|Molecular formula||C 18 H 20 FN 3 O 4|
Slightly yellowish powder
|External identifiers / databases|
|Mechanism of action||
Inhibition of the bacteria own enzyme DNA gyrase
|Molar mass||361.37 g · mol -1|
218-220 ° C
|As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .|
Levofloxacin came onto the market in Japan in 1993 and in Germany in 1998, and was approved by the FDA in the USA in 1996 . In 2008 and 2013, the FDA reported on newly observed severe side effects with systemically used fluoroquinolones and ordered appropriate measures. In 2015, according to medical reports, it reassessed the risk-benefit ratio of Cipro-, Levo-, Moxi- and Ofloxacin and significantly restricted its use in 2016. Warnings and restrictions on use of fluoroquinolones have also been issued several times in EU countries. The European Medicines Agency last reassessed the serious, potentially permanent and quality of life-impairing side effects in 2018 and recommended restrictions on use. The Federal Institute for Drugs and Medical Devices then issued a comprehensive notification on April 8, 2019, further restricting the indications for fluoroquinolones and ordering a further update of the instructions for use and specialist information in order to point out possibly irreversible side effects. Doctors were informed via a Rote-Hand-Brief on April 8, 2019 that they would no longer use fluoroquinolones for simple infections.
The multi-step synthesis of levofloxacin is described in the literature.
Mechanism of action and spectrum of action
Levofloxacin has a bactericidal effect . Like other fluoroquinolones , it inhibits the enzyme gyrase , which is responsible for DNA supercoiling in bacteria during their reproduction cycle. However, an inhibition of DNA replication cannot adequately explain the bactericidal effect of the fluoroquinolones, which is why other mechanisms of action are assumed.
The areas of application are largely the same as those of ofloxacin. Since levofloxacin can be compared to ofloxacin has a higher antibacterial activity, and also higher doses, it is also displayed for the pneumococcal pneumonia .
Fluoroquinolones are recommended not to be used for infections that get better untreated or are not severe . These include infections of the throat, abacterial (chronic) prostatitis , bronchitis , sinusitis , prophylaxis of travelers' diarrhea and recurring infections of the lower urinary tract ( urinary tract infections that do not go beyond the bladder). They should only be used to treat mild or moderate bacterial infections if other antibiotics commonly recommended for these infections cannot be used. It is important that fluoroquinolones should generally be avoided in patients who have previously had serious side effects with a fluoroquinolone or quinolone antibiotic. They should be used with particular caution in the elderly, patients with kidney disease, and patients who have had an organ transplant , as these patients are at higher risk of tendon injury .
As with all fluoroquinolones, unwanted effects can occur with levofloxacin . Single, multiple, delayed, and persistent or progressive side effects are possible after taking levofloxacin. Serious side effects with levofloxacin resulted in physical disability in 27% of cases. Compared to other common antibiotics, fluoroquinolones are responsible for most of the permanent disabilities. Deaths and serious side effects are already documented from a single dose. Fluoroquinolone side effects last an average of 14 months to 9 years. A total of 210,705 suspected side effects and 2,991 deaths were reported to the FDA for fluoroquinolones through 2016. For levofloxacin, a total of 98,710 suspected side effects and 1,594 deaths were reported in 24,777 patients. Due to the low reporting rate of 1–10%, the unreported number of fluoroquinolone-associated side effects is estimated at 2–21 million and the unreported number of deaths is estimated at 29,000 to over 299,000.
Musculoskeletal, connective tissue and bone diseases
The risk of tendon damage with levofloxacin is 1: 104. In a group of 65-year-olds and older patients, 2.1% suffered a tendon rupture , 1.1% an aortic aneurysm, and 0.2% a retinal detachment after taking fluoroquinolones . In Germany, a few years after marketing authorization, a significant increase in reports of levofloxacin-induced Achilles tendon ruptures was registered. The drug commission of the German medical profession suggests an increased risk of tendopathy with levofloxacin compared to other fluoroquinolones. This is more likely to affect the elderly and those who take corticoids . However, independent experts found that in many cases these risk factors were not critical. According to FDA reviewers, the risk of tendopathy with fluoroquinolones is almost the same in younger and older patients, with persistent neuromusculoskeletal damage being observed most frequently in the 30 to 59 year old age group (74%). Physical exercise can contribute to an increased risk of tendopathy with fluoroquinolones. This is attributed to an increased need for ATP during muscular exertion, which can increase fluoroquinolone-induced impairments of mitochondrial function and energy supply .
In vitro studies of the effects of fluoroquinolones on human tendon cells show that an inhibition of collagen synthesis and the proliferation of fibroblasts as well as significant mitochondrial damage and cell death occur at concentrations that are reached after only a short application in the blood plasma of quinolone-treated patients. According to pharmacokinetic calculations, levofloxacin can accumulate in the tendon tissue after just two single doses, thereby promoting an increased risk of rupture during exercise. The Achilles tendon is particularly affected by this, as it has to withstand forces that are 12.5 times body weight when running.
