Portal de Periódicos da CAPES

Antibiotic Therapy for Musculoskeletal Infections

2001; Wolters Kluwer; Volume: 83; Issue: 12 Linguagem: Inglês

10.2106/00004623-200112000-00017

1535-1386

Jon T. Mader, Jue Wang, Jason H. Calhoun,

Antibiotics Pharmacokinetics and Efficacy

Antibiotics are grouped into categories on the basis of their mechanisms of action. These categories include cell-wall active antibiotics, ribosomal active antibiotics, RNA active antibiotics, DNA active antibiotics, antimetabolites, and the reducing compounds. Cell-Wall Active Antibiotics The cell-wall active antibiotics include penicillins, β-lactamase inhibitors, cephalosporins, other β-lactam antibiotics, and vancomycin. β-lactamase inhibitors are combined with the penicillins to enhance the antibiotic activity against β-lactamase-producing organisms. Penicillins The penicillin class of antibiotics is frequently used for the treatment of musculoskeletal infections. The penicillins can be divided into general groups on the basis of their antibacterial activity. The major penicillin groups of interest to an orthopaedic surgeon are natural penicillins, aminopenicillins, penicillinase-resistant penicillins, antipseudomonal penicillins (carboxypenicillins), and extended spectrum penicillins (ureidopenicillins). There is overlap among these groups; the differences are usually pharmacological in nature. The major side effects of all of the penicillins are hypersensitivity reactions that range in severity from a rash to anaphylaxis1. Immediate hypersensitivity reactions have been reported to occur in 0.0004% to 0.15% of patients2. Of those patients, urticaria occurs in 1% to 5% and a rash occurs in 2% to 9%. Hemolytic anemia and central nervous system toxicities can also occur with penicillin administration. Serum sickness rarely occurs with penicillins. Additionally, exfoliative dermatitis and erythema multiforme are rare forms of allergic reactions to penicillin. Penicillin G is the major natural penicillin. Although penicillin G has a half-life of thirty to sixty minutes, it can be combined with procaine or benzathine to produce a repository penicillin. Penicillin is the drug of choice for the treatment of Streptococcus pyogenes, Streptococcus agalactiae, and Clostridium perfringens. In addition, penicillin has a good anaerobic spectrum of activity except for the Bacteroides fragilis group. Streptococcus pneumoniae continues to become more resistant to penicillin. Currently, Streptococcus pneumoniae has an intermediate resistance to penicillin in 15% of cases and a high-level resistance to penicillin in 15%. The major side effects of the natural penicillins are immediate hypersensitivity reactions, including anaphylaxis, bronchospasm, and hives, as well as delayed reactions, including skin rashes3. Other potential side effects are renal failure, Coombs-positive hemolytic anemia, and seizure activity, which usually occurs with aqueous penicillin doses of >20 ¥ 106 U/day. The parenteral penicillinase-resistant penicillins are methicillin, nafcillin, and the isoxazolyl penicillins (including oxacillin, cloxacillin, dicloxacillin, and flucloxacillin). The most active parenteral semisynthetic penicillins are nafcillin and oxacillin. These drugs are resistant to Staphylococcal β-lactamase and are used when methicillin-sensitive Staphylococcus aureus is present or suspected. The semisynthetic penicillins are also active against Streptococcus pyogenes and Streptococcus pneumoniae. However, they have no activity against Enterococcus species or gram-negative bacilli. Methicillin is associated with the greatest potential for producing interstitial nephritis4. Nafcillin and oxacillin may cause interstitial nephritis, leukopenia, and reversible hepatic dysfunction5,6. Cloxacillin and dicloxacillin are the oral semisynthetic penicillins of choice in the United States, and they have fewer side effects than the parenteral semisynthetic penicillins. The major aminopenicillins include ampicillin and amoxicillin. Ampicillin may be given parenterally or orally, whereas amoxicillin may be given only orally. The antibacterial activities of the aminopenicillins are similar. They are the antibiotics of choice for the treatment of sensitive Enterococcus species(Enterococcus faecalis andEnterococcus faecium)7. The aminopenicillins are also active against many highly susceptible gram-negative rods, such as Escherichia coli and Proteus mirabilis. They are not stable to β-lactamase and are less active than penicillin G against Streptococcus pyogenes and Streptococcus agalactiae. While the aminopenicillins may cause skin rashes, an idiosyncratic rubella-form rash occurs in 99% of patients who have mononucleosis and are given the aminopenicillins. Ticarcillin (carboxypenicillin) is an antipseudomonal penicillin. Ticarcillin has a β-lactam ring and is susceptible to β-lactamase of both gram-positive and gram-negative organisms. Ticarcillin has a gram-negative spectrum