Levofloxacin

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Levofloxacin
Systematic (IUPAC) name
(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid
Clinical data
Trade namesEVO (Beximco, Bangladesh),Levaquin, Quixin
AHFS/Drugs.commonograph
MedlinePlusa697040
Licence dataUS FDA:link
Pregnancy cat.C (US)
Legal status Prescription only
RoutesOral, IV, ophthalmic
Pharmacokinetic data
Bioavailability99%
Protein binding24 to 38%
MetabolismRenal
Half-life6 to 8 hours
ExcretionUrinary
Identifiers
CAS number100986-85-4 YesY
ATC codeJ01MA12 S01AE05
PubChemCID 149096
DrugBankDB01137
ChemSpider131410 YesY
UNIIRIX4E89Y14 N
KEGGD08120 YesY
ChEMBLCHEMBL33 YesY
NIAID ChemDB002307
Synonyms(S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl) -7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij] quinoline-6-carboxylic acid
Chemical data
FormulaC18H20FN3O4 
Mol. mass361.368 g/mol
 N (what is this?)  (verify)
 
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Levofloxacin
Systematic (IUPAC) name
(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid
Clinical data
Trade namesEVO (Beximco, Bangladesh),Levaquin, Quixin
AHFS/Drugs.commonograph
MedlinePlusa697040
Licence dataUS FDA:link
Pregnancy cat.C (US)
Legal status Prescription only
RoutesOral, IV, ophthalmic
Pharmacokinetic data
Bioavailability99%
Protein binding24 to 38%
MetabolismRenal
Half-life6 to 8 hours
ExcretionUrinary
Identifiers
CAS number100986-85-4 YesY
ATC codeJ01MA12 S01AE05
PubChemCID 149096
DrugBankDB01137
ChemSpider131410 YesY
UNIIRIX4E89Y14 N
KEGGD08120 YesY
ChEMBLCHEMBL33 YesY
NIAID ChemDB002307
Synonyms(S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl) -7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij] quinoline-6-carboxylic acid
Chemical data
FormulaC18H20FN3O4 
Mol. mass361.368 g/mol
 N (what is this?)  (verify)

Levofloxacin (Levaquin (U.S.), Tavanic (E.U.), and others) is a broad spectrum antibiotic of the fluoroquinolone drug class.[1][2] Its spectrum of activity includes most strains of bacterial pathogens responsible for respiratory, urinary tract, gastrointestinal, and abdominal infections, including Gram-(-) (Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), Gram-(+) (methicillin-sensitive but not methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes), and atypical bacterial pathogens (Chlamydophila pneumoniae and Mycoplasma pneumoniae). Levofloxacin and other fluoroquinolones are valued for this broad spectrum of activity, excellent tissue penetration, and for their availability in both oral and intravenous formulations.[3] (Many antibacterials used in serious infections must be dosed intravenously.) Levaquin is used alone or in combination with other antibacterial drugs to treat certain bacterial infections including pneumonia,[4] urinary tract infections,[5][6] and abdominal infections.[7]

Levofloxacin is a chiral fluorinated carboxyquinolone. Investigation of ofloxacin, an older drug that is the racemic mixture, found that the (–)-(S) enantiomer (also known as the S isomer)[8] is more active. This specific component is levofloxacin.[9][10] Levofloxacin and other fluoroquinolones are generally well tolerated, but in rare instances have produced serious and life-threatening adverse reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy. Tendon damage may manifest months after therapy had been completed and in severe cases may result in life-long disabilities. Other controversies associated with this drug include increasing resistance due to their overuse. This overuse includes situations in which antibiotic therapy is unnecessary, and others in which the use of a less broad spectrum agent would produce equivalent results.

As of 2011, the U.S. Food and Drug Administration (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.[11]

Contents

Medical uses

Levofloxacin is used to treat infections including: respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, endocarditis, meningitis, pelvic inflammatory disease, traveler's diarrhea, tuberculosis and plague.[12]

In the adult population Oral and I.V. levofloxacin is used for the treatment of bacterial infections such as:

Within the pediatric population Oral and I.V. levofloxacin is limited to:

Note: Levofloxacin has shown moderate activity against anaerobes, and is about twice as potent as ofloxacin against mycobacterium tuberculosis and other mycobacteria, including mycobacterium avium complex.[25]

Oral and I.V. Levaquin are not licensed by the FDA for use in children other than the exception (inhalational anthrax),[26] due to the risk of injury to the musculoskeletal system.[27] Levofloxacin is not to be considered a first line agent for inhalational anthrax in the pediatric population due to severe adverse reactions involving the musculoskeletal system and other serious adverse reactions.[27][28][29]

The fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Note: levofloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.

