___________________________________________________________________________ Antibiotics Review
SPECIAL POPULATIONS Erythromycin is pregnancy category B, with an erythromycin estolate preparation as the preferred form because it is less likely to cause hepatotoxicity. Surveillance studies have not shown any increase in adverse outcomes. Azithromycin is also category B [6]. The CDC recommends the use of azithromycin for the treatment of Chlamydia during pregnancy. Treatment with erythromycin is an approved alternative regimen [109]. Clarithromycin is pregnancy category C, based on the finding that it causes growth retardation in monkeys and adverse effects on other mammals, including fetal loss. A postmarketing sur- veillance study did not find any evidence of teratogenicity, but a Danish study found a doubling in the frequency of miscarriages among women treated with clarithromycin [110; 111]. The manufacturer recommends that clarithromycin not be used in pregnant women unless there are no alternative therapies [6]. Erythromycin is excreted in breast milk, but the AAP considers it usually compatible with breastfeeding [57]. Clarithromycin is excreted in breast milk, but breastfeeding is considered accept- able when the relative infant dose is less than 10% [112]. One systematic review and meta-analysis demonstrated a significant association between post-natal use of erythromycin and infan- tile hypertrophic pyloric stenosis [113]. QUINOLONES The first quinolone, nalidixic acid, was introduced in 1962. It was developed as a result of chloroquine synthesis. Later, derivatives with broader spectrum antimicrobial coverage were produced, leading to the current class of quinolone drugs (fluoroquinolones). As with other classes of synthetic and semisynthetic antimicrobials, alterations of side chains affect antimicrobial activity and pharmacokinetics [114]. MECHANISM OF ACTION Quinolones inhibit DNA gyrase and DNA topoisomerase, enzymes that mediate DNA supercoiling, transcription, and repair [6; 115]. Quinolones convert these enzymes into cellular toxins, inhibit replication of bacterial DNA by blocking and/ or inhibiting the enzymes, relax DNA supercoils, and enable DNA replication and repair. The interference with replication and transcription processes can lead to permanent chromo- somal breaks. If the breaks overwhelm the SOS response and other DNA repair pathways, cell death can occur [116; 117]. Bacterial resistance develops as a result of spontaneous muta- tions that change the binding sites for quinolones on the DNA gyrase and the DNA topoisomerase [116]. Mutations that decrease the ability of quinolones to cross the cell membrane also occur. Plasmids that carry quinolone resistance genes have been identified as an emerging clinical problem [117; 118].
PHARMACOKINETICS The quinolones are active against many gram-positive cocci, gram-negative bacilli, and atypical bacteria (e.g., Legionella , Mycoplasma ). Older quinolones have poor activity against streptococci and anaerobes, at achievable serum levels, is rela- tively poor, although newer agents, such as moxifloxacin, have better coverage against streptococci (including S. pneumoniae with reduced penicillin sensitivity) and some anaerobes [119]. Gram-negative coverage includes Campylobacter , Enterobacter , E. coli , H. influenzae , Klebsiella , Salmonella typhi , Shigella , and Vibrio cholerae [119]. Indications for the use of quinolones include urinary tract infections, non-gonococcal infections of the ure- thra and cervix, pneumonia, sinusitis, soft-tissue infections, and prostatitis. Ciprofloxacin is indicated for post-exposure prophylaxis for anthrax, and levofloxacin has an indication for the treatment of inhalation anthrax infection [6]. The quinolones are absorbed well after oral administration, and peak serum levels in the elderly and those with reduced renal function approximate those achieved with intravenous usage. Food may delay the time to reach peak serum concentration but does not decrease total absorption. Oral absorption is diminished by coadministration of aluminum, magnesium, calcium, zinc, and/or iron preparations [119]. The drugs are distributed well throughout all tissues, including the prostate, although the levels in the CSF and prostatic fluid are lower than serum levels [6]. Most quinolones are metabolized in the liver and excreted in the urine, reaching high levels in urine. Moxifloxacin is mainly excreted nonrenally. It is metabolized, via glucuronide and sul- fate conjugation in the liver, to an inactive metabolite [6; 119; 120]. Ciprofloxacin has a mixed route of elimination. As much as 35% to 70% of the ciprofloxacin dose is excreted renally [6]. In renal insufficiency, the quinolones that are primarily excreted renally and those with mixed routes of elimination require dosage adjustments [6]. Moxifloxacin doses do not have to be adjusted for mild hepatic insufficiency [6]. SIDE EFFECTS/TOXICITY The most common side effect with the use of quinolones is GI upset. Less common side effects include headache, insomnia, dizziness, peripheral neuropathy, tendon rupture, elevated liver enzymes, and interstitial nephritis [6; 121; 122]. Rarely, hematologic toxicities have occurred, resulting in hemolytic anemia (more likely to occur in patients with glucose-6-phos- phate dehydrogenase [G6PD] deficiency), aplastic anemia, and agranulocytosis [123]. Very rarely, hepatic necrosis and hepatic failure have been reported [6; 124].
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