of activity similar to ampicillin but is more active than ampicillin against Pseudomonas species, Enterobacter species, Serratia species, and certain strains of the Bacteroides fragilis group. Ticarcillin has poor activity against Klebsiella species8. The side effects of this class of penicillins include sodium-loading and bleeding problems secondary to platelet dysfunction9. The extended spectrum penicillins (ureidopenicillins) include mezlocillin and piperacillin. They have an antibacterial spectrum similar to that of ticarcillin. In vitro, these antibiotics are active against Enterococcus species and Streptococcus species, and they inhibit the majority of Klebsiella species. They are also more active than ticarcillin against Haemophilus influenzae and the Bacteroides fragilis group10,11. These drugs act in synergy with the aminoglycosides against Pseudomonas aeruginosa and most of the Enterobacteriaceae. They have the same side effects as ticarcillin, except they cause less sodium-loading and bleeding dysfunction. Penicillins as a group have a number of drug interactions. However, these interactions are generally uncommon. The carboxypenicillins and ureidopenicillins inactivate the aminoglycosides12,13. This drug interaction is seen in patients who have underlying renal dysfunction14,15. Probenecid inhibits tubular secretion of the penicillins and increases the drug half-life of these agents16. b-lactamase Inhibitors β-lactamase of gram-positive species is an exoenzyme. Clavulanic acid, sulbactam, and tazobactam are potent inhibitors of β-lactamase produced by gram-positive and gram-negative organisms17. Clavulanic acid, sulbactam, and tazobactam have been shown to inhibit β-lactamase for a number of clinically important gram-positive organisms, including Staphylococcus aureus and Staphylococcus epidermidis18.β-lactamase of both gram-negative and most anaerobic organisms is situated in the periplasmic space and is chromosome and plasmid-induced19. Clavulanic acid, sulbactam, and tazobactam inhibit β-lactamase of many gram-negative organisms, including Escherichia coli, and most Klebsiella and Bacteroides species. Currently, clavulanic acid is commercially available with amoxicillin (Augmentin; SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania) and ticarcillin (Timentin; SmithKline Beecham Pharmaceuticals). Sulbactam is available with ampicillin (Unasyn; Pfizer, New York, NY). Tazobactam is combined with piperacillin (Zosyn; Lederle, Pearl River, New York). The β-lactam inhibitors enhance the gram-positive coverage and, to a lesser extent, the gram-negative spectrum of these antibiotics. The side effects are the same as those of the penicillin class of antibiotics. Cephalosporins The cephalosporins have been divided into first, second, third, and fourth-generation agents. The first-generation cephalosporins include cephalothin, cephapirin, cephradine, and cefazolin and are active against Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus species. They have limited gram-negative activity but are active against Escherichia coli, Klebsiella species, and Proteus mirabilis. The first-generation cephalosporins are safe antibiotics but are occasionally associated with allergic reactions, drug eruptions, phlebitis, and diarrhea. Cefazolin is the first-generation cephalosporin used by the orthopaedic community for the treatment of staphylococcal infections, including osteomyelitis. The large amounts of β-lactamase produced by Staphylococcus aureus (109 organisms per gram of tissue) inactivate cefazolin20. However, high numbers of Staphylococcus aureus are not the norm in staphylococcal osteomyelitis; £105 organisms per gram of bone are usually found. Cefazolin has a longer half-life and higher serum concentration than the other first-generation cephalosporins21. The remainder of the first-generation cephalosporins are comparable. They are all more stable to β-lactamase than cefazolin is. There are many second-generation cephalosporins, but the major parenteral ones are cefamandole, cefoxitin, cefotetan, and cefuroxime. The major oral cephalosporins are cefuroxime, cefprozil, and loracarbef. The second-generation cephalosporins are somewhat more active against gram-negative organisms than are the first-generation agents, but they are less active than the third-generation agents. Cefoxitin and cefotetan are more active against the anaerobes, especially the Bacteroides fragilis group, than are the first-generation or the other second-generation cephalosporins22. The second-generation cephalosporins have the same toxicity potential as the first-generation cephalosporins with the exception of those that have a methylthiotetrazole side chain. The major third-generation cephalosporins are cefotaxime, ceftriaxone, ceftizoxime, cefoperazone, and ceftazidime. Compared with the first-generation cephalosporins, the third-generation cephalosporins are generally less active against gram-positive organisms but are