Continuing Education Activity

Quinolones are a class of broad-spectrum antibiotics used in the management and treatment of many different bacterial infections. This activity reviews the indications, contraindications, mechanism of action, adverse events, and other critical elements of quinolone therapy in the clinical setting pertinent for healthcare team members in managing the care of patients with bacterial infections treated with quinolones and their potential sequelae.

Objectives:

• Identify the mechanism of action of quinolones.
• Describe the potential adverse effects of quinolones.
• Summarize some situations in which quinolone use should be avoided or heavily monitored for potential severe adverse events.
• Explain the importance of antibiotic stewardship and how it affects antimicrobial selection as it pertains to improving care coordination among the interprofessional team when initiating antibiotic therapy with quinolones.

Indications

Quinolones are a class of broad-spectrum antibiotics with excellent oral bioavailability and can be used to treat a wide variety of bacterial infections. Their clinical utility is restricted, particularly in the outpatient setting, due to their potential for severe side effects. Due to these safety concerns, quinolones are not recommended as first-line agents by the FDA if there are other available antibiotic options with less potential for severe adverse events. There are currently four generations of quinolones. While initial quinolones were effective only against Gram-negative bacteria, succeeding generations gained activity against Pseudomonas sp., Gram-positive, and atypical bacterial strains. Many different quinolones have undergone development, and among them, the ones currently approved by the FDA for systemic use include moxifloxacin, ciprofloxacin, gemifloxacin, levofloxacin, delafloxacin, and ofloxacin. A few key differences exist in the spectrum of activity between the quinolones. Ciprofloxacin is ineffective against S. pneumoniae. Moxifloxacin lacks sufficient activity against Pseudomonas aeruginosa but is effective in treating anaerobes (along with delafloxacin). Delafloxacin is the only quinolone effective against methicillin-resistant S. aureus (MRSA).[1]

FDA-approved indications for certain quinolones in adults include treatment of urinary tract infections, pyelonephritis, sexually transmitted infections, prostatitis, gastrointestinal and intraabdominal infections, skin and soft tissue infections, community-acquired and nosocomial pneumonia, and bone and joint infections. Additionally, quinolones such as moxifloxacin, gatifloxacin, and levofloxacin are seeing increased off-label usage in the treatment of drug-resistant tuberculosis or cases of intolerance to other anti-tuberculosis drugs.[2][3][4][5]

Pediatric-approved uses for quinolones are limited due to their potential adverse effects on immature cartilage. Hence, the FDA has only approved the use of specific quinolones (ciprofloxacin and levofloxacin) for the treatment of inhalation anthrax and the plague. Ciprofloxacin is also FDA-approved for the pediatric treatment of complicated urinary tract infections. Other non-FDA-approved indications for quinolone use in pediatric patients include treating multidrug-resistant infections (particularly in cystic fibrosis patients), intra-abdominal infections, and complicated or recurrent urinary tract infections.[6][7]

Further studies are currently underway to extend the use of quinolones into other therapeutic fields, such as cancer treatment and as an anti-protozoan agent.[3][8][9][10]

Mechanism of Action

Quinolones are bactericidal antibiotics that directly kill bacterial cells. They act on bacterial type II topoisomerases, DNA gyrase, and topoisomerase IV, inhibiting their function and converting them into toxic enzymes that produce permanent double-stranded breaks in the bacterial chromosome. DNA topoisomerases are essential for normal physiologic functions of the bacteria, such as DNA replication, transcription, recombination, and condensed DNA remodeling. They function by performing transient single- and double-stranded breaks, which help to facilitate their fundamental roles in removing torsional stress and knots in the bacterial chromosome that form during regular nucleic acid processes. Quinolone antibiotics stabilize the enzyme-DNA cleavage complexes by inhibiting DNA ligation. When the gyrase and topoisomerase IV create breaks in the bacterial chromosome to perform their physiological functions, it leads to fragmentation of the bacterial chromosome. When the DNA strand breaks overwhelm the cell’s ability to repair the DNA, it leads to cell death.[2][3][9][11]

Growing bacterial resistance against quinolones is a rising concern in antibiotic use. There have been three main mechanisms of resistance documented, include target-mediated, plasmid-mediated, and chromosome-mediated resistance. The most common is target-mediated resistance, in which specific mutations in the quinolone target enzymes weaken interactions between the quinolone active site and the enzyme. Plasmid-mediated resistance has become increasingly common, allowing for the horizontal spread of extrachromosomal elements encoding for proteins that can either disrupt quinolone-enzyme interactions, alter the metabolism of the drug, or increase the efflux of the drug from the cell. While it usually only confers a lower level of resistance, it can lead to the continued selection of mutants with even higher levels of quinolone resistance. Chromosome-mediated resistance involves either the underexpression of porins, which normally allow quinolones to enter the cell, or the overexpression of efflux pumps that can remove quinolones from the cell, decrease their intracellular concentrations, and decreasing their efficacy against the bacteria.[2][3][12]

