Fluoroquinolones

INTRODUCTION — Fluoroquinolones are highly effective antibiotics with many advantageous pharmacokinetic properties including high oral bioavailability, large volume of distribution, and broad-spectrum antimicrobial activity. With widespread use, antimicrobial resistance to fluoroquinolones has grown. In addition, fluoroquinolones carry risk of serious adverse effects (eg, Clostridioides difficile infection, tendinopathy, neuropathy) and have multiple drug-drug interactions. Thus, fluoroquinolone use is typically reserved for cases in which the benefits clearly outweigh the risks.

The spectrum of activity, mechanisms of action and resistance, important resistance patterns, and adverse effects of commonly available fluoroquinolones (ie, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin) will be reviewed here. Detailed information on pharmacokinetics, pharmacodynamics, and drug interactions can be found by using the Lexicomp drug interactions tool included within UpToDate.

BENEFITS AND RISKS OF USE

Restriction of use for uncomplicated infections — In general, we find that the risks of fluoroquinolone use outweigh the benefits for the treatment of uncomplicated infections such as acute rhinosinusitis, uncomplicated cystitis, and acute bronchitis. Antibiotics are either not indicated for these conditions or alternate agents with lower toxicity profiles are usually available for their treatment. (See "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment" and "Acute simple cystitis in females" and "Acute bronchitis in adults".)

This approach is in line with recommendations from the US Food and Drug Administration (FDA) derived from their 2016 safety review, which showed that systemic fluoroquinolone use is associated with uncommon but potentially permanent and disabling adverse effects involving the musculoskeletal and nervous systems [1]. (See 'Adverse effects' below.)

Use for more severe infections — When treating more severe infections, we weigh the benefits and risks of fluoroquinolone use in each individual patient.

For the majority, fluoroquinolones are well tolerated. The most common adverse effects are mild and include gastrointestinal upset, headaches, dizziness, or a transient change in mood or sleep. Although their exact incidence is unknown, gastrointestinal and central nervous system adverse effects are estimated to be three times more common with fluoroquinolones when compared with other antibiotics [2]. The incidence of C. difficile infection also appears to be higher with fluoroquinolone use when compared with some other antibiotics [3,4]. Thus, when equally efficacious and narrower spectrum options are available, we tend to select them over fluoroquinolones.

Less common but potentially severe adverse effects include tendinopathies and tendon rupture, peripheral neuropathy, QT interval prolongation, and putatively aortic dissection and rupture. Rarely, tendinopathies and neuropathies can be permanent and/or disabling; thus, we try to avoid fluoroquinolones in patients with known tendinopathies and neuropathies or in those at risk. Similarly, we avoid fluoroquinolone use in patients with prolonged QT intervals or in patients taking other medications that prolong the QT interval. (See 'Tendinopathy' below and 'Peripheral neuropathy' below and 'QT interval prolongation' below.)

Aortic dissection and rupture is a putative, but potentially devastating, adverse effect associated with fluoroquinolone use. Although the putative risk is small, the FDA warns against fluoroquinolone use in patients with known aortic aneurysms and those with risk factors for aneurysm such as Marfan syndrome, Ehlers Danlos syndrome, peripheral atherosclerotic vascular diseases, uncontrolled hypertension, and/or advanced age [5]. The risk-benefit ratio clearly varies among such individuals. As an example, for an older patient with severe community-acquired pneumonia, the benefits of fluoroquinolone use may outweigh the small potential risk of aortic aneurysm rupture. By contrast, the risk-benefit ratio is likely greater for an individual with a known aneurysm and a questionable indication for fluoroquinolone use. (See 'Aortic aneurysm and dissection' below.)

Fluoroquinolones also interact with a variety of other drugs, which need be taken into account when prescribing (see 'Drug interactions' below). Additional uncommon adverse effects are also discussed below. (See 'Adverse effects' below.)

Special populations

Pregnancy and breastfeeding — Fluoroquinolones should generally be avoided during pregnancy and lactation unless a safer alternative is not available. In animal models, fluoroquinolone use during pregnancy has been associated with cartilage and bone toxicity in developing fetuses [6-9]. While similar effects have not been observed in humans, available data are limited and follow-up times generally do not exceed time of birth [10,11]. Reassuringly, in one meta-analysis of observational studies evaluating over 2800 pregnant women exposed to fluoroquinolones, no differences in congenital malformations, spontaneous abortion, or prematurity were detected when compared with unexposed pregnant women [11]. While a small decrease in the live birth rate was detected among pregnant women exposed to fluoroquinolones when compared with controls in this study, this appears to correlate with an increase in elective pregnancy terminations, possibly due to a misperceived risk to the newborn.

Children — Routine use of systemic fluoroquinolones should be avoided in children due to the potential risk of musculoskeletal toxicity. However, it is reasonable to use a systemic fluoroquinolone in children when no safe or effective alternative exists or when parenteral therapy can be avoided by using an oral fluoroquinolone [12-17]. This approach is consistent with recommendations from the American Academy of Pediatrics [12]. FDA-approved uses in children are limited and include treatment of complicated urinary tract infections and pyelonephritis as well as treatment and prevention of inhalation anthrax.