more active against the Enterobacteriaceae23. Cefotaxime, ceftriaxone, and ceftizoxime are third-generation cephalosporins with similar antibacterial activity. They are highly resistant to β-lactamase, and they have activity against gram-positive organisms with the exception of the Enterococcus species. They have good activity against most gram-negative organisms except for Pseudomonas aeruginosa. Cefotaxime, ceftizoxime, and ceftriaxone have half-lives of 1.1, 1.7, and 8.0 hours, respectively. Ceftazidime is similar to cefotaxime, ceftizoxime, and ceftriaxone with regard to activity against the Enterobacteriaceae, but it has superior activity against Pseudomonas aeruginosa24. For serious Pseudomonas aeruginosa infections, it should be combined with an aminoglycoside25. The activity of ceftazidime against gram-positive organisms is half that of cefotaxime, ceftizoxime, and ceftriaxone. The fourth-generation cephalosporins are represented by cefepime. Cefepime has excellent activity against aerobic gram-positive organisms, including methicillin-sensitive Staphylococcus aureus, and gram-negative organisms, including Pseudomonas aeruginosa. In vitro data have suggested increased activity of cefepime against multiresistant Enterobacter species. Like other cephalosporins, cefepime has no activity against Enterococcus species. In general, the cephalosporins have a low prevalence of adverse reactions. A cross-reactivity occurs in 3% to 7% of patients with an allergy to penicillin. This may be a true cross-reactivity (allergy) or those patients may be more allergic. The allergic reactions to the cephalosporins include a type-I immediate hypersensitivity reaction, including bronchospasm, hives, and skin rashes, occurring three to five days after the initiation of therapy. Fever, lymphadenopathy, eosinophilia, and serum-sickness reactions may also occur. The cephalosporins cause a Coombs-positive anemia in approximately 3% of patients. Neutropenia occurs in approximately 1% of patients, usually after three weeks of the therapy. Liver function abnormalities, with elevation of liver enzyme levels, occur in 1% to 7% of patients. Antibiotic-associated colitis is associated with cephalosporin administration as well. Some second and third-generation cephalosporins, including cefotetan and cefamandole (second generation) as well as moxalactam and cefoperazone (third generation), have the methylthiotetrazole side chain. Antibiotics with the methylthiotetrazole side chain can cause a disulfiram reaction when a patient drinks alcohol26-30, and they are also associated with hypoprothrombinemia31-35. The cephalosporins have very few reported drug-drug and drug-food interactions. Other b-lactam Antibiotics Aztreonam is a monocyclic β-lactam antibiotic, which is active against most Enterobacteriaceae and Pseudomonas aeruginosa36. Aztreonam has no appreciable antibacterial activity against aerobic gram-positive or anaerobic bacteria. The drug must be given parenterally. No major adverse reactions have been reported with this antibiotic37,38. Minor reactions to aztreonam include nausea, vomiting, and diarrhea. On occasion, the drug may cause elevated levels of liver transaminases. Aztreonam has a low probability of cross-reactivity (allergy) in patients allergic to penicillin or cephalosporin. Imipenem is an antimicrobial agent belonging to the β-lactam class of antibiotics. Biochemically, it is a carbapenem. Imipenem also has excellent in vitro activity against aerobic gram-positive organisms, including Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcal species. Imipenem also has excellent activity against gram-negative organisms, including the Enterobacteriaceae and Pseudomonas aeruginosa. In addition, imipenem inhibits most anaerobic species, including the Bacteroides fragilis group39. Some patients have nausea, vomiting, and diarrhea with imipenem therapy. Penicillin cross-reactivity occurs with imipenem. Grand mal seizures occur in 1% to 4% of patients receiving this antibiotic. The prevalence of seizures is increased in patients with renal dysfunction40,41 and/or a history of seizure activity. Finally, resistance to Pseudomonas aeruginosa and fungal superinfection may develop during therapy. Vancomycin Vancomycin has excellent activity against Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus species. It is the antibiotic of choice for individuals who are unable to tolerate either the penicillins or the cephalosporins42. Vancomycin is also the antibiotic of choice for the treatment of methicillin-resistant Staphylococcus aureus43 and coagulase-negative Staphylococcus species44. Recent reports on vancomycin-resistant Enterococcus species have dictated increased vigilance and caution45,46. When used as monotherapy, the end organ toxicity of vancomycin is minimal. The "red man syndrome"47,48 may be observed with vancomycin therapy. This syndrome includes flushing of the head, neck, and upper torso and is often associated