Availability

Levofloxacin is available in tablet form, injection, oral solution, as well as used in prescription eye and ear drops.[9]

Contraindications

Levofloxacin 750mg IV

There is one contraindication now found within the 2008 package insert for Levaquin, namely that Levaquin is to be avoided in patients with a known hypersensitivity to levofloxacin or other quinolone drugs.[9]

Caution should be exercised in prescribing to patients with liver disease.[30]

Levofloxacin is also considered to be contraindicated in patients with epilepsy or other seizure disorders.[citation needed]

Pregnancy

According to the FDA approved Prescribing Information, levofloxacin is Pregnancy Category C. This designation indicates that animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans but the potential benefit to the mother may in some cases outweigh the risk to the fetus. Other flouroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child.[31][32]

Pediatric use

Oral and I.V. Levofloxacin is not licensed for use in the pediatric population, except as noted above, due to the risk of injury to the pediatric patient. In one study,[33][34] 1534 juvenile patients (age 6 months to 16 years) treated with levofloxacin as part of three efficacy trials were followed up to assess all musculoskeletal events occurring up to 12 months post-treatment. At 12 months follow-up the cumulative incidence of musculoskeletal adverse events was 3.4%, compared to 1.8% among 893 patients treated with other antibiotics. In the levafloxacin-treated group, approximately two-thirds of these musculoskeletal AEs occurred in the first 60 days, 86% were mild, 17% were moderate, and all resolved without long-term sequelae.

In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or the ceftriaxone in 712 children with community-acquired pneumonia, serious adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these were considered by the treating physician to be unrelated or doubtfully related to the study drug. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the FDA Adverse Effects Reporting System at the time of the 20 September 2011 FDA Pediatric Drugs Advisory Committee include musculoskeletal events (39, including 5 cases of tendon rupture) and CNS events (19, including 5 cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period.[35]

Special precautions

Levofloxacin should be administered only as described within the Dosage Guidelines table found within the most current package insert. The status of the patient's renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. Levofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver and the intestine. Modification of the dosage is recommended using the table found within the package insert for those with impaired liver or kidney function (particularly for patients with severe renal dysfunction). Within the package insert, it is stated "...since the drug is known to be substantially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function."[9] The duration of treatment depends upon the severity of infection, in the range of 3 days to 60 days.[9]

Adverse effects

Most adverse reactions are mild to moderate; however, on occasion, serious adverse effects occur.[36][37][38] additional warnings and safety information added to the package inserts, which includes Black Box Warnings[39] 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),[40][41] tendon damage,[42][43] heart problems (prolonged QT Interval / Torsades de pointes),[14][40] Pseudomembranous colitis, Rhabdomyolysis (muscle wasting),[44][45][46] Stevens-Johnson Syndrome,[47] as well as concurrent usage of NSAIDs contributing to the severity of these reactions.[40]

Subsequent to this, on 25 June 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."[48][49]

The serious adverse effects that may occur as a result of levofloxacin therapy include irreversible peripheral neuropathy,[41][50] spontaneous tendon rupture and tendonitis,[51][52][53][54][55] QTc prolongation/torsades de pointes,[51] toxic epidermal necrolysis (TEN)[51] and Stevens-Johnson syndrome, erythema multiforme,[56] severe central nervous system disorders (CNS), including seizures[57] and clostridium difficile associated disease (CDAD: Pseudomembranous colitis)[58][59][60][61] photosensitivity/phototoxicity reactions,[56][62] fatal hypoglycemia, kidney damage, rhabdomyolysis (muscle wasting),[44][45][46] as well as anaphylactoid reactions[63][64] and myasthenia crisis.[65]

Additional serious adverse reactions include acute pancreatitis,[66][67] temporary as well as permanent loss of vision, irreversible double vision,[68] impaired color vision, exanthema, abdominal pain, malaise, drug fever,[69] dysaesthesia and eosinophilia. Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure),[70] has been reported to occur as a serious adverse reaction to levofloxacin. Another serious adverse effect is autoimmune hemolytic anemia.[71]

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.[9] 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.[9][52]

Children and the elderly are at a much greater risk of experiencing such adverse reactions.[72][73] Such reactions may manifest during, as well as long after fluoroquinolone therapy had been discontinued.[74]

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.[75][76] As noted previously permanent double vision (diplopia) has also been reported.[68]

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.[77] 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.[78]

Overdose

In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.[9]

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.[9]

Some of the endogenous compounds that are affected by the levofloxacin include GABA receptors (inhibitor), OCTN2 (inhibitor),[79] blood glucose (alteration) potassium channels (in myocardial cells – inhibitor),[80] pancreatic β-cell potassium channels (inhibitor)[81] and glutathione (depletor). Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers and can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies.[82]

Pharmacokinetics

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 LEVAQUIN Tablets 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.[9][83] Glucuronidation and hydroxylation have been cited as one of the major metabolic pathways for levofloxacin hydrochloride.[84] However the drug card for levofloxacin (DB01137) states that the biotransformation information is not available.[83] Specific information regarding biotransformation does not appear to be readily available within the package inserts.

