e1-20: Quinolones

The quinolones are synthetic analogs of nalidixic acid with a broad spectrum of activity against many bacteria. The mode of action of all quinolones involves inhibition of bacterial DNA synthesis by blocking the enzyme DNA gyrase.

The earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) did not achieve therapeutic systemic antibacterial levels after oral intake and thus were useful only as urinary antiseptics. The fluoroquinolone derivatives (ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin) have more potent antibacterial activity and achieve therapeutic levels in blood and tissues. Delafloxacin, a novel fluoroquinolone, accumulates at acidic pH and may offer an advantage against intracellular infections.

With some exceptions, the spectrum of activity is similar among the available agents. In general, these medications have moderate to excellent activity against Enterobacteriaceae but are also active against other gram-negative bacteria such as Haemophilus, Neisseria, Moraxella, Brucella, Legionella, Salmonella, Shigella, Campylobacter, Yersinia, Vibrio, and Aeromonas organisms. Fluoroquinolone resistance to E coli, including ESBL-producing pathogens, has steadily increased, with many centers reporting up to 20–30% resistance. Ciprofloxacin, levofloxacin, and delafloxacin have activity against P aeruginosa, but resistance limits their utility against this pathogen. None of these agents have reliable activity against S maltophilia or B cepacia or against certain genital tract pathogens, such as Mycoplasma hominis, U urealyticum, and Chlamydia. M tuberculosis is sensitive to the quinolones, as is M fortuitum and Mycobacterium kansasii.

In general, the fluoroquinolones are less potent against gram-positive bacteria when compared with gram-negative organisms. The exception is delafloxacin, which shows enhanced activity against gram-positive organisms, including levofloxacin-nonsusceptible methicillin-resistant S aureus. Gemifloxacin, levofloxacin, and moxifloxacin also have excellent gram-positive activity, including against streptococci, pneumococci, and S aureus and S epidermidis, as well as some methicillin-resistant strains. However, the emergence of resistant strains of staphylococci, particularly with monotherapy, has limited the use of these medications in infections caused by these organisms. Use of fluoroquinolones to treat tuberculosis in South Africa has been associated with emergence of invasive disease due to levofloxacin-nonsusceptible S pneumoniae. T pallidum and Nocardia are resistant to all fluoroquinolones.

Moxifloxacin and delafloxacin demonstrate modest activity against many of the significant anaerobic pathogens, including B fragilis and mouth anaerobes, but only moxifloxacin is approved for the treatment of intra-abdominal infection. Moxifloxacin also provides the most reliable coverage of M tuberculosis.

After oral administration, the fluoroquinolones are well absorbed and widely distributed in body fluids and tissues and are concentrated intracellularly. Fluoroquinolones bind some heavy metals; thus, absorption is inhibited when administered concomitantly with iron, calcium, and other multivalent cations. Optimal oral bioavailability is achieved if fluoroquinolones are taken 1 hour before or 2 hours after meals. The serum half-life ranges from 4 hours (ciprofloxacin) to 12 hours (moxifloxacin). Most are eliminated via mixed renal and nonrenal pathways. As a result, only modest accumulation takes place in the presence of kidney disease. Exceptions are ofloxacin and levofloxacin, which are primarily dependent upon the kidney for elimination.

While fluoroquinolones previously were considered medications of choice in the empiric treatment of uncomplicated UTI, the IDSA now recommends against using these agents as medications of choice for the treatment of UTI in women. Fluoroquinolones are not recommended for the treatment of acute bacterial sinusitis; however, the “respiratory fluoroquinolones” (gemifloxacin, levofloxacin, moxifloxacin) are recommended by the IDSA for high-risk patients with community-acquired pneumonia. The respiratory fluoroquinolones are exquisitely active against the most common community-acquired pneumonia pathogens, including S pneumoniae, H influenzae, and the “atypical pathogens,” eg, Legionella, Mycoplasma, and Chlamydophila pneumoniae.

Quinolones have excellent penetration into prostatic secretions and effective in the treatment of acute and chronic bacterial prostatitis due to susceptible pathogens.

Fluoroquinolones have been used successfully to treat complicated skin and soft tissue infections and osteomyelitis caused by gram-negative organisms. Ciprofloxacin, 500–750 mg orally twice daily for at least 6 weeks, has been effective in the treatment of malignant otitis externa.

While previously reliably active against Campylobacter, extensive fluoroquinolone resistance has resulted in macrolides now replacing them as drugs of choice. However, fluoroquinolones are active against the other major bacterial pathogens associated with diarrhea (Salmonella, Shigella, toxigenic E coli). Consequently, they have been used for the therapy of traveler's diarrhea as well as domestically acquired acute diarrhea.

Ciprofloxacin, similar to rifampin, has been used to eradicate meningococci from the nasopharynx of carriers.

Fluoroquinolones are effective for prophylaxis against gram-negative infections in the neutropenic patient; however, development of resistance is well-documented.

As discussed previously, gemifloxacin, levofloxacin, and moxifloxacin, the “respiratory fluoroquinolones,” are useful in the treatment of community-acquired pneumonia. However, their broad aerobic gram-negative spectrum and the rapid emergence of resistance suggests that they should be reserved for the treatment of refractory infections or high-risk patients, including those with comorbidities or with recent receipt of beta-lactam antibacterials. One setting in which ciprofloxacin is indicated for the therapy of lower respiratory tract infections is in cystic fibrosis, in which P aeruginosa is the predominant pathogen. However, the increasing rate of pseudomonal resistance to ciprofloxacin and levofloxacin has diminished their utility for this indication.

The most prominent adverse effects of the quinolones are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, seizures, insomnia, impaired liver function, and skin rashes have been observed as well as more serious reactions such as acute kidney injury, hypoglycemia (especially with gatifloxacin, which has been removed from the US market, and moxifloxacin), and anaphylaxis. With the exception of delafloxacin, all fluoroquinolones likely prolong the QT interval; it is unclear whether any one agent is implicated more than another. Quinolones should be used cautiously in patients with a history of prolonged QT or concomitant use of drugs known to prolong QT. Prolongation of the prothrombin time and the international normalized ratio has been observed in some patients receiving stable doses of warfarin after ciprofloxacin has been given, but this interaction is unpredictable and modest if it exists at all. Tendinitis and tendon rupture have been reported with quinolone agents. The proposed mechanisms for this adverse event are not completely understood. It is known that fluoroquinolones decrease type I collagen, elastin, fibronectin, and beta-1-integrin and inhibit cell proliferation and synthesis of matrix ground substance (fibroblast metabolism). However, the true mechanism for this complication is unclear. Nonetheless, risk factors are well known and include concomitant corticosteroid use, age older than 60 years, kidney dysfunction, and organ transplant. The FDA has required a black box warning for tendinopathy. Patients experiencing musculoskeletal symptoms while receiving fluoroquinolones should discontinue therapy. In addition, the FDA has issued warnings regarding peripheral neuropathy. Its onset can be within a few days of initiation of therapy and can be permanent in some patients. Lastly, while rare, fluoroquinolones are associated with an increased rate of aortic aneurysm and dissection, and the FDA recommends against use of fluoroquinolones in patients at high risk for these complications, including older adult patients and those with a history of high blood pressure, vessel blockages, and other genetic disorders.