Administration

Quinolones are most often administered through oral and intravenous (IV) routes, though topical formulations in the form of ophthalmic solutions also exist. Oral quinolones are rapidly absorbed in the gastrointestinal tract and possess a high oral bioavailability, allowing the oral and IV routes of administration to be used interchangeably for certain quinolones.[13][14] Though quinolones are widely distributed throughout the body, the degree of penetration into tissues and bodily fluids depends on the individual quinolone. For example, while levofloxacin penetration into the cerebrospinal fluid is relatively poor, moxifloxacin has been noted to have good penetration into the cerebrospinal fluid, allowing it to be used effectively for tuberculosis meningitis.[15] Most quinolones are predominantly eliminated unchanged by the kidney via glomerular filtration and some degree of tubular secretion.[16][17] They are typically eliminated through the hepatic and trans-intestinal routes to a lesser extent, though the degree to which they undergo elimination through these routes depends on the individual quinolones.[18][19] The only quinolone predominantly eliminated by the liver is pefloxacin.[20][21]

Concurrent consumption of food (including dairy products) with oral quinolones has minimal effect on its absorption and activity.[20][22] However, oral absorption of quinolones substantially decreases when taken together with other medications containing metallic cations due to the chelation that occurs between quinolone functional groups and the cations, leading to the formation of an insoluble compound.[23][24] These can include multivitamin supplements containing iron or zinc and magnesium or aluminum-based antacids. The degree of absorption impairment depends on the individual quinolone, but generally, the recommendation is to stagger medications to avoid these interactions, with many studies suggesting that quinolones be taken either 1 to 2 hours before or 3 to 4 hours after the administration of metallic cation compounds.[23][24] One apparent exception to this interaction is calcium supplements, which were shown to only slightly reduce the rate of absorption of moxifloxacin to a clinically insignificant degree.[25][26][27][28][29][30]

Adverse Effects

The most common reported adverse effects of quinolones include gastrointestinal events such as nausea, vomiting, and diarrhea. Antibiotic-associated colitis is a common sequela of quinolone use due to its effect on the gut flora. The use of quinolones may result in higher rates of clostridium difficile infection compared to other antibiotics.[31][32] Arthralgias are also a common adverse effect, especially in the pediatric population, and self-resolve after discontinuing therapy. Some patients may also experience serious anaphylactic and skin reactions, ranging from a minor rash and/or photosensitivity to Stevens-Johnson syndrome or toxic epidermal necrolysis.[33][34]

Rare adverse events of note are tendinopathies and tendon rupture associated with quinolone use. Tendon rupture is often bilateral and is most commonly associated with the Achilles tendon. When using quinolones for extended periods, more severe adverse events like tendon rupture, nerve damage, and fluoroquinolone-associated disability syndrome can occur, causing damage that researchers theorize to be potentially permanent.[6][7]

Reports exist for a large range of serious adverse events for novel quinolone agents, some of which have led to the withdrawal of these agents from the US market.[33][32] These include QTc interval prolongation, hepatotoxicity, dysglycemia, neuropathy, nephropathy, ocular toxicity, aortic aneurysm/dissection, aortic and mitral regurgitation, phototoxicity, hematologic toxicity, immunological effects, and exacerbation of myasthenia gravis.[35][36] Central nervous system-related adverse effects such as confusion, weakness, headache, anxiety, loss of appetite, tremor, or depression are also of particular concern, especially in the elderly, where they can be mistakenly attributed to other conditions.[37][38][39]

Contraindications

Quinolones have been relatively contraindicated for use in pregnant women and children due to the nature of their mechanism of action as well as their arthropathic potential in children.