The concern over musculoskeletal toxicity is based on the association between fluoroquinolones and tendinopathies as well as studies in juvenile animals, which have demonstrated a dose- and duration-dependent association with erosive arthropathy in weight-bearing joints with fluoroquinolone use [12]. Available clinical trial data suggest that adverse musculoskeletal events are usually mild and not long term. As an example, in a retrospective cohort study evaluating 2233 children, reports of musculoskeletal toxicity were higher among children who received levofloxacin when compared with a non-fluoroquinolone antibiotic (3.4 versus 1.8 percent) over a one-year period [18]. Arthralgia was the most common musculoskeletal adverse event, reported in over 80 percent of symptomatic children in both groups. Children who had persisting musculoskeletal adverse events during the first year of follow-up were requested to enroll in four additional years of follow-up [19]. Of children identified with a musculoskeletal adverse event during years 2 through 5 following treatment, the number that were considered "possibly related" to drug therapy was equal for both groups (1 of 1340 in the levofloxacin group; 1 of 893 in the comparator group). No musculoskeletal adverse event was considered "likely related" to levofloxacin.

Patients with myasthenia gravis — Fluoroquinolones should be avoided in individuals with myasthenia gravis because they have neuromuscular-blocking activity that may precipitate myasthenic crises [20]. Postmarketing reports have included death and respiratory failure requiring mechanical ventilation in patients with myasthenia gravis receiving fluoroquinolones. The label carries a boxed warning from the FDA advising against use in this population [21].

MECHANISM OF ACTION — Fluoroquinolones are bactericidal antibiotics that directly inhibit bacterial deoxyribonucleic acid (DNA) synthesis [22,23]. All fluoroquinolones bind to complexes of DNA with each of two enzymes that are essential for DNA replication, DNA gyrase and DNA topoisomerase IV, and this binding generates DNA cleavage. The potency with which fluoroquinolones inhibit one enzyme or the other varies among bacterial species. In general, fluoroquinolone generation of DNA cleavage complexes results in cessation of DNA replication, DNA damage, and, ultimately, cell death.

PHARMACOKINETICS — High oral bioavailability and a large volume of distribution are key pharmacokinetic properties of most fluoroquinolones (table 1).

Each fluoroquinolone is absorbed from the upper gastrointestinal tract [24-28]. Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and delafloxacin all have oral and intravenous formulations that allow direct estimates of oral bioavailability, with values of 59 percent for delafloxacin, 70 percent for ciprofloxacin, 86 percent for moxifloxacin, and >95 percent for ofloxacin and levofloxacin [28,29]. Norfloxacin has an oral formulation only, and its estimated bioavailability is approximately 30 to 40 percent.

Peak concentrations in serum are usually attained within one to three hours of administering an oral dose. Food does not substantially reduce fluoroquinolone absorption but may delay the time to reach peak serum concentrations [30,31]. However, dairy, antacids, multivitamins containing zinc, certain medications (eg, sucralfate), and other sources of divalent cations (aluminum, magnesium, calcium) can substantially decrease absorption (presumably by formation of cation-quinolone complexes). Concurrent use should be avoided or these substances should be given several hours apart from the fluoroquinolone in order to avoid their interaction [32].

The volumes of distribution of quinolones are high and, in most cases, exceed the volume of total body water, indicating accumulation in some tissues. Concentrations in prostate tissue, stool, bile, lung, and neutrophils as well as macrophages usually exceed serum concentrations. Concentrations in urine and kidney tissue are high for the quinolones with a major renal route of elimination (all except moxifloxacin). Concentrations of quinolones in saliva, prostatic fluid, bone, and cerebrospinal fluid are usually lower than drug concentrations in serum.

Detailed information on metabolism (table 1), dose adjustments, and other pharmacokinetic properties can be found using the Lexicomp drug information monographs included within UpToDate. (See "Ciprofloxacin (systemic): Drug information" and "Levofloxacin (systemic): Drug information" and "Moxifloxacin (systemic): Drug information" and "Delafloxacin: Drug information" and "Ofloxacin (systemic): Drug information" and "Norfloxacin (United States: Not available): Drug information" and "Gemifloxacin (United States: Not available): Drug information" and "Gatifloxacin: Drug information".)

SPECTRUM OF ACTIVITY — Fluoroquinolones are broad-spectrum antibiotics with potent activity against aerobic, enteric gram-negative bacilli and many common respiratory pathogens. In addition, some fluoroquinolones are active against Pseudomonas species, selected gram-positive organisms, anaerobes, and mycobacteria. The relative potency against specific pathogens within these categories varies among fluoroquinolones. Because resistance to fluoroquinolones is common, knowledge of local epidemiology is important when selecting an antibiotic. (See 'Antimicrobial resistance' below.)

Fluoroquinolones are also important for the treatment of less common infections including tuberculosis, non-tuberculous mycobacterial infections, and anthrax.

Although some fluoroquinolones have activity against certain gram-positive organisms and anaerobes, clinical experience with their use for these organisms is limited and their potency is often less than that of other antibiotics. Thus, fluoroquinolones are generally not used as first-line agents for susceptible organisms within these categories.