Mechanism 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,[85] 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 activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases, and are toxic to cultured mammalian cells and in vivo tumor models.

Interactions

Levofloxacin interacts with other drugs, as well as 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.[83]

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.[86] 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.[87]

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.[83]

Significant drug interactions

Levofloxacin has been reported to interact with other drugs, as well as 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. Ciprofloxacin has been shown to interact with thyroid medications (levothyroxine) resulting in unexplained hypothyroidism.[88] As such it is possible that levofloxacin may interact with thyroid medications as well.

The use of NSAIDs (Non-Steroid 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.[89] 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.[90]

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.[42][91]

Fluoroquinolones are associated with false-positive results for opiates on urine opiate screening drug test. Of the fluoroquinolones, 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.[92]

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.

History

Levofloxacin is a fluoroquinolone antibiotic, marketed by Sanofi-Aventis under the tradename "Tavanic".[93] Levaquin is also marketed worldwide for oral and IV use, as well as used in ophthalmic solutions. Daiichi Sankyo had granted an exclusive license to Sanofi-Aventis to make, use and sell pharmaceutical preparations containing levofloxacin in the UK and Mexico.[94] Other manufacturers include Novell Pharmaceutical Laboratories (Levores).

Levaquin has proven to be a blockbuster drug for Johnson and Johnson / Ortho McNeil, generating billions of dollars in additional revenue. In 2007 alone, Levaquin accounted for 6.5% of Johnson and Johnson's total revenue, generating $1.6 billion, an 8% increase over the previous year.[95] Ranking 37th within the top 200 prescribed drugs in the United States for 2007, and ranked 19th in world sales in 2007, total sales for Levaquin were in excess of 1.6 billion dollars.[96] Levaquin was the most prescribed fluoroquinolone drug in the world for 2007.[97]

Levofloxacin was first patented in 1987 (Levofloxacin European patent – Daiichi Pharmaceutical Co., Ltd.) and was approved by the United States Food and Drug Administration on 20 December 1996 for use in the United States to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia, uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis.[98] Levofloxacin is described in some publications as a second generation fluoroquinolone.[99][100][101] Other publications describe it as a third-generation fluoroquinolone.[102][103]

Levofloxacin is considered to be same as Ofloxacin by the U.S. Food and Drug Administration (FDA), with the exception of the potency shown in vitro against mycobacteria. In vitro, it is, in general, twice as potent as ofloxacin, whereas d-ofloxacin is less active against mycobacteria.[104][105]

The current United States patent is held by Ortho-McNeil-Janssen.[96] Ranked 19th in world sales in 2007, sales for Levaquin exceeded $1.4 billion.[96] Levaquin was the most prescribed fluoroquinolone drug in the world for 2007.[106]

Levaquin sample boxes showed a macron over the letter "e," indicating pronunciation with a long-"e" sound, although Merriam-Webster indicates a short-"e" pronunciation. Levofloxacin would typically be pronounced with the long-e from the Latin prefix "levo-" (meaning left).

Levofloxacin is marketed worldwide under many brand names, making post-marketing surveillance difficult.[107][108]

In addition, generic versions of levofloxacin had been available since 2004 and marketed as a generic drug under a variety of different brand names. However, Daiichi Sankyo-Johnson and Johnson-Ortho McNeil filed numerous patent lawsuits to prevent such generic equivalents from being marketed, claiming that their patent did not expire until 23 June 2009.[109] see Generic equivalents

Regulatory history in the United States

Levofloxacin was first patented in 1987, and was subsequently approved for use in Japan (1 October 1993), Korea (4 April 1994), Hong Kong (3 October 1994), and China (3 May 1995). Levofloxacin received FDA approval in the United States 20 December 1996. Floxin (ofloxacin – floxacin) was patented in 1982 (European patent Daiichi) and received FDA approval 28 December 1990. The U.S. patent is owned by Daiichi Sankyo and exclusively licensed to Ortho-McNeil.[98][110]

Many of the clinical isolates that were initially tested within the NDA for levofloxacin against Floxin (ofloxacin –floxacin) disks instead of levofloxacin disks but reported as susceptible or resistant to levofloxacin. When levofloxacin disks were not available in early clinical trials, a 5-pg Floxin (ofloxacin –floxacin) disk was substituted. The FDA medical reviewers considered the two drugs to be one and the same and hence interchangeable.[98]

The FDA requested updating the carton and container labels to include a statement to let dispensers know that a Medication Guide must be dispensed with the product, in compliance with the Medication Guide Regulations as specified in 21 CFR 208.24 (d).

