Levofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes.
Levofloxacin is a chiral fluorinated carboxyquinolone. Investigation of ofloxacin, an older drug that is the racemic mixture, found that the l form [the (–)-(S) enantiomer] is more active. This specific component is levofloxacin.
Levofloxacin interacts with a number of other drugs, as well as a number of herbal and natural supplements. Such interactions increase the risk of cardiotoxicity and arrhythmias, anticoagulation, the formation of non-absorbable complexes, as well as increasing the risk of toxicity.
Levofloxacin is associated with a number of serious and life-threatening adverse reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy. Such reactions may manifest long after therapy had been completed and in severe cases may result in life-long disabilities. Hepatoxicity has also been reported with the use of levofloxacin.
As of 2011 the FDA has added two Black Box warnings for this drug in reference to spontaneous tendon ruptures and the fact that levofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Such an adverse reaction is a potentially life-threatening event and may require ventilatory support.
1. Clinical pharmacology
Levofloxacin is the L-isomer of the racemate ofloxacin, a quinolone antimicrobial agent. In chemical terms, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate. The empirical formula is C18H20FN3O4 • ½ H2O, and the molecular weight is 370.38. Levofloxacin is a light-yellowish-white to yellow-white crystal or crystalline powder.
Some of the endogenous compounds that are affected by the levofloxacin include GABA receptors (inhibitor), OCTN2 (inhibitor), blood glucose (alteration) potassium channels (in myocardial cells - inhibitor), pancreatic β-cell potassium channels (inhibitor) and glutathione (depletor).
Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Levofloxacin is rapidly and, in essence, completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for oral preparation when equal doses (mg/mg) are administered. Levofloxacin is excreted largely as unchanged drug in the urine.
The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. Glucuronidation and hydroxylation have been cited as one of the major metabolic pathways for levofloxacin hydrochloride. However the drug card for levofloxacin (DB01137) states that the biotransformation information is not available. Half-life is 6–8 hours.
3. Mode of action
Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase iv, which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division.
The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases, and are toxic to cultured mammalian cells and in vivo tumor models. Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone-induced DNA damage was first reported in 1986.
Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei. As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.
There continues to be debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non-abating adverse reactions experienced by some patients following fluoroquinolone therapy.
4. Drug interactions
The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Coadministration may dangerously increase warfarin (Coumadin) activity; INR should be monitored closely. They may also interact with the GABA A receptor and cause neurological symptoms; this effect is augmented by certain non-steroidal anti-inflammatory drugs. Quercetin, a flavonol, a kind of flavonoid, occasionally used as a dietary supplement, may interact with fluoroquinolones, as quercetin competitively binds to bacterial DNA gyrase. Some foods such as garlic and apples contain high levels of quercetin; whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.
Specific drug interaction studies have not been conducted with levofloxacin. However, the systemic administration of some quinolones has been shown to interfere with the metabolism of caffeine, elevate plasma concentrations of theophylline, and enhance the effects of the warfarin and its derivatives. In patients receiving systemic cyclosporine concomitantly, transient elevations in serum creatinine has been noted.
4.1 Significant drug interactions
Levofloxacin has been reported to interact with a significant number of other drugs, as well as a number of herbal and natural supplements. Such interactions increased the risk of cardiotoxicity and arrhythmias, anticoagulant effects, the formation of non-absorbable complexes, as well as increasing the risk of toxicity.
Some drug interactions are associated with molecular structural modifications of the quinolone ring, specifically interactions involving NSAIDS and theophylline. The fluoroquinolones have also been shown to interfere with the metabolism of caffeine and the absorption of levothyroxine. The interference with the metabolism of caffeine may lead to the reduced clearance of caffeine and a prolongation of its serum half-life, resulting in a caffeine overdose. Ciprofloxacin has been shown to interact with thyroid medications (levothyroxine) resulting in unexplained hypothyroidism. As such it is possible that levofloxacin may interact with thyroid medications as well.
The use of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) while undergoing fluoroquinolone therapy is contraindicated due to the risk of severe CNS adverse reactions, including but not limited to seizure disorders. Fluoroquinolones with an unsubstituted piperazinyl moiety at position 7 have the potential to interact with NSAIDs and/or their metabolites, resulting in antagonism of GABA neurotransmission. Whether or not such reactions occur after completion of therapy is unclear. Patients have reported reactions to NSAIDS long after completion of fluoroquinolone therapy, but there does not appear to be any research that would either confirm or deny this association other than these anecdotal reports.
