Fluoroquinolone Ciprofloxacin Cyclic Lipopeptide Daptomycin
Mechanism of Action
Ciprofloxacin inhibits two bacterial enzymes: DNA gyrase and topoisomerase IV. Both are needed for DNA replication and cell division. DNA gyrase converts closed circular DNA into a supercoiled configuration. In the absence of supercoiling, DNA replication cannot take place. Topoisomerase IV helps separate daughter DNA strands during cell division. Because the mammalian equivalents of DNA gyrase and topoisomerase IV are largely insensitive to fluoroquinolones, cells of the host are spared. Ciprofloxacin is rapidly bactericidal.
Antimicrobial Spectrum
Ciprofloxacin is active against a broad spectrum of bacteria, including most aerobic gram-negative bacteria and some gram-positive bacteria. Most urinary tract pathogens, including Escherichia coli and Klebsiella species, are sensitive. The drug is also highly active against most bacteria that cause enteritis (e.g., Salmonella and Shigella species, Campylobacter jejuni, E. coli). Other sensitive organisms include Bacillus anthracis, Pseudomonas aeruginosa, Haemophilus influenzae, meningococci, and many streptococci. Activity against anaerobes is fair to poor. Clostridium difficile is resistant.
Bacterial Resistance
Resistance to fluoroquinolones has developed during treatment of infections caused by Staphylococcus aureus, Serratia marcescens, C. jejuni, P. aeruginosa, and N. gonorrhoeae. Two mechanisms appear responsible: (1) alterations in DNA gyrase and topoisomerase IV and (2) increased drug export. Bacteria do not directly inactivate fluoroquinolones, and there have been no reports of resistance through transfer of R factors.
Pharmacokinetics
Ciprofloxacin may be given by PO or IV route. After oral dosing, the drug is absorbed rapidly but incompletely. High concentrations are achieved in urine, stool, bile, saliva, bone, and prostate tissue. Drug levels in cerebrospinal fluid remain low. Ciprofloxacin has a plasma half-life of about 4 hours. Elimination is by hepatic metabolism and renal excretion.
Therapeutic Uses
Ciprofloxacin is approved for a wide variety of infections. Among these are infections of the respiratory tract, urinary tract, gastrointestinal (GI) tract, bones, joints, skin, and soft tissues. Also, ciprofloxacin is a preferred drug for preventing anthrax in people who have inhaled anthrax spores. Because ciprofloxacin is active against a variety of pathogens and can be given orally, the drug represents an alternative to parenteral treatment for many serious infections. Owing to high rates of resistance, ciprofloxacin is a poor choice for staphylococcal infections. The drug is not useful against infections caused by anaerobes.
Because of concerns about tendon injury (see later), systemic ciprofloxacin is generally avoided in children younger than 18 years. Nonetheless, the drug does have two approved pediatric uses: (1) treatment of complicated urinary tract and kidney infections caused by E. coli and (2) postexposure treatment of inhalational anthrax.
Adverse Effects
Ciprofloxacin can induce a variety of mild adverse effects, including GI reactions (nausea, vomiting, diarrhea, abdominal pain) and central nervous system (CNS) effects (dizziness, headache, restlessness, confusion). Candida infections of the pharynx and vagina may develop during treatment. Very rarely, seizures have occurred. In older adults, ciprofloxacin poses a significant risk for confusion, somnolence, psychosis, and visual disturbances.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
Antibacterial Drugs
| Life Stage | Patient Care Concerns |
| Infants | See later entry “Breastfeeding women.” |
| Children/adolescents | Ciprofloxacin and levofloxacin are the only fluoroquinolones approved for use in children. Because of concerns regarding tendon injury, fluoroquinolones are generally avoided in this population. |
| Pregnant women | Although data reveal little potential for fluoroquinolone toxicity in the fetus, these data are limited. Risks and benefits must be considered for administration during pregnancy. |
| Breast-feeding women | Effects of fluoroquinolones on the nursing infant are largely unknown. Consider other medications if possible. |
| Older adults | Fluoroquinolones are generally well tolerated in older adults. Calculate creatinine clearance for safe dosing. |
Black Box Warning: Fluroquinalones and Tendon Rupture
Rarely, ciprofloxacin and other fluoroquinolones have caused tendon rupture, usually of the Achilles tendon. The incidence is 1 in 10,000 or less. People at highest risk are those 60 years and older, those taking glucocorticoids, and those who have undergone heart, lung, or kidney transplantation.
Fluoroquinolones damage tendons by disrupting the extracellular matrix of cartilage in immature animals. A similar mechanism may underlie tendon rupture in humans. Because tendon injury is reversible if diagnosed early, fluoroquinolones should be discontinued at the first sign of tendon pain, swelling, or inflammation. In addition, patients should refrain from exercise until tendinitis has been ruled out. Although there are no controlled studies on the use of ciprofloxacin during pregnancy or lactation, limited data indicate that such use poses little or no risk for tendon damage to either the fetus or nursing infant. Because of the relative lack of data, alternative drugs should be given if possible.