●Ciprofloxacin – Ciprofloxacin primarily targets and has the greatest activity against aerobic, enteric gram-negative bacilli (eg, Enterobacterales, including Escherichia coli, Klebsiella spp, Proteus spp), as well as Pseudomonas aeruginosa. This spectrum of activity makes ciprofloxacin a great option for intra-abdominal infections and other infections caused by enteric bacteria. Although ciprofloxacin also has potent activity against aerobic gram-negative respiratory pathogens (eg, H. influenzae, M. catarrhalis), it has limited to no activity against gram-positive organisms (eg, S. pneumoniae, Staphylococcus aureus).

●Levofloxacin – Levofloxacin has activity against gram-positive organisms (eg, Streptococcus pneumoniae, Staphylococcus aureus, some strains of coagulase-negative staphylococci) and reduced, but still adequate activity, against aerobic, enteric gram-negative organisms and P. aeruginosa. Levofloxacin is also active against most common respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and intracellular or cell wall-deficient bacteria (ie, Legionella spp, Mycoplasma spp, and Chlamydia pneumoniae).

●Moxifloxacin – Moxifloxacin has activity against gram-positive organisms (eg, Streptococcus pneumoniae, Staphylococcus aureus, some strains of coagulase-negative staphylococci) and reduced, but still adequate activity, against aerobic, enteric gram-negative organisms (eg, Enterobacterales, including Escherichia coli, Klebsiella spp, Proteus spp). Moxifloxacin is less active than ciprofloxacin or levofloxacin against Pseudomonas aeruginosa, Providencia spp, Proteus spp, and Serratia marcescens and is generally not used to treat these organisms. Moxifloxacin is also active against most common respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and intracellular or cell wall-deficient bacteria (ie, Legionella spp, Mycoplasma spp, and Chlamydia pneumoniae). Additionally, moxifloxacin has activity against some anaerobes and is most active against mycobacteria compared with other fluoroquinolones. Given its overall spectrum of activity, although data are limited, moxifloxacin appears to be similarly effective as ampicillin-sulbactam for anaerobic lung infections (eg, aspiration pneumonia or lung abscess) [33] and is the only fluoroquinolone that has sufficient activity against anaerobic bacteria for clinical use. Resistance among Bacteroides species limits its use for the treatment of intra-abdominal infections.

●Delafloxacin – Delafloxacin has activity against gram-positive organisms (eg, Streptococcus pneumoniae, Staphylococcus aureus, some strains of coagulase-negative staphylococci) and reduced, but still adequate activity, against aerobic, enteric gram-negative organisms (eg, Enterobacterales, including Escherichia coli, Klebsiella spp, Proteus spp) and P. aeruginosa.

Delafloxacin is the only fluoroquinolone with reliable activity against methicillin-resistant Staphylococcus aureus (MRSA). However, clinical experience with delafloxacin is limited. Delafloxacin also has activity against anaerobes in vitro [34], but in vivo data are lacking. (See "Anaerobic bacterial infections".)

●Other antimicrobial activity of fluoroquinolones

•Enterococci – Although some fluoroquinolones have in vitro activity against enterococci, they are generally not used for the treatment of enterococcal infections because achievable serum concentrations are frequently close to the minimum inhibitory concentrations and efficacy data are limited. (See "Treatment of enterococcal infections".)

•Mycobacterium tuberculosis – Fluoroquinolones also have excellent activity in vitro against Mycobacterium tuberculosis and are used as second-line agents in the setting of resistance and/or intolerance to first-line agents. In general, moxifloxacin and levofloxacin are preferred over other fluoroquinolones because of their greater potency. (See "Antituberculous drugs: An overview".)

•Nontuberculous mycobacteria – Fluoroquinolones are also active against many nontuberculous mycobacteria including M. fortuitum, M. kansasii, and some strains of M. chelonae. Activity against M. avium complex is fair to poor. Moxifloxacin and ofloxacin are active against M. leprae. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum" and "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Leprosy: Treatment and prevention".)

•Other atypical bacteria – Fluoroquinolones are among first-line options for the treatment of susceptible infections caused by Bacillus anthracis, Francisella tularensis, and Salmonella enterica Serovar Typhi (typhoid fever). Specific recommendations vary by site and severity of infection. (See "Treatment of anthrax" and "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention".)

ANTIMICROBIAL RESISTANCE

Mechanisms of resistance — Resistance to quinolones may occur via mutations in bacterial chromosomal genes or via acquisition of resistance genes on plasmids.