with hypotension. It occurs in 5% to 13% of patients, especially when the infusion is given over less than one hour. Allergic reactions rarely occur with vancomycin therapy. Vancomycin may be associated with nephrotoxicity49-52 or ototoxicity, especially when given concurrently with an aminoglycoside. Vancomycin may also cause neutropenia53,54 and thrombocytopenia55,56. Ribosomal Active Antibiotics The ribosomal active antibiotics include clindamycin, macrolides, quinupristin/dalfopristin, tetracyclines, oxazolidinones, and aminoglycosides. Clindamycin Clindamycin is one of the antibiotics most active against clinically important anaerobic bacteria, particularly the Bacteroides fragilis group. However, clindamycin is ineffective against clostridial species, other than Clostridium perfringens, in 10% to 20% of cases57. In addition to its anaerobic activity, clindamycin is also effective against Staphylococcus aureus, coagulase-negative Staphylococcus species, and the Streptococcus species. Clindamycin has a half-life of 2.4 hours and is ideally given every eight hours. Clindamycin demonstrates good penetration into most tissues, including bone58,59, and penetrates well into abscesses. Clindamycin is relatively nontoxic but causes diarrhea and pseudomembranous colitis in approximately 8% of patients60. In 10% of patients who have antibiotic-associated diarrhea, pseudomembranous colitis develops secondary to toxins produced by the overgrowth of Clostridium difficile. Hypersensitivity reactions, including rashes, urticaria, and erythema multiforme, may occur with clindamycin administration. Clindamycin drug interactions are rare, but clindamycin may potentiate the action of neuromuscular blocking agents61-63. Macrolides Erythromycin is the prototype of the macrolide class of antibiotics64. These agents work at the ribosomal level and are bacteriostatic. Erythromycin has in vitro activity against Streptococcus species, Listeria monocytogenes, Moraxella catarrhalis, Mycoplasma pneumoniae,Legionella pneumophila, and Chlamydia pneumoniae. The new macrolides (clarithromycin and azithromycin) can inhibit Mycoplasma pneumoniae, Legionella species, and Chlamydia pneumoniae at lower concentrations. They are also more active against Haemophilus influenzae, Mycobacterium avium-intracellulare, and other atypical mycobacteria. The new macrolides are active against the agent of Lyme disease, Borrelia burgdorferi. Because of its high intracellular concentration, azithromycin is more active against Chlamydia trachomatis and Toxoplasma gondii and clarithromycin is very active against Helicobacter pylori. The macrolides are indicated for the treatment of upper and lower respiratory tract infections and skin structure infections. The new macrolides are the agents of choice for Mycobacterium avium-intracellulare infections. The macrolides are generally considered to be very safe drugs. They cause gastrointestinal reactions, including nausea, vomiting, and abdominal cramps, in approximately 20% of patients. These problems are less frequent with newer erythromycins such as azithromycin and clarithromycin. The macrolides have a number of drug interactions. They stimulate hepatic microsomal activity with cytochrome P-450 complexes. This stimulation causes increased levels of theophylline, warfarin, cyclosporin, carbamazepine, and cisapride. Azithromycin has the least drug-interaction potential of the macrolides. Quinupristin/Dalfopristin Quinupristin/dalfopristin (Synercid; Aventis, Parsippany, New Jersey) is a fixed combination of two streptogramins in a ratio of 30:70. This antibiotic produces in vitro inhibitory and bactericidal activity against most gram-positive organisms, including vancomycin-resistant Enterococcus faecium65. Quinupristin/dalfopristin also has a role in the treatment of methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus species infections in patients who cannot tolerate vancomycin therapy. Adverse reactions66 to quinupristin/dalfopristin appear to be mild and include self-limited local reactions such as itching, pain, and burning as well as vomiting and diarrhea67. Major side effects are phlebitis, especially in the smaller veins. The antibiotic should be given through a central line. In a recent study68, the drug caused severe myalgia in approximately 15% to 20% of thirty-two patients who received it. Tetracyclines The tetracyclines are divided into three groups: the short-acting compounds (chlortetracycline, oxytetracycline, and tetracycline), an intermediate group (demeclocycline), and the more recently developed longer-acting group (doxycycline and minocycline). The tetracyclines are primarily bacteriostatic. They are useful drugs for the treatment of relatively uncommon diseases, including brucellosis and granuloma inguinale. Tetracyclines are also active against mycoplasma, rickettsia, and Lyme disease (Borrelia burgdorferi). In addition, they also are useful in the treatment of chlamydial