Ciprofloxacin and other fluoroquinolones pose a risk for phototoxicity (severe sunburn), characterized by burning, erythema, exudation, vesicles, blistering, and edema. These can occur after exposure to direct sunlight, indirect sunlight, and sunlamps—even if a sunscreen has been applied. Patients should be warned about phototoxicity and advised to avoid sunlight and sunlamps. People who must go outdoors should wear protective clothing and apply a sunscreen. Ciprofloxacin should be withdrawn at the first sign of a phototoxic reaction (e.g., burning sensation, redness, rash).
Ciprofloxacin and other fluoroquinolones increase the risk for developing C. difficile infection (CDI), a potentially severe infection of the bowel. CDI results from killing off intestinal bacteria that normally keep C. difficile in check.
Black Box Warning: Ciprofloxacin and Myasthenia Gravis
Ciprofloxacin and other fluoroquinolones can exacerbate muscle weakness in patients with myasthenia gravis. Accordingly, patients with a history of myasthenia gravis should not receive these drugs.
Drug and Food Interactions
Cationic Compounds
Absorption of ciprofloxacin can be reduced by compounds that contain cations. Among these are (1) aluminum- or magnesium-containing antacids, (2) iron salts, (3) zinc salts, (4) sucralfate, (5) calcium supplements, and (6) milk and other dairy products, all of which contain calcium ions. These cationic agents should be administered at least 6 hours before ciprofloxacin or 2 hours after.
Elevation of Drug Levels
Ciprofloxacin can increase plasma levels of several drugs, including theophylline (used for asthma), warfarin (an anticoagulant), and tinidazole (an antifungal drug). Toxicity could result. For patients taking theophylline, drug levels should be monitored and the dosage adjusted accordingly. For patients taking warfarin, prothrombin time should be monitored and the dosage of warfarin reduced as appropriate.
Preparations, Dosage, and Administration
Preparations
Ciprofloxacin is available for PO and IV administration. For PO therapy, ciprofloxacin is supplied in immediate-release tablets (100, 250, 500, and 750 mg) sold as Cipro, a 500 mg/5 mL suspension, and extended-release tablets (500 and 1000 mg) sold as Cipro XR. For IV therapy, ciprofloxacin is supplied in solution (400 mg/200 mL) sold as Cipro I.V.
Dosage and Administration
Oral.
Dosing may be done with or without food. The dosage for complicated UTIs is 250 or 500 mg 2 times a day, usually for 7 to 14 days. For other infections, dosages range from 500 to 750 mg 2 times a day. Dosage should be reduced for patients with renal impairment. Dosages for anthrax prevention are presented later.
Intravenous.
Intravenous dosages range from 200 to 400 mg every 12 hours. Dosages for anthrax prevention are presented later.
Inhalational Anthrax.
Ciprofloxacin is used to reduce the incidence of anthrax or prevent anthrax progression in people who have inhaled B. anthracis spores. The dosage for adults is 500 mg PO (or 400 mg IV) every 12 hours for 60 days. The dosage for children is 15 mg/kg PO (or 10 mg/kg IV) every 12 hours for 60 days (with the provision that individual oral doses not exceed 500 mg, and individual IV doses not exceed 400 mg).
Other Systemic Fluoroquinolones
Ofloxacin
Basic Pharmacology
Ofloxacin is similar to ciprofloxacin in mechanism of action, antimicrobial spectrum, therapeutic applications, and adverse effects. Like ciprofloxacin, the drug is administered orally. Bioavailability is high (90%) in the absence of food and is greatly reduced in the presence of food. Ofloxacin is widely distributed to tissues and excreted in the urine. Like ciprofloxacin, ofloxacin can cause a variety of mild adverse effects, including nausea, vomiting, headache, and dizziness. In addition, ofloxacin may intensify sensitivity to sunlight, thereby increasing the risk for severe sunburn. Like other fluoroquinolones, ofloxacin can (1) exacerbate muscle weakness in patients with myasthenia gravis; (2) increase the risk for CDI; and (3) cause tendinitis and tendon rupture, especially among those older than 60 years, those taking glucocorticoids, and those who have undergone a heart, lung, or kidney transplantation. Ofloxacin elevates plasma levels of warfarin, but, in contrast to ciprofloxacin, has little effect on levels of theophylline. Absorption of oral ofloxacin is reduced by cationic substances: milk, milk products, sucralfate, iron and zinc salts, and magnesium- and aluminum-containing antacids.
Preparations, Dosage, and Administration
Ofloxacin is available in tablets (200, 300, and 400 mg) for dosing with or without food. The usual daily dosage is 200 to 400 mg every 12 hours. Treatment duration ranges from 1 day to 6 weeks. Dosage should be reduced in patients with renal impairment.
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