Mutations in chromosomal genes occur in genes that [35]:

●Encode the subunits of DNA gyrase and topoisomerase IV (altered target mechanism)

●Regulate the expression of cytoplasmic membrane efflux pumps or proteins that constitute outer membrane diffusion channels (altered permeation mechanism)

Major plasmid-mediated resistance mechanisms include [36-42]:

●Qnr proteins, which protect DNA gyrase and topoisomerase IV from quinolone activity

●Fluoroquinolone-modifying enzymes (encoded by an aminoglycoside acetyltransferase variant gene [AAC(6′)-Ib-cr]), which acetylates fluoroquinolones and reduces their activity

●Efflux pumps (encoded by qepA and oqxAB genes), which pump fluoroquinolones (particularly ciprofloxacin and norfloxacin) out of the cell

Plasmid-mediated resistance mechanisms typically confer low-level resistance. However, high-level resistance can result when plasmid-mediated mechanisms accumulate or co-occur with chromosomal mutations. The likelihood of developing resistance is believed to be related to the intensity and duration of antibiotic therapy. As an example, ≥5 days of fluoroquinolone exposure was associated with significant resistance in an in vitro model [43].

Plasmid-mediated resistance mechanisms can confer resistance to other antimicrobial classes directly or because they are linked to other drug-resistance genes encoded on the same plasmid.

Important resistance patterns — Resistance to fluoroquinolones is common, and rates are growing worldwide among many targeted bacteria. Thus, fluoroquinolone use may be precluded or limited for certain indications unless susceptibility is documented such as the following:

●Sexually transmitted infections, particularly with Neisseria gonorrhoeae (see "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents", section on 'Fluoroquinolones')

●Urinary tract infections (see "Acute complicated urinary tract infection (including pyelonephritis) in adults", section on 'Management' and "Acute simple cystitis in females", section on 'Management')

●P. aeruginosa infections (see "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections")

●Typhoid and paratyphoid (see "Enteric (typhoid and paratyphoid) fever: Treatment and prevention" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention", section on 'Antimicrobial resistance')

●Infections with Shigella spp and Campylobacter spp (see "Shigella infection: Treatment and prevention in adults", section on 'Antibiotic resistance' and "Campylobacter infection: Clinical manifestations, diagnosis, and treatment", section on 'Resistance')

Fluoroquinolone resistance is relatively uncommon among S. pneumoniae, H. influenzae, and M. catarrhalis. (See "Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole" and "Moraxella catarrhalis infections" and "Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae".)

ADVERSE EFFECTS

General considerations — Fluoroquinolones are generally safe and well tolerated. However, rare but severe adverse events have been reported, leading to restrictions in their use [1] and, in some cases, their removal from the market [44-47].

Much of the data regarding adverse effects are derived from passive reporting systems and observational studies, which are prone to confounding. In some cases, uncommon side effects were only recognized with more extensive clinical use after regulatory approval. Because safety and tolerability are best assessed in randomized trials, our knowledge of adverse effects associated with fluoroquinolone use continues to evolve.

Delafloxacin is structurally designed to have a lower adverse effect profile, particularly for central nervous system events and phototoxicity [48]. Randomized trial data suggest that treatment-related adverse events may be less common with delafloxacin when compared with other fluoroquinolones [49]. However, only limited numbers of patients have thus far been treated with delafloxacin, and long-term data are lacking.

Gastrointestinal

Gastritis — The most common adverse effect associated with fluoroquinolone use is transient and mild gastrointestinal upset (eg, anorexia, nausea, vomiting, or abdominal discomfort). Diarrhea is less common.

C. difficile-associated disease — Because of their broad-spectrum, fluoroquinolones may confer greater risk of C. difficile-associated disease when compared with some other antibiotics [3,4]. Reductions in fluoroquinolone prescriptions have been associated with declines in C. difficile rates both in the community and in health care institutions [50-52].

Certain epidemic strains of C. difficile (ie, NAP1/BI/027) are fluoroquinolone resistant; use of fluoroquinolones during outbreaks caused by such strains has been a risk factor for the development of C. difficile-associated disease [53]. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology".)

Hepatoxicity — As a class, fluoroquinolones are associated with low risk of mild elevation of aminotransferase levels. Among commonly used fluoroquinolones (ie, ciprofloxacin, levofloxacin, moxifloxacin), severe hepatic failure is rare but reported [54-58].

In a population-wide propensity-matched retrospective study of all Swedish patients aged 40 to 85 years, receipt of an oral fluoroquinolone was associated with a higher risk of acute liver injury compared with those who received amoxicillin (hazard ratio [HR] 2.32, 95% CI 1.01-5.35), although absolute incidence was only 2.98 and 1.27 per 10,000 person-years, respectively [59]. A similar increase in risk of hepatotoxicity has also been observed in multiple case control studies [60,61].

Trovafloxacin warrants mention because it was removed from the market worldwide for its association with fatal hepatoxicity [46,47]. Gatifloxacin has the second strongest association with hepatoxicity; it is no longer available in the United States, and worldwide availability is limited.

Neurologic — Neurologic adverse effects are among the most common adverse effects associated with fluoroquinolones [2]. Most neurologic adverse effects are mild, such as headache, dizziness, or transient change in mood or sleep patterns. Less commonly, more serious central nervous system adverse effects can occur, ranging from delirium to hallucination to seizures. The peripheral nervous system can also be affected; peripheral neuropathy predominates.

Altered mental status — The labels of all systemic fluoroquinolones include US Food and Drug Administration (FDA) warnings about the risk of delirium, memory impairment, disorientation, agitation, and disturbances in attention. Such adverse effects have been reported after a single fluoroquinolone dose, and the offending drug should be stopped if they occur [62].

