemiological studies, an additional risk can be determined for selected adverse drug reactions and harmful effects compared to treatment with better-tolerated antibiotics (Gorelik et al. 2018; Morales et al. 2019; Pasternak et al. 2018; Persson et al. 2019 ; Tandan et al. 2018). Due to such estimates and reports of possible persistent side effects in the nervous system and musculoskeletal system, the use of fluoroquinolones has now been further restricted. The estimates show that out of one hundred thousand fluoroquinolone users, an additional 1,161 cases of side effects on the nervous system (especially confusion and restlessness), 33 tendon ruptures (tendon tears), 8.2 aortic aneurysms (vascular damage to the main artery) and four cardiovascular deaths can occur. Assuming that one or even more of the side effects listed above can in principle occur when taking each pack, this would correspond to a number of more than 40,000 such side effects in 3.5 million drug treatments in 2018 that did not occur when using another antibiotic would be. These calculations do not take into account a large number of other complications, for example hyperglycemia in diabetics, the additional increased risk in older people or with simultaneous treatment with corticosteroids. In addition, according to these study results, it can be assumed that 140 deaths could have been avoided by using other antibiotics or by not using antibiotics.
Areas of application of fluoroquinolones
When analyzing the fluoroquinolone regulations, the question arises as to which indications these active ingredients are used for. This question cannot be answered directly because in Germany there are currently no indications or diagnoses that trigger the prescription on the medication prescription (the prescription sheet). However, the statutory health insurance companies have the doctors' quarterly documented diagnoses available for billing purposes. This information can be used to indirectly determine which diagnoses were documented by the doctor who issued the fluoroquinolone prescription. This makes it possible to answer whether the reasons for medical prescriptions of fluoroquinolones have changed over the years due to the state of knowledge and corresponding recommendations or restrictions. This article looks at the proportions of the various diagnoses in a quarter among doctors prescribing fluoroquinolone. This analyzes which diseases fluoroquinolones are used for: Since the use of fluoroquinolones has been restricted over the years for specific indications, such diagnoses should have decreased. The anonymized prescription data available in the WIdO of all AOK insured persons from 2006 to 2018 were used for the analyses. Because medical diagnosis information is only available quarterly, insured person quarters (“quarterly patients”) were always chosen as the unit of analysis.
But for which indications were restrictions imposed on the use of fluoroquinolones? Fluoroquinolones have received approval over the years for a variety of indications, including serious infections such as tuberculosis, complicated abdominal and soft tissue infections, or infections in immunocompromised patients. Fluoroquinolones are still essential for these serious infections. Indication restrictions were made in particular for areas of application such as uncomplicated urinary tract infections, middle ear infections or infections of the upper respiratory tract (cold, acute sinusitis, pharyngitis or laryngitis, etc.), as well as for bacterial infections, for which fluoroquinolones are only used after better-tolerated alternatives have failed (last line). (bacterial infections of the upper respiratory tract and pneumonia) (BfArM 2019, EMA 2019).
For the following analyses, those AOK insured persons were considered who received at least one antibiotic prescription and/or one fluoroquinolone prescription in one quarter of the respective year. In these cases, the confirmed diagnoses of the doctor issuing the prescription were considered. This means that a total of 141.6 million AOK-insured quarterly antibiotic patients, including 19.4 million fluoroquinolone quarterly patients, were taken into account in the analysis for the years 2006 to 2018. It becomes clear that AOK-insured antibiotic patients have been treated more cautiously with fluoroquinolones over the years (see Figure 3). The analysis chosen below based on treated patients results in a significantly higher fluoroquinolone
proportion than in Figure 2 when looking at daily doses, since treatment with fluoroquinolones is usually significantly shorter than with other antibiotics. This shows that more than a sixth of patients who were prescribed antibiotics were treated with a fluoroquinolone in 2018 (17.5 percent). This roughly corresponds to the proportion calculated for the statutory health insurance in Table 1.
If the restricted indication areas described above for the use of fluoroquinolones are focused on, it becomes clear that among all AOK patients with one of these diagnoses and antibiotic prescription, the proportion of patients treated with fluoroquinolones was on average 8.5 percent in 2018. In 2006 the share was 11.3 percent. This means that the proportion of patients treated with fluoroquinolones with the diagnoses discussed has fallen overall by a quarter (–25.2 percent). The comparison between 2006 and 2018 shows a decline in almost all of these diagnostic groups (Figure 4). In individual diagnostic groups such as “Pneumonia, pathogen unspecified” (–47.4 percent), “Acute bronchitis” (–43.4 percent) and “Unspecified chronic bronchitis” (–41.9 percent) the shifts have disappeared from fluoroquinolones to other antibiotics is above average. For other indications such as “other diseases of the urinary system” (-24.8 percent) or “cystitis” (-26.6 percent), based on the current state of knowledge and the resulting recommendations, it would be expected that fluoroquinolones would be prescribed much more cautiously. At the same time, the proportion of prescriptions compared to other antibiotics for patients diagnosed with colds and non-purulent otitis media has hardly changed at all.
The numerous reports - both in the specialist media and in the lay press - appear to have had an impact on the prescribing doctors even before the BfArM intervened. However, with the available data it cannot be examined whether fluoroquinolones are really only prescribed as the last-line option that is now required. In the future, the doctor should be able to better consider whether each possible use of fluoroquinolone is necessary and useful.
What can we learn from it?
Millions of antibiotic patients in Germany have been exposed to additional risks for years, even though pharmaceutical manufacturers were already aware of the particular dangers of fluoroquinolones and the resulting measures from other countries. In a European comparison, Germany occupies a top position with its share of systemic quinolones and cephalosporins in all systemic antibiotics with 30%. In Denmark, the proportion of these two antibiotic groups is only 3% or in Great Britain it is 4% of all outpatient systemic antibiotic prescriptions (OECD 2016). According to WIdO estimates, in the last two years alone - while the risk assessment process was being carried out - a total of 86,000 patients were burdened with these additional complications, mostly unnecessarily. The suffering of the affected patients cannot be reversed. However, the question arises as to whether more could be achieved by making manufacturers liable and regulating care and rehabilitation in the event of damage in an uncomplicated manner for patients. Although the manufacturer is strictly liable under the Medicines Act, it is currently almost impossible for individual patients to claim compensation for damage caused by fluoroquinolone-related injuries from the pharmaceutical company. In some cases, there are months between taking the drug and the occurrence of a side effect, making it difficult to prove a medical connection in individual cases. At the same time, however, it has been clearly proven that fluoroquinolones cause precisely defined damage. There must be a legal reversal towards strengthening patients' rights, also in order to ensure that pharmaceutical manufacturers carry out a forward-looking risk assessment. If there are indications of toxic side effects, they would then react more quickly with a market recall or an adjustment to the specialist information. Otherwise they would have to fear lawsuits with high financial compensation claims. In this way, initial suspicions about the risks of medicines could reach the practice much more quickly and increase patient safety.
It now remains to be seen how the still high proportion of controversial fluoroquinolones will develop in prescription practice following the BfArM's warning. In view of the numerous information, such as the more than 40 Red Hand letters on various medicines in 2018, there is a risk that individual information will be ignored in the individual prescription. This could result in fluoroquinolones continuing to be used for indications that are now prohibited given the current state of knowledge. In times of digitalization, prescribers should be given even better support. One approach to a solution is the binding documentation of a diagnosis that triggers the prescription on the prescription sheet. Specifically, the practice software can then help the doctor to only use medicines for indications with a positive benefit-risk ratio. If Red Hand letters are also directly assigned to individual medications, digital systems could be used precisely to provide patients with even better medication. <<