Fluoroquinolines: Past, Present and Future of a Novel Group of Antibacterial Agents

Transcription

1 Fluoroquinolines: Past, Present and Future of a Novel Group of Antibacterial Agents Eric M. Scholar 1 Department of Pharmacology, University of Nebraska College of Medicine, Nebraska Medical Center, Omaha NE PROLOGUE The fluoroquinolones are a group of antibiotics that have increased in numbers in recent years. Their usefulness has greatly expanded with the introduction of several new quinolones having improved properties compared to older members. This paper discusses the chemistry, mechanism of action, therapeutic uses, adverse effects and drug interactions of the fluoroquinolones. The advantages of the newer compounds in this group are emphasized. This paper includes material that is presented to second year medical and pharmacy students as part of a joint pharmacology course. The goal of this lecture is to help the student learn the fundamental properties of this important group of antibiotics. INTRODUCTION The fluoroquinolones are a relatively new group of broadspectrum antibacterial agents with a unique mechanism of action. Since the first quinolone, nalidixic acid, was introduced thousands of related quinolone compounds have been synthesized but most have been abandoned before development for several different reasons. A better understanding of structure activity relationships has allowed scientists to modify the basic quinolone structure to enhance or limit the extent of antimicrobial activity and improve properties such as the therapeutic uses, pharmacokinetics, drug interactions and toxicity of the quinolones. The search is continuing to produce the perfect quinolone (1). These drugs are unique among antibacterials in that they inhibit bacterial topoisomerase enzymes. Although the original quinolones were effective mainly against urinary tract infections and had antibacterial activity mainly against facultatively anaerobic gram-negative organisms, the newer quinolones have a wider clinical use and a broader spectrum of antibacterial activity including gram-positive and gramnegative aerobic and anaerobic organisms. Some of the newer quinolones have an important role in the treatment of community-acquired pneumonia and intra-abdominal infections. As a result of the recent threats of bioterrorism and the presence of anthrax spores in the mail it has come to light that ciprofloxacin is an important drug for the prevention and treatment of this disease. Quinolone resistance is also becoming an increasing problem due to the selective pressure from their extensive use. The newer quinolones have been found to produce additional toxicities to the heart that were not found with the older compounds. The material presented here is from a lecture presented to medical and pharmacy students. 1 Associate Professor of Pharmacology. Am. J. Pharm. Educ, 66, (2002); received 12/16/01, accepted 2/14/02. American Journal of Pharmaceutical Education Vol. 66, Summer

2 Table II. Classification of fluoroquinolones FIRST GENERATION Nalidixic Acid SECOND GENERATION Norfloxacin Fleroxacin a Ciprofloxacin Enoxacin Lomefloxacin Ofloxacin THIRD GENERATION Sparfloxacin Grepafloxacin FOURTH GENERATION Trovafloxacin Clinafloxacin Moxifloxacin Gatifloxacin a Not FDA approved Fig. 1. Fluoroquinolones. CHEMISTRY The quinolones that are used clinically are 4-quinolones and contain a carboxylic acid moiety in the three position of the basic ring structure. The main chemical feature that distinguishes fluoroquinolones from the early quinolones is the presence of a fluorine at position six. The quinolones are now classified into first, second, third and fourth generations with nalidixic acid the first quinolone considered as a first generation compound. There are several differences in chemical makeup among the members of the different generations. The most significant differences are between the two early generation compounds and the third and fourth generation quinolones. This last group is significantly different in mechanism of action, antibacterial activity therapeutic uses and in adverse effects. Several reviews have extensively characterized the structure-activity and structure-toxicity relationships of the quinolone antibiotics (2-4). Table I shows the classification of the approved fluoroquinolones. Figure 1 shows the structure of a first, second and fourth generation quinolone with important structural features highlighted. A key change made in progressing from nalidixic acid to the later generation compounds was the addition of a fluorine at position 6 of the 4-quinolone and the replacement of the 7-methyl side-chain of nalidixic acid with a piperazine group. These changes enhanced antibacterial activity markedly. The addition of the cylcopropyl group in compounds like ciprofloxacin resulted in agents with greater bio avail ability. Modifications made in the piperazine group in the third and fourth generation compounds resulted in enhanced activity against streptococcal organisms. Enhanced activity vs.anaerobes resulted from changes such as the addition of the 8-methoxy group in gatifloxacin. ANTIMICROBIAL PROPERTIES As a group, the fluoroquinolones have excellent in vitro activity against a wide range of both gram-positive and gramnegative bacteria (5,6). Significant differences in antibacterial activity exist among the different fluoroquinolones some of which have broad-spectrum activity against both gramnegative and gram-positive species (7,8). Some of the fluoroquinolones such as norfloxacin and lomefloxacin however, are less active against gram-positive pathogens. In general, the fluoroquinolones are less active against staphylococci and streptococci than against the aerobic gramnegative rods. Until the introduction of the newer fluoroquinolones, these drugs did not have reliable activity against gram-positive bacteria and they were not considered suitable for infections such as the empiric treatment for suspected pneumococcal pneumonia(9). However, the newer quinolones are more active here, with clinafloxacin being the most active and trovafloxacin, grepafloxacin, sparfloxacin, moxifloxacin and gatifloxacin also having good activity against these organisms, (10-12). Somewhat less active are ciprofloxacin and ofloxacin, although they have significant activity against most Staphylococcus aureus isolates, including methicillin-sensitive and penicillin-sensitive strains. Although quinolones demonstrated acceptable activity against methicillin-resistant Staph. aureus when they were first available, they are no longer reliably active against these organisms (13). The older quinolones have only marginal activity against Streptococcus pneumoniae (pneumococci). On the other hand most of the newer quinolones, including trovafloxacin, clinafloxacin, moxifloxacin, sparfloxacin, grepafloxacin, temafloxacin and ofloxacin, are very active against S. pneumoniae, with the potencies for these compounds being several fold greater than those seen for ciprofloxacin and ofloxacin. The quinolones traditionally have excellent activity against gram-negative bacteria such as members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis and Moraxella (Branhamella) catarrhalis(13,14). In addition to the Enterobacteriaceae most of the common gram-negative bacteria that cause urinary tract infections are very sensitive to the fluoroquinolones. Several intracellular bacteria are inhibited by fluoroquinolones at concentrations that can be achieved in plasma. These include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium. The newer fluoroquinolones like levofloxacin, sparfloxacin, grepafloxacin and trovafloxacin have excellent activity against the atypical pathogens Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. Ciprofloxacin and ofloxacin are moderately active against Mycobacterium tuberculosis, M.for-tuitum and M. kansasii. Activity against the M. avium complex is moderate with growth of perhaps one-third of the strains isolated from patients with AIDS inhibited by some of the quinolones(15,16). In general, the fluoroquinolones have poor activity against American Journal of Pharmaceutical Education Vol. 66, Summer