Peripheral neuropathy — Peripheral neuropathy is an uncommon but well-described adverse effect of fluoroquinolone use [63,64]. Peripheral neuropathy can occur at any time during treatment with a fluoroquinolone and can last for months to years after the drug is stopped or be permanent. In reported cases, the onset of peripheral neuropathy was rapid, often within a few days.

Symptoms of peripheral neuropathy may include pain, burning, tingling, numbness, weakness, or a change in sensation to light, touch, pain, temperature, or the sense of body position. If symptoms of peripheral neuropathy develop while receiving a fluoroquinolone, the fluoroquinolone should be stopped, and the patient should be switched to an antibiotic from a different class, unless the benefit of continuing the fluoroquinolone outweighs the risk. Generally, the management of fluoroquinolone-associated peripheral neuropathy is similar to the management of other drug-induced neuropathies, which includes stopping the offending agent and providing symptomatic care. (See "Overview of polyneuropathy", section on 'Management'.)

Although the precise incidence is unknown, in a case-control study of men aged 45 to 80 years, current users of fluoroquinolones were at a higher risk of developing peripheral neuropathy than controls (rate ratio [RR] 1.83, 95% CI 1.49-2.27) [63]. Similar findings were reported in another nested case-control study comparing 5357 cases of peripheral neuropathy to matched controls [65]. Risk was highest among men and patients >60 years old; risk increased by approximately 3 percent with each day of exposure and persisted for 180 days. The number needed to harm for a 10-day course was 152,083 patients (95% CI 117,742-202,778).

The exact mechanism by which peripheral neuropathy occurs remains unknown [66]. Hypotheses include direct nerve inflammation with or without ischemia caused by toxic metabolite and free radical accumulation [67].

Other adverse effects — Other neurologic adverse effects are uncommon and include:

●Seizure – Seizures are very rare complications of fluoroquinolone use. In some cases, seizures may result from theophylline accumulation or from the ability of theophylline and nonsteroidal anti-inflammatory drugs to augment fluoroquinolone-mediated displacement of gamma-aminobutyric acid from its receptors [68-70]. (See 'Drug interactions' below.)

●Pseudotumor cerebri – Fluoroquinolone use has also been associated with secondary pseudotumor cerebri syndrome, as illustrated by the findings of a case-control study evaluating health care records from over six million patients [71]. Compared with nonuse, fluoroquinolone use within 15 or 30 days of diagnosis increased the risk of developing secondary pseudotumor cerebri syndrome (adjusted rate ratios for 15 days 5.67, 95% CI 2.72-11.83). Although the overall rate of the disorder was low, estimated at about 2 per 100,000 overall and 1 in 166,000 due to fluoroquinolones, clinicians should be aware of this potential risk in patients with characteristic symptoms (eg, headache, tinnitus, diplopia).

●Myasthenia gravis exacerbations – Fluoroquinolones have neuromuscular-blocking activity and may exacerbate muscle weakness in individuals with myasthenia gravis [20]. Postmarketing reports have included death and respiratory failure requiring mechanical ventilation in patients with myasthenia gravis receiving fluoroquinolones. Thus, fluoroquinolones should be avoided in individuals with myasthenia gravis. (See "Myasthenic crisis", section on 'Precipitants'.)

Cardiovascular

QT interval prolongation — Fluoroquinolones can prolong the QT interval by inhibiting cardiac KCHN2 potassium voltage-gated channels, potentially leading to torsades de pointes (a life-threatening arrhythmia) [72]. When safe and effective alternatives are available, we avoid fluoroquinolone use for patients taking other QT-prolonging drugs and patients with long QT syndromes or other significant risk factors for arrhythmia (table 2).

Available clinical data suggest that, among available fluoroquinolones, moxifloxacin has the highest association with QT interval prolongation, arrhythmia, and cardiovascular mortality, followed by levofloxacin and then ciprofloxacin [73-76]. Delafloxacin, which came to market in 2018, has not been associated with QT interval prolongation, but clinical experience is limited [28,77]. Sparfloxacin, grepafloxacin, and gatifloxacin each had strong associations with QT interval prolongation [78]. However, these agents have either been removed from the market or have limited availability.

In a meta-analysis of five large observational studies and one randomized trial evaluating >7 million patients, fluoroquinolone use was associated with an increased risk of arrhythmia (odds ratio [OR] 1.85, 95% CI 1.22-2.81) when compared with either placebo or other antibiotic use [76]. Concordantly, an increased risk of cardiovascular mortality was detected in a meta-analysis of one randomized trial and two observational studies evaluating over three million patients (OR 1.71, 95% CI 1.39-2.09). Based on a network meta-analysis of clinically available fluoroquinolones, the risk of arrhythmia was highest with moxifloxacin use followed by levofloxacin and ciprofloxacin [76]. A similar trend was observed for cardiovascular mortality, although the increase in risk with moxifloxacin when compared with levofloxacin did not reach statistical significance. Delafloxacin was not evaluated.