According to clinical observations, tendopathies are possible just a few hours after taking the first dose of levofloxacin. Since there can be a month-long latency period between the start of fluoroquinolone therapy and the appearance of the first symptoms, many cases of tendinitis are not recorded and only a few retrospective studies are available on the incidence of fluoroquinolone-induced tendopathies, a high number of unreported cases is assumed.
In connection with levofloxacin-induced Achilles tendon ruptures, there are indications of serious complications, including fall-related hip fractures, deep vein thrombosis, pulmonary embolism, or fatal organ failure. Levofloxacin and structurally analogous fluoroquinolones can also damage other areas of the tendons and muscles. These include the rotator cuff, the biceps and triceps tendons, the epicondyle, hand and finger tendons, hip flexors and gluteal tendons, thigh adductors, the patellar tendon and the plantar fascia. Multiple tendon damage is also possible. This is explained by an increased expression of matrix metalloproteases , which reduce the strength of the tendons . However, since cytotoxic and antiproliferative (growth-inhibiting) effects as well as damage to the mitochondrial DNA have also been observed, a complex pathomechanism can be assumed. Histopathologically, necroses , vascular - ischemic lesions and interstitial edema can be seen .
Fluoroquinolone-induced tendon damage is considered therapy-resistant and often requires surgery, medical rehabilitation , orthopedic aids or the use of a wheelchair. However, these measures cannot prevent long recovery times and consequential functional damage.
Musculoskeletal complications also include myopathies , arthropathies, and impaired fracture healing . Studies on the musculoskeletal toxicity of the fluoroquinolones in juvenile rats suggest that levofloxacin after administration of a single maximum dose fibroblasts and endothelial damage, the permeability of the capillaries is increased and in addition to multiple joint damage and lesions of the tendons, tendon sheaths , synovium and fascia and muscle atrophy triggers on a possible loss of muscle fibers . Serious myalgias as well as myopathies and myasthenias are already possible after a single therapeutic dose and, like arthralgia , can occur frequently. In connection with levofloxacin, cases of persistent myalgia, muscle weakness, muscle atrophy, and muscle spasms and fasciculations have been documented in previously healthy patients; The tongue, throat, larynx and respiratory muscles can also be affected. In patients without predisposing risk factors, potentially life-threatening complications of rhabdomyolysis have been observed even after short-term levofloxacin intake . Crisis deterioration of the neuromuscular disease myasthenia gravis is also possible after a short period of use. The muscle-damaging mechanism of fluoroquinolones is based on an inhibition of neuromuscular transmission and is linked to an intramuscular increase in lactate, disorders of the mitochondrial energy metabolism and increased intracellular calcium concentrations . Inhibition of RYR1 or sarcoplasmic Ca 2+ -ATPase ( SERCA ) by the covalently bound fluorine atom is assumed to be a possible cause of the disturbed calcium homeostasis .
Experimental studies on the arthro- and chondrotoxicity of the fluoroquinolones show osteochondrotic changes and irreversibly progressive joint damage in juvenile rats as well as necrosis in healthy adult human cartilage at subtherapeutic concentrations. Fluoroquinolone-related cartilage and joint damage can be accompanied by insertion tendinopathies or myalgias and manifest themselves in the form of joint swelling, joint effusions , bursitis , synovitis , Baker's cysts , polyarthralgia and acute arthritis or chronic lumbar back pain and frequent crepitation during joint movements. Furthermore, the it can cause arthritic changes in the hip or knee -, shoulder - and ankle come. With long-term use there is a risk of destructive polyarthropathy with osteonecrotic changes, which requires the use of knee and hip prostheses .
Persistent and progressive damage to the skeletal musculature was observed after only a short period of use of levofloxacin and can lead to disabling work incapacity, bed rest and need for care.
Liver and gallbladder diseases
The most common side effects are increased liver enzyme levels as well as nausea and diarrhea.
Acute liver damage occurs at a frequency of 1: 154.
A study by the Canadian Child and Family Research Institute found that oral administration of fluoroquinolones was associated with a statistically 4.5-fold increased risk of retinal detachment during treatment . The risk disappears immediately after stopping the medication. Similar disorders in the collagen and connective tissue of the vitreous body are suspected to be the pathomechanism, as are the basis for the observed tendon ruptures. Fluoroquinolones can also cause anaphylactic shock , which is attributed to fluoroquinolone-induced mast cell activation.
The risk of aortic aneurysms and dissections after systemic and inhalation use is increased, especially in older patients, which is why a corresponding warning has been included in the product information.
Indication restrictions due to severe side effects
The Federal Institute for Drugs and Medical Devices has restricted on the recommendation of the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency (EMA), the indication for the antibiotic levofloxacin. 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".
Statistics of suspicious activity reports
|Number of reported suspected cases||Adverse effect||Frequency according to the package insert|
|2228||Tendinitis / pain||Very rare|
|1571||Tendon tear||Not known|
|632||Pain in one limb||Not known|
Levofloxacin must not be used in children and adolescents who are growing, during pregnancy and breastfeeding, in patients in patients with epilepsy, and in patients with a history of tendon problems after previous use of fluoroquinolones.
- Tablets, infusion solution: Tavanic (EU, CH), Levaquin (USA, CND), Cravit (J), various generics
- Eye drops: Oftaquix (D, A)
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