Fluoroquinolone antibiotic

from Wikipedia, the free encyclopedia
Basic structure of the fluoroquinolone antibiotics:
The blue marked residue R is almost always a piperazinyl residue.
The fluorine atom is drawn in red .

Fluoroquinolone antibiotics (also: fluoroquinolones for short ) are a subgroup of the quinolone antibiotics to which they are structurally related. Like these, they act as so-called " gyrase inhibitors " by inhibiting bacterial topoisomerase II (gyrase), an enzyme that plays a role in DNA synthesis. Compared to other gyrase inhibitors, they are characterized by a broader spectrum of activity. Since newer fluoroquinolones are not only active against topoisomerase of type II, but also against other types such as topoisomerase IV , the name gyrase inhibitor has meanwhile become internationally unusual.

Fluoroquinolones are used in both human and veterinary medicine . In 2015, more than four million people with statutory health insurance were prescribed almost 5.9 million medication packs of fluoroquinolones. Since they can cause severe, sometimes irreversible damage to the nervous system and musculoskeletal system , their systemic use in Germany has been restricted since April 8, 2019.

From a chemical point of view, the fluoroquinolones in the backbone are fluorinated at C-6 and also have a piperazine substituent .

Mechanism of action

The bacteria own enzyme gyrase causes the DNA to spiral ( supercoiling ). The fluoroquinolones inhibit the enzyme. The mechanical energy stored in the chromosome of the bacteria decreases and the chromosome length increases. As a result, the bacterial DNA can no longer be replicated correctly . First, the bacterial growth stops (bacteriostatic effect), then the cells die (bactericidal effect). However, an inhibition of DNA replication cannot adequately explain the bactericidal effect of the fluoroquinolones, which is why further mechanisms of action are assumed. Newer representatives of the fluoroquinolones are also effective against bacterial topoisomerase enzymes, which also control the topology of the DNA molecules.

Fluoroquinolones have a very broad spectrum of activity against most gram-negative and gram-positive bacteria , some anaerobes and various streptococci a resistance have. Almost all bacterial infections are considered medical indications , with urinary tract and respiratory tract infections in the foreground. For urinary tract infections, they are recommended in regions with resistance to other antibiotics, especially co- trimoxazole .

Overview of the medicinal substances

The Paul Ehrlich Society for Chemotherapy has proposed a division of fluoroquinolone antibiotics into the following four groups according to pharmacokinetics and spectrum of activity:

  • Group I: Oral fluoroquinolones with indication of urinary tract infection
  • Group II: Systemically applicable fluoroquinolones with broad indication
  • Group III: Fluoroquinolones with improved effectiveness against gram-positive and atypical pathogens
  • Group IV: Fluoroquinolones with improved effectiveness against gram-positive and atypical pathogens as well as against anaerobes .

The substances of higher groups are generally also newer products.

Fluoroquinolones used in human medicine

As of 2019, only the following five are approved in Germany: Norfloxacin, Ciprofloxacin, Ofloxacin, Levofloxacin and Moxifloxacin.

The table below provides an overview of the market withdrawals for human medical fluoroquinolones.

year Non-proprietary name Reason for withdrawal
1992 Temafloxacin Liver and kidney toxicity, HUS, anaphylaxis, anemia
1993 Lomefloxacin Phototoxicity, liver toxicity, CNS ADRs
1998 Rosoxacin Marketing decision
1999 Trovafloxacin Liver failure, liver toxicity
1999 Grepafloxacin Cardiotoxicity
2000 Pefloxacin Marketing decision, but also: phototoxicity, tendinitis
2001 Clinafloxacin Phototoxicity, influence on sugar metabolism
2001 Sparfloxacin Phototoxicity, CNS ADRs
2004 Fleroxacin Phototoxicity, CNS ADRs
2004 Gatifloxacin Influence on the sugar metabolism
2016 Enoxacin Interactions

Fluoroquinolones used in veterinary medicine

Side effects

During fluoroquinolone treatment, 4-10% of patients experience adverse effects. Some of these are class-specific. According to recent manufacturer information, the incidence of side effects is 25–30%. This increase is explained by the intensification of clinical studies to assess the potential for side effects of the newer fluoroquinolones. The most common side effects are gastrointestinal disorders such as nausea and diarrhea, and central nervous disorders. Psychiatric disturbances with suicidality , blood sugar decompensation in diabetics and tendinitis and ruptures, such as an Achilles tendon rupture, are rarer .

The decrease in tendon strength can occur with all gyrase inhibitors, even after short-term use. The frequency with levofloxacin may be increased. The elderly and those taking corticosteroids are at greater risk. This is explained by an increased expression of matrix metalloproteinases , which reduce the strength of the tendons. Fluoroquinolones can remove the cofactor iron through iron chelation of the α-ketoglutarate -dependent dioxygenase . This probably interferes with collagen maturation . The authors suggest this as a cause of the fluoroquinolone-induced kidney damage and tendinopathy (tendon damage). There is also evidence of direct cytotoxic and antiproliferative (growth-inhibiting) effects as well as damage to the mitochondrial DNA . Histologically, necrosis has been documented in connection with fluoroquinolone-related tendon and kidney damage . The frequency of tendon damage is given in a document from the drug commission of the German medical profession as 1: 227 for ciprofloxacin and 1: 104 for ofloxacin / levofloxacin.

Since all fluoroquinolones have a phototoxic potential, exposure to sunlight or UV light should be avoided. A suspected increased risk of retinal detachment could not be verified in a large Danish study. However, two subsequently published large studies from Taiwan and France could statistically prove an increased risk of rhegmatogenic and exudative retinal detachment when taking fluoroquinolones.