Because most studies evaluating the effect of fluoroquinolones on the QT interval are observational, they are prone to confounding by indication (eg, fluoroquinolone use for pneumonia carries greater baseline risk of adverse cardiovascular effects than does amoxicillin use for acute sinusitis). In addition, most studies do not account for comorbidities that may augment risk of arrhythmia. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)

Aortic aneurysm and dissection — Several observational studies have suggested that fluoroquinolone use may be associated with an increased risk of aortic aneurysm or dissection [79-83]. However, the causal role of fluoroquinolones in the development of aortic aneurysms and dissection is unclear.

Based on these studies, the FDA issued a warning in December 2018 highlighting this association and recommended avoiding fluoroquinolones in patients with known aortic aneurysms or those with risk factors for aneurysm such as Marfan syndrome, Ehlers Danlos syndrome, peripheral atherosclerotic vascular diseases, uncontrolled hypertension, and/or advanced age [5]. In one nationwide cohort study in Sweden, fluoroquinolone use (360,088 fluoroquinolone treatment episodes) was associated with an increased risk of aortic aneurysm within 60 days from the start of treatment when compared with amoxicillin use (1.2 versus 0.7 cases per 1000 person-years; HR 1.66, 95% CI 1.12-2.46) in propensity-matched controls. The estimated absolute difference was 82 cases of aortic aneurysm or dissection per 1 million treatment episodes [82].

The observational nature of this study leaves room for potential confounders (eg, severity of the infection for which the antibiotic was prescribed, smoking status, baseline blood pressure). If a causal role for fluoroquinolones and aortic aneurysm or dissection exists, the absolute risk is small and likely limited to individuals with predisposing risk factors. Whether preferentially avoiding fluoroquinolones in patients with any risk factor for aortic aneurysm or dissection (eg, hypertension or older age) versus those with strong risk factors (eg, known aneurysm) provides benefit is unclear. When considering fluoroquinolone use, we take this uncertainty into account and weigh the overall risk-benefit ratio in each patient.

Other adverse effects — Aortic and mitral valve regurgitation have been associated with fluoroquinolone use in a single large observational study [84]. However, whether this association is causal is uncertain. In a nested case-control study of >135,000 patients extracted from the United States PharMetrics Plus database, current fluoroquinolone use was associated with an increased risk of aortic or mitral regurgitation when compared with amoxicillin (RR 2.40, 95% CI 1.82-3.16) and azithromycin (RR 1.75, 95% CI 1.34-2.29). No increase in risk was detected for past fluoroquinolone use. Patients with valvular regurgitation also had higher rates of coronary artery disease, heart failure, and atrial fibrillation, suggesting that there may be residual confounding in the analysis. Additional study is needed to confirm or refute these findings.

Musculoskeletal

Tendinopathy — Fluoroquinolone use has been associated with a broad range of tendinopathies, including tendon rupture [85-91]. The Achilles tendon is most often affected, although any tendon can be involved [90,92]. Thus, when prescribing a fluoroquinolone, we advise patients to discontinue the medication if any sign of tendinopathy develops (ie, pain, swelling). In addition, we generally advise patients to avoid exercise, contact their physician for evaluation, and transition to a non-fluoroquinolone antibiotic when appropriate. This approach is consistent with recommendations from the FDA [90].

The incidence of tendinopathies associated with fluoroquinolone use is not well established but is estimated to be low (ie, approximately 3 to 4 cases per 100,000 for the Achilles tendon) [93,94]. Most cases occur early in the course of therapy, with a median of eight days based on case reports [89,92,94].

In a cohort study reviewing 28,907 cases of Achilles tendinopathy and 7685 cases of tendon rupture, fluoroquinolone use was associated with increased risk of tendinopathy (OR 4.3, 95% CI 3.2-5.7) and tendon rupture (OR 2.0, 95% CI 1.2-3.3) when compared with other antibiotics [91]. Risk appeared to be higher among persons >60 years old (OR 8.3 versus 1.6), nonobese (OR 7.7 versus 2.4), and those using oral glucocorticoids (OR 9.1 versus 3.2). Kidney, heart, and lung transplantation have been identified as potential additional risk factors [90].

It is unclear whether any one fluoroquinolone confers greater risk of tendinopathy over another, although one study demonstrated a higher risk of tendon ruptures with levofloxacin [67,92,95].

The mechanisms of fluoroquinolones’ effects on connective tissues are not well understood. Data suggest that tenocyte toxicity is due to local boosting of metalloprotease activity and magnesium chelation from high concentrations of fluoroquinolone accumulated in tendons and possibly other connective tissues [96,97].

Arthropathy — Arthropathy with cartilage erosions and noninflammatory effusions occurs in the weight-bearing joints of juvenile animals given quinolones. Experience with use of quinolones in children has increased, particularly in children with cystic fibrosis given ciprofloxacin. These children and others receiving nalidixic acid and norfloxacin have only uncommonly had joint symptoms, which have been reversible [13,98]. Studies to identify subclinical cartilage damage by magnetic resonance imaging of joints of treated children have also been negative [99]. (See 'Children' above.)