In multiple animal studies, quinolones have demonstrated to accumulate in the immature articular cartilage of juvenile animals, leading to the development of arthropathies and damage to the cartilage of weight-bearing joints. There are concerns regarding the potential of permanent damage to growing cartilage in human children, but there are only limited safety studies on quinolone use in pediatric patients. However, of the studies performed, all cases of arthropathy or other related musculoskeletal adverse events in children appear to self-resolve after discontinuation of the drug.[6][7] Additionally, there is no current data regarding severe adverse events such as tendinopathy or tendon rupture occurring in children. Regardless, as more extensive studies are still necessary, quinolones should be used cautiously in pediatric patients, given their propensity to accumulate in growing cartilage.[32][40]

Quinolones act by impairing DNA synthesis through the inhibition of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). In pregnant women, there are theoretical concerns that the quinolones could potentially inhibit DNA synthesis in the growing fetus, leading to fetal organ agenesis, mutagenesis, and carcinogenesis.[11] Though animal models have demonstrated possible teratogenic effects of quinolones, research has not yet found an association between quinolone use in the first trimester and major fetal malformations. Also, quinolone use in the first trimester of pregnancy was not associated with risk for preterm delivery or stillbirth. However, one case-control study did demonstrate an associated increased risk of spontaneous abortion with quinolone use. In light of these potential risks, quinolone use requires caution in pregnant women and not as a first-line agent, especially for those still in the first trimester of pregnancy.[41][42][43]

Monitoring

When prescribing quinolones, many factors must merit consideration to avoid the many potential severe adverse events that can result from quinolone use. Of major note is tendon rupture associated with quinolone use. Risk factors identified for tendon rupture include advanced age (>60 years old), concurrent steroid therapy, and certain conditions such as hypercholesterolemia, gout, rheumatoid arthritis, end-stage renal disease, and history of previous renal transplantation. Athletes are also among the higher-risk individuals for tendon rupture and, as such, must have careful monitoring for tendonitis when taking quinolones or otherwise opt for another antibiotic, if available.[6][20][44]

Multiple studies have observed an increase in the elimination half-life of various quinolones with decreasing creatinine clearance.[45] As such, patients with renal impairment should have their quinolone dosage adjusted according to their renal function.[46][47] While recommendations across studies vary, extended dosing intervals should be considered once creatinine clearance falls below 50 mL/min, and dosages generally require adjustment in patients with a creatinine clearance of less than 30 mL/min.[48][49] Quinolones are minimally removed from plasma during both hemodialysis and continuous ambulatory peritoneal dialysis, and thus supplemental doses are not necessary following dialysis.[50][51][52]

QTc interval prolongation is an adverse event that usually occurs with newer quinolones. Though certain quinolones display more cardiotoxicity than others, it is important to consider the possibility of QTc prolongation due to the potentially severe nature of this event, regardless of which quinolone the patient is using. As such, quinolones are not recommended for patients on other medications that can also cause QTc interval prolongation as they risk developing Torsades de pointes, a severe life-threatening arrhythmia. These medications may include antiarrhythmics, antifungals, antipsychotics, antidepressants, and certain anti-tuberculosis drugs. Clinicians should avoid quinolone use in patients with known QTc prolongation as well as those with hypokalemia. If a patient must take these medications concurrently, they need careful monitoring with an electrocardiogram.[7][20][35]

Toxicity

If a patient begins to display signs of potential tendinitis or tendon rupture, the recommendation is to immediately discontinue the quinolone and avoid using the affected joint. Such signs can include tendon pain, swelling, or inflammation. It is also recommended to discontinue quinolones and initiate immediate supportive measures in cases with serious adverse events, including Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatotoxicity, and anaphylaxis.[52]

Enhancing Healthcare Team Outcomes

Quinolones are a commonly prescribed class of antibiotics because of their broad spectrum of activity and high oral bioavailability. As such, they are prone to overuse, leading to the further development of antimicrobial resistance and undesirable side effects for patients. While empiric use of quinolones is often sufficient to treat patients on an outpatient basis, physicians must follow up with patients to confirm the effectiveness of the treatment and ensure the full completion of their antibiotic course. In cases where culture and sensitivity are available, patients should be placed on more targeted antibiotics to allow for the discontinuation of quinolones.

Before prescribing a quinolone, the clinician, pharmacist, or nurse should perform a thorough, detailed history. Renal dysfunction, history of arrhythmias, and underlying medical conditions that may predispose to more adverse events with quinolone use should especially merit consideration. If a patient is at high risk for severe adverse events, clinicians should consider utilizing another antibiotic if possible. A pharmaceutical consult may be helpful to discuss alternative antibiotics, verify dosing, and identify potential drug-drug interactions. Both the physician and the pharmacist should educate the patient and their care providers on the signs and symptoms of severe side effects that can occur with quinolone use. This way, the interprofessional healthcare team can be alerted more quickly regarding severe adverse events, and the drug can be promptly discontinued and supportive care given. [Level 5]