The ingestion of fluoroquinolones can lead to the development of peripheral neuropathy , which can occur a few days after the start of therapy, both orally and intravenously, and then persist for a year or more. The problem here is that this side effect is often not taken seriously enough by doctors and the switch to another antibiotic is therefore delayed.

Retrospective clinical studies associate fluoroquinolone intake with a more than 2-fold increase in risk of aortic aneurysm and aortic dissection . The results of a meta-analysis show that the risk of fluoroquinolone-related aortic damage is increased by at least a factor of 2, with 618 fluoroquinolone prescriptions accounting for aortic damage in the risk group of over 65s. Experimental data suggest that fluoroquinolone-induced aortic dissections are based on necroptosis (in vivo) or apoptosis of aortic smooth muscle cells (in vitro) and destruction of the extracellular matrix of the aortic wall and can lead to fatal aortic ruptures if atherosclerosis is also present . The Federal Institute for Drugs and Medical Devices has on 26 October 2018 due to the increased risk for aortic aneurysms and dissections in a Red Hand Letter ordered the inclusion of a mention in the product information texts of all systemic and inhaled applied fluoroquinolones and new on 8 April 2019 Application restrictions published.

Fluoroquinolone-Associated Disability

In 2015, the FDA first summarized the side effects of fluoroquinolones into a defined disease under the name Fluoroquinolone-Associated Disability (FQAD) . Quinolones are now approved for the treatment of severe infections in children and adolescents and in patients with cystic fibrosis. They should be used with caution, since animal experiments have indicated toxic effects on articular cartilage and the epiphyseal plate .

According to the FDA, the serious side effects of fluoroquinolones outweigh the benefits of treating patients with sinusitis , otitis media , bronchitis, and uncomplicated urinary tract infections for which alternative antibiotics are available. In patients with these diseases, fluoroquinolones should therefore only be used as the last resort after all alternative antibiotics have failed. The safety review showed that systemically applied fluoroquinolones (in the form of tablets and capsules or intravenously ) can lead to disability and potentially permanent severe chronic side effects, several of which can occur at the same time. These side effects include: a. Tendons , muscles , joints , nerves and the central nervous system . Examples are the occurrence of tendinitis , tendopathy , tendon rupture , effects on the central nervous system and peripheral neuropathy . They can lead to permanent impairment in some of the patients. As a result, on July 26, 2016, the American FDA ordered a corresponding update of the package inserts . Of all antibiotics , fluoroquinolones cause the most permanent disability.

In November 2016, fluoroquinolone victims, reported on by Bayerischer Rundfunk and Der Spiegel , created and submitted an online petition to the German Bundestag for co-signature. In the petition, they demand, among other things, a warning symbol on the drug packs and the use of fluoroquinolones only in life-threatening situations.

In February 2017, the Federal Institute for Drugs and Medical Devices ( BfArM ) initiated a European risk assessment process for the serious side effects of fluoroquinolones and quinolones, which can lead to severe impairment of quality of life and possibly permanent impairment. In October 2018, the recommended Pharmacovigilance Committee for Risk Assessment (Pharmacovigilance Risk Assessment Committee, PRAC) of the European Medicines Agency for the revaluation of the risk-benefit ratio Limitations. In the case of certain mild to moderate infections, these agents should no longer be used if possible, and in certain patient groups (e.g. elderly patients, patients with renal impairment, patients after organ transplantation or patients under systemic corticosteroid therapy) only with caution.

Class-specific side effects

Representatives of groups III and IV can lengthen the QT interval in the ECG and thus trigger the QT syndrome with ventricular arrhythmias. For moxifloxacin and norfloxacin, hepatotoxic effects resulting in death have been described extremely rarely (only 8 cases in more than 50 million patients). Itching and headache have also been described as side effects . In animal experiments, cartilage damage occurred in growing animals (dogs) .

The Federal Institute for Drugs and Medical Devices has restricted the indication for the antibiotic levofloxacin on the recommendation of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) . The CHMP had classified levofloxacin as a reserve antibiotic in May 2012 . The approved indications are acute bacterial sinusitis , acute exacerbation of chronic bronchitis , community-acquired pneumonia and complicated skin and soft tissue infections. In future, however, their use must be strictly limited to situations in which "other antibiotics that are usually recommended for the initial treatment of the relevant infections are not considered to be indicated".

Due to their effect not only on bacterial but also on human DNA gyrase, some gyrase inhibitors - such as fleroxacin, gatifloxacin, grepafloxacin , sparfloxacin and trovafloxacin - had to be withdrawn from the market, mainly because of severe toxic complications and intolerance reactions, some of which resulted in death.

history

As the first fluorinated quinolone, norfloxacin was patented in 1979 by the pharmaceutical manufacturer Kyorin Seiyaku Kabushiki Kaisha and approved in Switzerland in 1983. Norfloxacin had good bioavailability, a longer half-life and, above all, affects a wider range of pathogens than nalidixic acid . In the year 1981 by the company Bayer then ciprofloxacin developed and patented 1983rd Levofloxacin was developed by Daiichi Seiyaku and came onto the market in Japan in 1993 and in Germany in 1998.

In 1986, US researchers observed that, in contrast to non-fluorinated quinolones, C-6-fluorinated quinolones have an antibacterial inhibitory effect that is up to 126 times stronger and that the fluorine atom at position 6 binds to the gyrase complex up to 17 times and is up to 70 times stronger - times stronger cell penetration, whereas other substituents introduced at position 6 favor a very weak inhibitory effect. In 1996 the SOS Chromotest showed that C-6-fluorinated quinolones are genotoxic, whereas the non-fluorinated quinolone nalidixic acid is not genotoxic. Between 1988 and 2003, over 350 million patients worldwide were treated with ciprofloxacin, over 250 million with levofloxacin and over 13 million with moxifloxacin.

Web links

Individual evidence

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