[Frontiers in Bioscience 2, e63-71, August 15, 1997]
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ORAL ANTIBIOTICS IN THE NINETIES: NEW DRUGS AND NEW CHALLENGES IN PRIMARY CARE

Robert A. Bonomo1, John Aucott2, and Robert A. Salata3

Division of Geriatrics1 and Division of Infectious Diseases3, University Hospitals of Cleveland, and Division of General Internal Medicine2 Veterans Affairs Medical Center, Cleveland, Ohio

Received 6/12/97 Accepted 8/10/97

4. QUINOLONES

The quinolone class of antimicrobials are proving to be one of the most important antimicrobials used in the management of outpatient infectious diseases. These broad spectrum agents are easily administered, have excellent gastrointestinal absorption and tissue penetration, and lack many unwanted side effects. An important feature of this class of drugs is the ability of medicinal chemists to manipulate the nucleus of the 4-quinolones. This has permitted an explosion of derivative compounds with differing antimicrobial activity, pharmacokinetics, and metabolic properties (42).

With the introduction of the quinolones, clinicians are now able to orally treat chronic Gram negative bacillary osteomyelitis, Pseudomonas aeruginosa urinary tract infections, prostatitis, invasive otitis externa, bacterial gastroenteritis, mycobacterial infections in AIDS patients, sexually transmitted disease due to gonococcus and Chlamydia and respiratory infections in cystic fibrosis patients. These drugs have also been used as prophylactic agents in protecting against meningococcal meningitis (43). In preliminary studies, they have also been used as prophylactic agents in patients with hematologic malignancies (45), in bone marrow transplant recipients (46), in patients with recurrent urinary tract infections (47), in prophylaxis against travelers' diarrhea (48), and in the prevention of bacteremia and spontaneous bacterial peritonitis in cirrhotics (49). Quinolones have not been successful in treating Helicobacter pylori (50).

The quinolones are well absorbed and have a bioavailability from 30% (norfloxacin) to greater than 90% (ofloxacin and levofloxacin). Penetration into body fluids is quite good and the highest concentration of drug is found in the urine and genitourinary tissues.

In the United States, levofloxacin, trovafloxacin, enoxacin, sparfloxacin, clinafloxacin, and lomefloxacin are the latest quinolones to join the ranks of ciprofloxacin, norfloxacin and ofloxacin. Enoxacin is marketed for the treatment of urinary tract infections and for the single dose treatment of urethral and cervical gonorrhea. Lomefloxacin is indicated only for the treatment of UTIs, acute bronchitis due to H. influenzae and Moraxella catarrhalis, and is recommended for prophylaxis before transurethral surgical procedures. These two drugs are not superior to ciprofloxacin against Pseudomonas. Levofloxacin, the L-enantiomer of the racemic mixture of ofloxacin, is advertised as being more effective than the parent mixture with little or no side effects. It can be dosed once-a-day (500 mg) either orally or intravenously. Levofloxacin promises to be effective against penicillin resistant pneumococci, methicillin-susceptible S. aureus, atypical respiratory pathogens such as Mycoplasma pneumoniae, Chlamydia, and Legionella pneumophilia, and Gram negative pathogens. Sparfloxacin is a once a day oral quinolone that is targeted to treat community-acquired respiratory infections. This quinolone, like levofloxacin, has been shown to be more effective than ciprofloxacin against penicillin resistant pneumococci. Phototoxicity (8% of patients) may prove to be an undesirable side effect of this drug and may limit its use. Both sparfloxacin and levofloxacin are somewhat active against anaerobes but the current drugs available are superior. Trovafloxacin will also cover the same organisms as ciprofloxacin but with enhanced Gram positive activity. Trovafloxacin has a broad spectrum of activity in vitro , especially against common respiratory pathogens including those causing the atypical pneumonia syndrome and penicillin resistant streptococcus pneumonia. This drug also has excellent antimicrobial activity against Streptococcus pyogenes, ciprofloxacin-susceptible staphylocci, and Enterococcus fecalis. clinafloxacin is among the newest of the quinolones to be investigated (51). This synthetic broad-spectrum fluroquinolone is available for parenteral and oral administration. Clinafloxacin demonstrates excellent Gram negative activity but is also very active against Gram positive pathogens and strict anaerobes. This drug is also active against bacterial strains that are highly resistant to structurally-related drugs. It promises to be effective against Acinetobacter and Sternotrophomonas maltophilia, methicillin-sensitive and methicillin-resistant Staphylococcus aureus, as well as coagulase negative staphylococci, enterococci, and S. pneumoniae. It is hoped that this agent will establish itself as an effective alternative to intravenous vancomycin.

Like the macrolides, the quinolones have established themselves as important partner antibiotics in the treatment of mycobacterial infections (18). Ciprofloxacin has been successfully employed in treating MAC and has established itself as an essential drug in the treatment of multi-drug resistant tuberculosis.

At present, quinolones should be used with caution in children. Adverse side effects and drug interactions include elevations of cimetidine levels (all quinolones), elevated theophylline levels (except for lomefloxacin), and prolongation of the prothrombin time (ciprofloxacin potentiates the effect of coumadin) (38). The co-administration of aluminum and magnesium antacids and iron sulfate interferes with the absorption of the quinolones. An important interaction can occur when quiniolones are used in AIDS patients taking didanosine (DDI). The magnesium and aluminum buffers that increase the absorption of DDI also interfere with the absorption of ciprofloxacin. Central nervous system side effects of quinolones include headache, agitation, dizziness and sleep disturbance. These are reported in 1-4% of patients. Seizures occur rarely. The neurological side effects are believed to be due to interference with gaba-aminobutyric acid receptors.

Balancing the positive impact of quinolones is their widespread inappropriate use (2). Although, It is well recognized that ciprofloxacin has a limited role in the treatment of upper respiratory tract infections (where pneumococci and group A streptococci are commonly involved) and in the treatment of skin and soft tissue infections (where streptococci and staphylococci are the major pathogens), they are often inappropriately used to treat bronchitis, sinusitis, and cellulitis in the community. When treating upper respiratory tract infections it must be emphasized that S. pneumoniae is more sensitive to the macrolide or beta-lactam antibiotics. In fact, there have been a number of failures when ciprofloxacin has been used to treat pneumococcal infections (52,53). Anaerobic organisms (found in the sinuses) are less susceptible to the action of quinolones perhaps due to their less susceptible DNA gyrase or by inactivation of the quinolones in the anaerobic environment.

A major concern of primary care practitioners is the use of quinolones in the treatment of enterococcal infections. The quinolones as a class have varying activity against Enterococcus faecium and Enterococcus faecalis. Of all the quinolones, ciprofloxacin seems to be the most active. However, the MIC90 is very near the maximum achievable serum concentration. Hence, except for urinary tract infections where amoxicillin cannot be used, the quinolones are not considered to be clinically useful against the entercoccus (54).

It must be kept in mind that resistance to one quinolone means resistance to all quinolones. In the intrinsically less susceptible organisms, such as staphylococci and Pseudomonas spp., the MICs following a single mutation can readily exceed the therapeutic breakpoint. This is responsible for the failure of quinolones in serious infections with S. aureus and P. aeruginosa. In addition, the number of community isolates of other Gram negative pathogens demonstrating resistance to quinolones is increasing (55).

Clinicians should not forget the availability of cost-effective alternatives to quinolones for many uncomplicated infections. For example, trimethoprim remains an inexpensive choice for the treatment of simple cystitis in women, and trimethoprim-sulfa is an effective therapy for prostatitis and acute pyelonephritis (8).