diseases, including lymphogranuloma venereum, psittacosis, and trachoma. Minocycline is the most active drug of the tetracycline class against Staphylococcus aureus. Minocycline is often used in combination with rifampin for the oral treatment of methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus species. The tetracyclines have excellent tissue distribution probably because of their high lipid solubility. Minocycline is the most lipid-soluble tetracycline. The high lipid solubility and diffusion make it useful for the treatment of metabolically inactive organisms. Tetracyclines accumulate in bone. The tetracyclines have major side effects, including anorexia, nausea, vomiting, and diarrhea. Tetracyclines also cause hepatotoxicity, especially in pregnant women. They should not be given to children less than twelve years of age, as they cause gray-brown-yellowish discoloration of teeth and may impair bone growth in this age-group. Tetracyclines are catabolic and aggravate preexisting renal failure. They have a propensity to cause major photosensitivity reactions. Other side effects include esophageal ulcers and hypersensitivity reactions. Minocycline causes vestibular toxicity in some patients. Tetracycline antibiotics have a number of drug interactions. Divalent metals, including calcium, magnesium, and aluminum (antacids)69-71, when given concurrently, lead to decreased absorption of the tetracyclines. A number of drugs increase hepatic metabolism of the tetracyclines, which causes a decreased half-life of this class of antibiotics. Oxazolidinones The oxazolidinones72,73 are a new synthetic class of antimicrobials. These agents have bacteriostatic activity against a number of important organisms, including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus species74. They have efficacy when administered either parenterally or orally. Side effects include tongue discoloration, a folliculitis type of rash, nausea, vomiting, and diarrhea. Aminoglycosides The aminoglycosides, which include gentamicin, tobramycin, amikacin, and netilmicin, are the standard against which other antibiotics are measured for the treatment of aerobic gram-negative infections. The aminoglycosides generally have poor activity against gram-positive organisms. Initially, they may be used for the treatment of Staphylococcus aureus, but resistance may develop rapidly75,76. They have no effect against the Streptococcus species or anaerobes, but they have excellent activity against the Enterobacteriaceae and Pseudomonas aeruginosa. The aminoglycosides may be inactivated by enzymatic modification. Amikacin has fewer available sites than the other aminoglycosides for enzymatic inactivation. Consequently, the percentage of strains susceptible to amikacin is greater than that susceptible to tobramycin, gentamicin, or netilmicin77. There is no evidence that establishes whether amikacin has greater or lesser activity than the other aminoglycosides. The aminoglycosides can cause nephrotoxicity and ototoxicity. Ototoxicity reactions include hearing loss, tinnitus, ear fullness, and vestibular problems such as nausea, vomiting, vertigo, nystagmus, and difficulty with gait. Other aminoglycoside toxicities include neuromuscular blockade and hypersensitivity reactions. The aminoglycosides have some drug interactions. There is increased nephrotoxicity and ototoxicity when cyclosporin, vancomycin, amphotericin B, ethacrynic acid, neuromuscular blocking agents, nonsteroidal anti-inflammatory drugs, or radiographic contrast agents are given concurrently with the aminoglycosides. RNA Active Antibiotics (Rifampin) Rifampin exhibits bactericidal activity against a wide variety of gram-positive and gram-negative organisms. Rifampin is the most active antistaphylococcal agent known78. However, it is less active against most gram-negative bacteria than are the aminoglycosides. When rifampin is used alone for the treatment of bacterial infections, a rifampin-resistant subpopulation rapidly develops79. Expression of rifampin resistance can be lessened by the addition of a second effective antibiotic. Rifampin in combination with a semisynthetic penicillin has been used to treat osteomyelitis caused by methicillin-sensitive Staphylococcus species. Trimethoprim-sulfamethoxazole or minocycline and rifampin have been used to treat osteomyelitis caused by methicillin-resistant Staphylococcus species. Side effects of rifampin include orange-red discoloration of body fluids, gastrointestinal symptoms, hepatitis, and possibly mild immunosuppression. There are a number of rifampin drug interactions80-82. The co-administration of rifampin with INH (isoniazid) leads to a higher rate of hepatotoxicity83. Co-administration of rifampin with ketoconazole84 can result in a failure of either drug. Food interferes with the absorption of rifampin, and this antibiotic must be taken on an empty stomach. Rifampin induces hepatic microsomal enzymes and can decrease the level of