▪ The quinolones are synthetic antibiotics based on a nucleus of two fused six-membered rings
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The first drug in this class was nalidixic acid. It was of limited clinical value because of its relative inactivity and the rapid emergence of resistance. Since ciprofloxacin was introduced in the 1990s a number of quinolone analogs have been introduced that differ from each other in terms of their antibacterial activity and pharmacokinetics. The addition of a fluorine atom at position six of the quinolone nucleus markedly enhanced activity against Gram-negative bacteria and has led to a new generation of quinolone antibiotics known as fluoroquinolones. Fluoroquinolones inhibit DNA gyrase and topoisomerase IV to an extent that depends upon the bacteria. Quinolones inhibit bacterial
deoxyribonucleic acid (DNA) gyrase, the enzyme responsible for supercoiling, nicking and sealing bacterial DNA. Acquired resistance may develop through either decreased permeability or alterations in DNA gyrase.
The first generation of fluoroquinolones includes ciprofloxacin, ofloxacin and norfloxacin. They are active against Gram-negative and a few Gram-positive bacteria. A more recent fluoroquinolone, levofloxacin, has greater activity against Gram-positive and atypical bacteria. Fluoroquinolones are perhaps the best tolerated of all oral antibiotics, but are more expensive than most.
The quinolones are predominantly bactericidal and exhibit concentration-dependent killing. Fluoroquinolones are highly active against aerobic Gram-negative bacilli, including Enterobacteriaceae, Haemophilus species, Moraxella
catarrhalis and, in the case of ciprofloxacin, P. aeruginosa. They are active against some mycobacteria, including
most strains of M. tuberculosis. 'Older' fluoroquinolones, such as norfloxacin and ciprofloxacin, are weakly active against streptococci and staphylococci, and not active against anaerobes. Some of the newer fluoroquinolones (e.g. levofloxacin, gatifloxacin, gemifloxacin and moxifloxacin) have been called 'respiratory fluoroquinolones' because of increased activity against Streptococcus pneumoniae, including penicillin-resistant strains. Gatifloxacin and
moxifloxacin are also active against anaerobic bacteria.
THERAPEUTIC INDICATIONS
Fluoroquinolones are useful in the treatment of infections due to aerobic Gram-negative bacilli that are not susceptible to other drugs. In many instances, they are the only oral drugs active against certain aerobic Gram-negative bacilli, particularly P. aeruginosa, where fluoroquinolones can obviate the need for parenteral therapy. Of the currently available drugs, ciprofloxacin is the most active against Gram-negative bacteria and the most commonly used. It is available in oral, parenteral and ophthalmic formulations. The 'respiratory fluoroquinolones' can be used in the treatment of pneumonia, and may be particularly useful in regions where there is a high prevalence of penicillin- resistant Streptococcus pneumoniae.
They are renally excreted and have excellent oral bioavailability. They penetrate the prostate in therapeutically useful amounts and are therefore used to treat prostate infections. Although cerebrospinal fluid concentrations appear to be therapeutic, there is very little clinical experience in the use of quinolones for meningitis and their use is not
Like tetracyclines, fluoroquinolones are chelated by divalent and trivalent cations. Some quinolones, including ciprofloxacin, increase serum concentrations of theophylline when given concomitantly. In addition, as
fluoroquinolones cause cystic lesions in the articular cartilage of growing animals, they are relatively contraindicated in children and pregnant women.
The routes of administration of quinolones, as well as their pharmacokinetic profiles, are summarized in Table 6.18.
Ciprofloxacin
The most commonly used fluoroquinolone Has excellent oral bioavailability
Very active against aerobic Gram-negative bacilli Not active against anaerobes
Has only limited activity against streptococci and staphylococci
Nitroimidazoles
Nitroimidazoles are well-absorbed, predominantly bactericidal agents with antimicrobial activity restricted to strict anaerobes and certain protozoa. They can enter most bacteria but only susceptible organisms produce the
nitroreductase enzyme that is needed to reduce such nitroimidazoles to short-lived cytotoxic metabolites that bind to DNA and inhibit its synthesis. Aerobic bacteria are innately resistant due to a lack of nitroreductase activity.
Table 6-18. Route of administration and pharmacokinetics of quinolone antibiotics
Drug Routes of administration Oral
bioavailability
(%) Clearance route
Serum half-life (normal renal
function), (hours) Comments
Norfloxacin p.o. 40 Renal 3 Used for UTI only Ciprofloxacin p.o., i.v. 75 Renal 4 Very active against
aerobic Gram-negative bacilli;
Weak Gram-positive activity
Levofloxacin p.o., i.v. >95 Renal 7 Active against most
Streptococcus pneumoniae
Gatifloxacin p.o., i.v. Renal 8 Broad-spectrum fluoroquinolone Moxifloxacin p.o. 85 Hepatic >
renal 12 Broad-spectrum fluoroquinolone
i.v., intravenous; p.o., by mouth; UTI, urinary tract infection.
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Acquired resistance can develop as a result of: Decreased uptake of the drug.
Decreased nitroreductase production.
▪ Metronidazole is the only nitroimidazole currently licensed in the US
Metronidazole is active against most anaerobic bacteria, but has greatest activity against Gram-negative anaerobes including B. fragilis. For the reason given above it has no activity against aerobic bacteria. It is also very effective in the treatment of three important protozoal infections: giardiasis, amebiasis and trichomoniasis.
Metronidazole is useful in the treatment of a variety of anaerobic infections including bacterial vaginosis, which is the most common cause of abnormal vaginal discharge. In bacterial vaginosis, the bacterial flora of the vagina, which is normally dominated by Lactobacillus species, becomes replaced by an abnormal polymicrobial flora that is comprised predominantly of anaerobes. Metronidazole is usually considered the drug of choice for C. difficile enteritis. In addition to its use against specific microorganisms, metronidazole is useful in hepatic encephalopathy and in Crohn's disease, particularly where there is perianal involvement.
Both oral and i.v. preparations of metronidazole are available, with the oral form having close to 100% bioavailability. A topical formulation is available for the treatment of acne rosacea. Metronidazole achieves therapeutic
concentrations in both cerebrospinal fluid and brain parenchyma. It is given orally, i.v. or topically, and is >95% bioavailable. It is cleared mainly by the liver and has a serum half-life of about 10 hours.
▪ Metronidazole should be used with caution in pregnant women
Since metronidazole is mutagenic in bacteria and causes tumors in rodents, it should be used with caution in pregnant women. Its use in the first trimester should be avoided wherever possible. However, there is no evidence to date of human carcinogenicity with metronidazole.