Other adverse effects

Dysglycemia — Fluoroquinolones have been associated with both hypoglycemia and hyperglycemia in both diabetic and nondiabetic patients [100-105]. In July 2018, the FDA strengthened its warning about the risk of hypoglycemia associated with systemic fluoroquinolone use, particularly for older adults and those with diabetes mellitus [62].

Among moxifloxacin, levofloxacin, and ciprofloxacin, moxifloxacin appears to confer the highest risk of both hyperglycemia and hypoglycemia among diabetic patients [100]. Gatifloxacin was withdrawn from the market in the United States and Canada in June 2006 because it was associated with a greater frequency of symptomatic hypoglycemia and hyperglycemia when compared with other fluoroquinolones, including some fatal cases [101-103].

Retinal detachment — Retinal detachment has been reported with fluoroquinolone use; however, a causal relationship has not been established. Several large observational studies have attempted to assess whether an association between fluoroquinolone use and retinal detachment exists, with conflicting results [79,106-110].

A nationwide registry-based cohort study from Denmark that controlled for potential confounders found that neither recent nor current fluoroquinolone use was associated with an increased risk of retinal detachment [107]. Similarly, in a large population-based study in the United States, fluoroquinolone use was not associated with an increased risk of rhegmatogenous retinal detachment or symptomatic retinal breaks [108]. In contrast, a nested case-control study of patients in Canada who visited an ophthalmologist found an increased rate of retinal detachment in patients who were currently receiving an oral fluoroquinolone (3.3 percent of cases versus 0.6 percent of controls; aOR 4.5, 95% CI 3.6-5.7) [106]. The absolute increase in the risk of retinal detachment was 4 per 10,000 person-years. In a case-crossover study using French health care databases that included 27,540 patients with retinal detachment, there was an increased risk for retinal detachment during the 10-day period after being prescribed a fluoroquinolone (aOR 1.46, 95% CI 1.15-1.87) [109]. The risk was increased for both rhegmatogenous (full-thickness; aOR 1.41, 95% CI 1.04-1.92) and exudative (aOR 2.57, 95% CI 1.46-4.53) retinal detachment.

Considering all the data above and other reports, the FDA issued an update in May 2017 stating that available data do not support a causal association between fluoroquinolones and retinal detachment [111]. If an association exists, the risk of retinal detachment attributable to fluoroquinolone use is likely small and may be limited to individuals with additional predisposing risk factors.

Phototoxicity — Some fluoroquinolones carry a small risk of phototoxicity [47]. The effect seems to be most pronounced with older-generation fluoroquinolones (eg, lomefloxacin, sparfloxacin) due to their chemical structures [112]. The risk is lessened with most presently available fluoroquinolones and may be absent for delafloxacin, which is designed to avoid this adverse effect [113]. Sunscreen containing UVA blockers may offer some protection [114], although this has not been systematically studied.

Hypersensitivity reactions — Delayed-onset maculopapular rash is the most common type of hypersensitivity reaction to fluoroquinolones, occurring in approximately 2 to 3 percent of patients. Immediate reactions (eg, urticaria, pruritus, angioedema, wheezing, anaphylaxis) are less common but can be life-threatening. In clinical trials, an unusually high occurrence of maculopapular rash (14 percent) was reported in young women receiving gemifloxacin for seven or more days; biopsies showed no evidence of vasculitis [115]. Persons with a gemifloxacin-associated rash had a higher rate of rash to subsequent ciprofloxacin (5.9 percent) than those having received placebo [116]. Acute interstitial nephritis also occurs infrequently and has been associated with eosinophiluria but generally not crystalluria [117]. Hypersensitivity reactions to fluoroquinolones are discussed in greater detail separately. (See "Hypersensitivity reactions to fluoroquinolones".)

Persistent multisystem adverse effects — Persistent multisystem symptoms (termed fluoroquinolone-associated disability) have been reported following fluoroquinolone use [118,119]. However, whether fluoroquinolones are causal of such symptoms and what the potential mechanism of action may be is unclear.

In 2015, the FDA reviewed its database for all serious adverse events reported in previously healthy persons taking a fluoroquinolone for acute bronchitis, urinary tract infection, and acute rhinosinusitis between 1997 and 2015 [120]. Among 1122 reports, 178 met criteria for events involving two or more body systems and lasting for ≥30 days after stopping the fluoroquinolone. There was an unusually high proportion of direct patient reports for fluoroquinolones when compared with other drugs (85 versus 2 to 6 percent). Three-quarters of reported cases occurred in females and those aged 30 to 59. Almost all had musculoskeletal symptoms; two-thirds each had neuropsychiatric or peripheral nervous system symptoms. Patterns of symptoms and the extent of association were similar among the three most commonly reported (and used) fluoroquinolones, levofloxacin, ciprofloxacin, and moxifloxacin. Given the large numbers of fluoroquinolone prescriptions over the study period, the risk of the fluoroquinolone disability syndrome is likely exceedingly low.