certain drugs (Table I). Patients taking these medications must be carefully monitored, and their drug doses must be adjusted when indicated. TABLE I: - Drugs Affected by Rifampin* Acetaminophen Benzodiazepines Clofibrate Cyclosporine Digoxin Hydantoins Quinidine Theophyllines Oral anticoagulants Beta-blockers Oral contraceptives Digitoxin Enalapril Methadone Sulfones Tocainide Barbiturates Chloramphenicol Corticosteroids Disopyramide Estrogens Mexiletine Sulfonylureas Verapamil *Rifampin induces hepatic microsomal enzymes and can decrease the effect of these drugs. DNA Active Antibiotics (Fluoroquinolones) There are four generations of quinolones. The first generation, nalidixic acid, is used to treat urinary tract infections. The second, third, and fourth-generation quinolones may be used to treat musculoskeletal infections, including osteomyelitis85. The second-generation quinolones include ciprofloxacin and ofloxacin, which provide adequate serum, tissue, and urine concentrations and have efficacy against most gram-negative organisms. Most streptococcal strains and anaerobic organisms are resistant to ciprofloxacin and ofloxacin. Reports of resistance by some Staphylococcus aureus and Staphylococcus epidermidis strains dictate caution. Ciprofloxacin is advantageous in the treatment of gram-negative bone infections, which previously required prolonged parenteral antibiotic therapy85. The third-generation quinolones include levofloxacin and sparfloxacin, which provide higher serum levels than do either ciprofloxacin or ofloxacin. These agents have excellent activity against Streptococcus species, including penicillin-intermediate strains and resistant Streptococcus pneumoniae. They are also active against atypical respiratory pathogens (Mycoplasma pneumoniae, Legionella species, and Chlamydia pneumoniae). They have efficacy against most gram-negative organisms as well. The fourth-generation (trovafloxacin) quinolones have aerobic gram-positive and gram-negative organism coverage similar to that of the third-generation quinolones, but, unlike the third-generation quinolones, the fourth-generation quinolones have excellent anaerobic organism coverage86,87. In a small number of patients, trovafloxacin has been associated with serious liver injury leading to liver transplant and/or death. While this problem has been reported with both short and long-term therapy, treatment for more than two weeks is associated with an increased risk of liver injury. Currently, trovafloxacin may be used only for serious life or limb-threatening infections in a hospital or nursing-care facility. None of the quinolones have reliable Enterococcus species coverage88. The current quinolones have variable Staphylococcus aureus and Staphylococcus epidermidis coverage, and resistance to the second and third-generation quinolones is increasing89. Although second, third, and fourth-generation quinolones are formulated for parenteral administration, oral administration provides excellent serum concentrations and is associated with a decreased duration of hospitalization and reduced treatment costs. In most cases, treatment with quinolone is begun parenterally and, after one to two days, is switched to oral therapy unless that is contraindicated. Patients who have not completed puberty should not be treated with the quinolone class of antibiotics because altered bone growth has been found in studies on young beagles90. Overall, the toxicity of the quinolones is low91. Gastrointestinal disturbances consisting of nausea, vomiting, and/or dyspepsia occur in 2% to 5% of patients. Central nervous system reactions, including headache, dizziness, tiredness, and insomnia, occur in 1% to 2% of patients. The quinolones may cause hypersensitivity reactions, including skin rashes. Moderate-to-severe phototoxicity may be caused by some of the quinolones, especially lomefloxacin and sparfloxacin. The quinolones may also cause tendinitis and a predisposition to rupture of the Achilles tendon, and, rarely, this class of antibiotic may cause acute interstitial nephritis. While all quinolones cause mild toxicity, individual quinolones have the propensity for certain side effects. Sparfloxacin, for example, causes prolongation of the Q-T interval (Table II). The quinolones also have multiple drug-drug interactions92. Antacids, including sucralfate, iron, zinc, and calcium, decrease the absorption and the efficacy of most quinolones. Certain quinolones have specific drug-drug interactions (Table III). TABLE III: - Quinolone: Drug Interactions Drug Quinolone Effect Antacids (sucralfate, iron, zinc, and calcium) All Decreased absorption and efficacy Theophylline Enoxacin, ciprofloxacin Theophylline toxicity Caffeine Enoxacin Nervousness, insomnia Warfarin Enoxacin, ciprofloxacin, ofloxacin Increased prothrombin time Cyclosporine Ciprofloxacin Transient increased levels of cyclosporine Phenytoin Ciprofloxacin Increased or decreased phenytoin levels TABLE II: -