[8] As of 2016, the US Food and Drug Administration (FDA) recommended that "serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options.

As of 2007 the Infectious Disease Society of America (IDSA) and the American Thoracic Society recommended levofloxacin and other respiratory fluoroquinolines as first line treatment for community acquired pneumonia when co-morbidities such as heart, lung, or liver disease are present or when in-patient treatment is required.

[14] Levofloxacin also plays an important role in recommended treatment regimens for ventilator-associated and healthcare-associated pneumonia.

[23] According to the FDA approved prescribing information, levofloxacin is pregnancy category C.[3] This designation indicates that animal reproduction studies have shown adverse effects 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.

[25] Due to potential risks to the baby, the manufacturer does not recommend that nursing mothers take levofloxacin.

[25] Levofloxacin is not approved in most countries for the treatment of children except in unique and life-threatening infections because it is associated with an elevated risk of musculoskeletal injury in this population, a property it shares with other fluoroquinolones.

In the United States levofloxacin is approved for the treatment of anthrax and plague in children over six months of age.

[3] Levofloxacin is recommended by the Pediatric Infectious Disease Society and the Infectious Disease Society of America as a first-line treatment for pediatric pneumonia caused by penicillin-resistant Streptococcus pneumoniae, and as a second-line agent for the treatment of penicillin-sensitive cases.

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 adverse events occurred in the first 60 days, 86% were mild, 17% were moderate, and all resolved without long-term sequelae.

[28] The drug exhibits enhanced activity against the important respiratory pathogen Streptococcus pneumoniae relative to earlier fluoroquinolone derivatives like ciprofloxacin.

[38] The use of non-steroidal anti-inflammatory drugs (NSAIDs) in combination with high dose fluoroquinolone therapy may lead to seizures.

[40][41] A 2011 review examining musculoskeletal complications of fluoroquinolones proposed guidelines with respect to administration to athletes, that called for avoiding all use of fluoroquinolone antibiotics if possible, and if they are used: ensure there is informed consent about the musculoskeletal risks, and inform coaching staff; do not use any corticosteroids if fluoroquinolones are used; consider dietary supplements of magnesium and antioxidants during treatment; reduce training until the course of antibiotic is finished and then carefully increase back to normal; and monitor for six months after the course is finished, and stop all athletic activity if symptoms emerge.

However, severe, disabling, and potentially irreversible adverse effects sometimes occur, and for this reason it is recommended that use of fluoroquinolones be limited.

"[9] Rarely, tendinitis or tendon rupture may occur due to fluoroquinolone antibiotics, including levofloxacin.

[43] Such injuries, including tendon rupture, has been observed up to six months after cessation of treatment; higher doses of fluoroquinolones, being elderly, transplant patients, and those with a current or historical corticosteroid use are at elevated risk.

[44][45] The U.S. label for levofloxacin also contains a black box warning for the exacerbation of the symptoms of the neurological disease myasthenia gravis.

[42] A wide variety of other uncommon but serious adverse events have been associated with fluoroquinolone use, with varying degrees of evidence supporting causation.

[48] There is some disagreement in the medical literature regarding whether and to what extent levofloxacin and other fluoroquinolones produce serious adverse effects more frequently than other broad spectrum antibacterial drugs.

The most common adverse reactions leading to discontinuation were gastrointestinal, including nausea, vomiting, and constipation.

[54] Overdosing experiments in animals showed loss of body control and drooping, difficulty breathing, tremors, and convulsions.

[3] In the event of an acute overdosage, authorities recommend unspecific standard procedures such as emptying the stomach, observing the patient and maintaining appropriate hydration.

[55] Topoisomerase IV is necessary to separate DNA that has been replicated (doubled) prior to bacterial cell division.

[66] Daiichi, working with Johnson & Johnson as it had with ofloxacin, obtained FDA approval in 1996 under the brand name Levaquin[65] to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia, uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis.

[65] The federal patent court ruled in favor of J&J and Daiichi, and generic versions of levofloxacin did not enter the U.S. market until 2009.

The US Food and Drug Administration estimated that in 2011, over 23 million outpatient prescriptions for fluoroquinolones, of which levofloxacin made up 28%, were filled in the United States.

[68] As of 2012, Johnson and Johnson was facing around 3400 state and federal lawsuits filed by people who claimed tendon damage from levofloxacin; about 1900 pending in a class action at the United States District Court in Minnesota[69] and about 1500 pending at a district court in New Jersey.