Some quinolones exert an inhibitory effect on the cytochrome P-450 system, thereby reducing theophylline clearance and increasing theophylline blood levels. Coadministration of certain fluoroquinolones and other drugs primarily metabolized by CYP1A2 (e.g., theophylline, methylxanthines, tizanidine) results in increased plasma concentrations and could lead to clinically significant side-effects of the coadministered drug. In addition, other fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, also inhibit the metabolic clearance of theophylline.
Such drug interactions appear to be related to the structural changes of the quinolone ring and the inhibitory effect on the cytochrome P-450 system. As such, these drug interactions involving the fluoroquinolones appear to be drug-specific rather than a class effect.
Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients also taking the fluoroquinolones. This effect seems to be restricted to people aged 60 or over and within this group concomitant use of corticosteroids increases this risk substantially.
Fluoroquinolones' are associated with false-positive results for opiates on urine opiate screening drug test. Of the Fluoroquinolone's ofloxacin and levofloxacin are most likely to cause false positive results. Most levels detected are below (2000 ng/mL). A false-positive result may be ruled out by using a more specific test, usually gas chromatography/mass spectrometry (GC-MS). Therefore, any patient who screens positive for opiates but denies taking them and has recently taken a fluoroquinolone should be offered more specific testing.
Concommitant use with cardiac antidysrhythmics that prolong the QT interval should not be used in combination with levofloxacin due to the risk of torsades and R on T syndrome. Common medications still in use today include amiodarone, tykosin, and propafenone. Older medication such as ethmozine, quinidine, and mexilitine should be avoided as well.
5. Adverse reactions
Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. In most adverse reactions are mild to moderate; however, on occasion, serious adverse effects occur. There have been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings, additional warnings and safety information added to the package inserts, which includes Black Box Warnings together with the issuance of "Dear Doctor Letters" concerning the recent addition of the Black Box Warnings.
In 2004, the FDA requested new warning labels to be added to all of the fluoroquinolones, including levofloxacin, regarding peripheral neuropathy (irreversible nerve damage), tendon damage, heart problems (prolonged QT Interval / torsades de pointes), pseudomembranous colitis, rhabdomyolysis (muscle wasting), Stevens-Johnson syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.
Subsequent to this, on June 25, 2007, the FDA required the manufacturer to add an additional warning to the package inserts that stated that "Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including levofloxacin."
The serious adverse effects that may occur as a result of levofloxacin therapy include irreversible peripheral neuropathy, spontaneous tendon rupture and tendonitis, QTc prolongation/torsades de pointes, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, erythema multiforme, severe central nervous system disorders (CNS), including seizures and Clostridium difficile associated disease (CDAD: pseudomembranous colitis) photosensitivity/phototoxicity reactions, fatal hypoglycemia, kidney damage, rhabdomyolysis (muscle wasting), as well as anaphylactoid reactions and myasthenia crisis.
Additional serious adverse reactions include acute pancreatitis, temporary as well as permanent loss of vision, irreversible double vision, impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia. Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure), has been reported to occur as a serious adverse reaction to levofloxacin. Another serious adverse effect is autoimmune hemolytic anemia.
Older patients may have an increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use, and such patients may also be more susceptible to prolongation of the QT interval. Patients with known prolongation, those with hypokalemia, or being treated with other drugs that prolong the QT interval should avoid the use of Levaquin. Hematologic reactions (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses.
Children and the elderly are at a much greater risk of experiencing such adverse reactions. Such reactions may manifest during, as well as long after fluoroquinolone therapy had been discontinued.
Serious visual complications have also been reported to occur with ophthalmic fluoroquinolone therapy, which may also occur with levofloxacin eye drops, especially corneal perforation, but also evisceration and enucleation. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in stromal collagen, leading to a reduction in tectonic strength. As noted previously permanent double vision (diplopia) has also been reported.
Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones as well as legal action by the consumer advocate group Public Citizen. Partly as a result of the efforts of The State of Illinois and Public Citizen the FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.