Issuance of a Medication Guide and revisions to include new safety information. The FDA has determined that levofloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide. However the Medication Guide does not include any Black Box Warnings.[113]

Additional Black Box warning added to all the drugs within this class, including levofloxacin, stating that the fluoroquinolone class 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.

Note: Although the FDA had requested that the revised labeling (which were to include the Black Box Warnings)[115] accompany the package inserts for any newly shipped products (effective January 2009) there are continuing reports that as of July 2009, that the products continue to contain the older labels, and not the revised labels, and that the Medication Guides (absent of the Black Box Warnings) were not made available for distribution.

See also the Black Box Warnings section of the Quinolones article for a discussion of the history of these warnings and the role of public advocacy groups in their inclusion in the product label.

Antibiotic abuse and bacterial resistance

Resistance to levofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.[116] There are three known mechanisms of resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or Topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.[117]

Years ago, the FDA had added warnings regarding the proper use of Levaquin within the package inserts to combat such prescription abuse. Advising physicians that levofloxacin: "...should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria...."[49]

Though considered to be a very important and necessary drug required to treat severe and life-threatening bacterial infections, the associated prescription abuse of levofloxacin remains unchecked, which has contributed to the problem of bacterial resistance. The overuse of antibiotics, such as happens with children suffering from otitis media, has given rise to a breed of super-bacteria that are resistant to antibiotics entirely.[118]

Fluoroquinolones, including levofloxacin, had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study that was supported in part by the Agency for Healthcare Research and Quality.[119][120] In addition, they are commonly prescribed for medical conditions that are not even bacterial to begin, with such as viral infections, or those to which no proven benefit exists.

Social and economic impact

Patent extensions

From 2001–2008, patent extension legislation was signed into law that allowed a six-month patent extension for testing their products for safety in children, an under-represented category in clinical trials. The FDA granted Johnson and Johnson–Ortho McNeil pediatric exclusivity for Levaquin. This extended their patent until the end of 2010.

Generic equivalents

In 2005, the US Court of Appeals for the Federal Circuit had affirmed the validity of US patent (No. 5,053,407) on levofloxacin, held by Daiichi Sankyo Co., Ltd. On 17 October 2006, Daiichi Sankyo also won a patent infringement lawsuit in Canada involving the generic version of Levaquin. The Canadian Federal Appeals Court upheld a lower court's ruling handed down last October, which accepted the validity of Daiichi Sankyo's patent until 23 June 2009. Daiichi Sankyo and Janssen-Ortho Inc., a Johnson & Johnson subsidiary, filed a lawsuit with a federal court in Toronto after Teva Novopharm Ltd., started selling the generic version of levofloxacin in December 2004. The Canadian Federal Court in Toronto ordered Novopharm to suspend selling the generic version of the drug. Unsatisfied with the ruling, Novopharm appealed to the higher court.[109] On 7 June 2007, the Canadian Federal Appeal Court dismissed this appeal. Novopharm was prevented from making, using, offering to sell, or selling a generic version of levofloxacin tablets in the Canadian market until the expiration of patent on 23 June 2009. Novopharm's generic version of Levaquin, had been sold in Canada since 2004.

Current litigation

An official complaint has been filed by The US Justice Department with a Federal Court in Boston (January 2010) accusing Johnson and Johnson of illegally paying millions of dollars in kickbacks to Omnicare, one of the nation's largest pharmacies specializing in nursing home patients. In return, Omnicare nearly tripled its annual purchase of Johnson and Johnson's products; including Levaquin.

There are also cases currently pending before the United States District Court, District of Minnesota, involving Levaquin. On 13 June 2008, a Judicial Panel On Multidistrict Litigation (MDL) granted the Plaintiffs' motion to centralize individual and class action lawsuits involving Levaquin in the District of Minnesota over objection of Defendants, Johnson and Johnson / Ortho McNeil.[121] On 6 July 2009, The New Jersey Supreme Court had also designated litigation over Levaquin as a mass tort and has assigned it to an Atlantic County, N.J., judge. The suits charge that the drug has caused achilles tendon ruptures and other permanent damage.[122][123] Additional lawsuits have also been recently filed in the Illinois State Court. Of a total of about 3400 cases, 845 were recently settled out of court after Johnson and Johnson prevailed in three of the first four cases to go to trial[124][125]

On 8 April 2010 in the Beaumont Division of the Eastern District of Texas, a class action lawsuit was filed by Lisa Presley on behalf of herself and others similar situated against Johnson and Johnson, Ortho-McNeil Pharmaceuticals Inc. and Johnson and Johnson Pharmaceutical Research and Development LLC. (Case No 1:10cv00200.)[126]

The various manufacturers have countered these allegations stating that they believe that these drugs are both safe and effective antibiotics, well tolerated with a minimum of side-effects, that such reactions are rare and the benefits of such therapy outweigh the perceived risks.

References

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