DRUG INTERACTIONS — Fluoroquinolones interact with a variety of other drugs. This section will review the most important or frequent interactions. A complete listing is provided separately for each fluoroquinolone (see appropriate drug information topic reviews by searching on the drug name). In addition, details about specific interactions can be found using the Lexicomp drug interactions tool included within UpToDate.

●Most fluoroquinolones prolong the QT interval and should not be given in combination with other QT-prolonging medications. (See 'QT interval prolongation' above.)

●Ciprofloxacin inhibits hepatic cytochrome P450 isoenzyme 1A2, which can impair the elimination of substrate drugs (eg, clozapine, erlotinib, ibrutinib, ropinirole, tizanidine, theophylline, caffeine, and methylxanthines) [121,122]. Generally, ciprofloxacin should be avoided for patients taking these medications; if coadministration is unavoidable, dosing of substrate drugs should be reduced or levels monitored. Norfloxacin can also increase theophylline levels, but it is unclear if this is due to cytochrome P450 isoenzyme inhibition. Other fluoroquinolones do not inhibit or induce cytochrome P450 enzymes or xanthine metabolism to a clinically relevant extent (table 1).

●Nonsteroidal anti-inflammatory drugs (NSAIDs) may augment the central nervous stimulant effects of fluoroquinolones by displacing neurotransmitter gamma-aminobutyric acid from its receptors, potentially lowering the seizure threshold [69]. The extent to which concurrent use of quinolones with NSAIDs results in central nervous system toxicities is unclear, but patients receiving both classes of drugs should be cautioned about and monitored for these adverse effects.

●Rifampin and the long-acting rifamycin, rifapentine, lower the plasma concentration of moxifloxacin [123,124]. This interaction is potentially an important consideration when formulating treatment regimens for tuberculosis and other mycobacterial infections.

Other drug interactions have been studied less extensively. Ciprofloxacin has had effects on the pharmacokinetics of cyclosporine. Enoxacin and ciprofloxacin have been shown to reduce the clearance of the less active R-enantiomer of warfarin but have no clinically important effect on the more active S-enantiomer [125].

SUMMARY

●Characteristics of fluoroquinolones − Fluoroquinolones are bactericidal antibiotics with broad spectrum antimicrobial activity and many advantageous pharmacokinetic properties including high oral bioavailability and large volume of distribution (table 1). (See 'Introduction' above and 'Mechanism of action' above and 'Pharmacokinetics' above.)

●Spectrum of activity − The spectrum of activity includes aerobic, enteric gram-negative bacilli (eg, Escherichia coli) and many common respiratory pathogens, including atypical bacteria. Some fluoroquinolones are also active against Pseudomonas species, selected gram-positive organisms, anaerobes, and mycobacteria. (See 'Spectrum of activity' above.)

•Ciprofloxacin primarily targets gram-negative bacilli, including Pseudomonas aeruginosa.

•Levofloxacin, moxifloxacin, and delafloxacin have increased activity against gram-positive organisms (eg, Streptococcus pneumoniae) and reduced activity against P. aeruginosa when compared with ciprofloxacin.

•Moxifloxacin additionally has activity against some anaerobes and is most active against mycobacteria compared with other fluoroquinolones.

•Delafloxacin (the newest fluoroquinolone) also has activity against anaerobes and is the only fluoroquinolone with reliable activity against methicillin-resistant Staphylococcus aureus (MRSA). However, clinical experience with delafloxacin is limited.

●Antimicrobial resistance − Resistance to fluoroquinolones is growing worldwide and is commonly reported in most target bacteria, with the exceptions of S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Resistance mechanisms can be chromosomally encoded or plasmid mediated. Plasmid-mediated mechanisms are almost always associated with resistance to other antibiotics. (See 'Antimicrobial resistance' above.)

●Reserving use for complicated infections − Because of rising resistance rates, growing knowledge of potentially serious adverse effects (including Clostridioides difficile infection), and drug interactions, use of fluoroquinolones is generally reserved for complicated infections in which the benefits of use clearly outweigh the risks. (See 'Benefits and risks of use' above.)

●Avoiding use in children and pregnant and lactating women − Fluoroquinolones should generally be avoided in pregnant women, lactating women, and children, unless a safer alternative is not available. This avoidance is due to the potential for musculoskeletal toxicity in developing fetuses and children. (See 'Pregnancy and breastfeeding' above and 'Children' above.)

●Adverse effects − The most common adverse effects are mild and involve the gastrointestinal tract (eg, nausea) and central nervous system (eg, headache and dizziness). Less common but potentially severe adverse effects include QT interval prolongation, tendinopathies, dysglycemia, and putatively retinal detachment and aortic aneurysm or dissection. (See 'Adverse effects' above.)

●Drug interactions − Fluoroquinolones interact with multiple other medications. Additional detail can be found in the Lexicomp database and drug interactions tool included within UpToDate.

•Coadministration of other medications that prolong the QT interval should be avoided because of the risk of potentially fatal arrhythmias (table 2).

•Dairy, antacids, multivitamins containing zinc, certain medications (eg, sucralfate), and other sources of divalent cations can substantially decrease oral absorption. Concurrent use should be avoided or these substances should be given several hours apart from the fluoroquinolone in order to avoid their interaction.