3 anaerobes which limits their use in the treatment of intraabdominal infections (4,17,18). Of the available quinolones, only trovafloxacin demonstrates significantly improved in vitro activity against Bacteroides fragilis one of the most commonly encountered anaerobes in intra-abdominal infections. In addition to being active against B. fragilis, trovafloxacin has good activity against other anaerobes including Clostridium perfringens, C. difficile and Peptostreptococci (4,14,19,20). MECHANISM OF ACTION The fluoroquinolones have a rather unique mechanism of action for antimicrobial agents. They are now known to interact with two related but distinct targets within the bacterial cell, DNA gyrase (or topoisomerase II) and topoisomerase IV (21). Topoisomerase enzymes maintain cellular DNA in an appropriate state of supercoiling in both replicating and nonreplicating regions of the bacterial chromosome. For DNA replication to occur the two strands of double-helical DNA must be separated. However, separation of the strands results in excessive positive supercoiling or overwinding of the DNA in front of the separation point. To avoid this the bacterial enzyme DNA gyrase is responsible for continually introducing negative supercoils into DNA in an ATP-dependent reaction. Both strands of the DNA are cut during this process thus allowing passage of a portion of the DNA through the break which is then resealed. All of the quinolones inhibit bacterial DNA gyrase but they possess no activity against the mammalian type II enzyme, which is the target of several anticancer drugs, such as etoposide. Evidence that the quinolones also target DNA topoisomerase IV has only been recently established (22). This enzyme is also a bacterial II DNA topoisomerase but unlike the gyrase it cannot supercoil DNA. Topoisomerase IV carries out the ATP-dependent relaxation of DNA and is a more potent decatenase than DNA gyrase. Thus, it helps separate the daughter DNA molecules after DNA replication. It is well accepted that fluoroquinolone inhibition of these two enzymes are important components in their mechanism of action. However, it is not clear how quinolones bind to the topoisomerases or precisely how the enzyme inhibition kills the cells. The drugs apparently bind to a complex of the gyrase and the DNA. This stabilizes the complex and causes the lethal effect of these drugs as it leads to induction of DNA strand breaks and freezing of the replication fork or both (23). Complexes of DNA, quinolone and active topoisomerase IV appear to form physical barriers to DNA replication. Most recently, a quinolone-induced complex of DNA and topoisomerase IV has also been shown to inhibit the activity of several DNA helicases in E. coli, including the DnaB helicase, which is one component of the replication complex (24). Also blocks in the passage of RNA polymerase leading to premature termination of transcription occur with quinolone-gyrase DNA complexes (25). However, both of these complexes appear to be insufficient by themselves to generate double-strand DNA breaks which are thought to be necessary for quinolone produced bacterial lethality (23). RESISTANCE The emergence of pathogens resistant to the fluoroquinolones has been increasing thus potentially compromising the usefulness of these drugs. Resistance to these drugs has now been found to be considerably more complicated than previously thought (26). Bacterial resistance to the fluoroquinolones can occur by two main mechanisms, alterations in the target mole- cule (e.g., DNA gyrase or topoisomerase IV) or by reduced intracellular accumulation of the quinolone antibiotics (27,28). Reduced accumulation in turn could result from a decreased uptake of the antibiotic into the cell or by an increased efflux of antibiotic from the cell through multidrugresistant efflux systems (29,30). Although both mechanisms have been shown to play a role, increased efflux seems to be the most important of the two. in a clinical setting resistance by either of these mechanisms occurs most likely from genomic mutations. No specific quinolone-modifying ordegrading enzymes have been found as a mechanism of bacterial resistance to fluoro-quinolones (29). The fluoroquinolones are an attractive group of drugs to use for the therapy of an extensive range of conditions. As a result, there has been a heavy and indiscriminate use of these drugs in some areas which has resulted in fluoroquinolone resistance emerging more rapidly than anticipated in certain pathogens, especially those that were formerly only marginally susceptible (31). There is a widespread concern that resistance will soon develop to some of the more potent quinolones that have been recently released. As a result, it is very important that these drugs be reserved for situations where they are drugs of choice and that drugs that have a lower likelihood of resistance be used (32). PHARMACOKINETICS Absorption The fluoroquinolones as a group exhibit rapid but not always complete absorption following oral administration. The oral bioavailability varies with the individual members of this class. It is approximately 30 to 50 percent for norfloxacin, and 70 to 85 percent for ciprofloxacin. With the newer members of this group such as ofloxacin and fleroxacin it approaches 100 percent (33,34). This excellent bioavailability allows oral dosing with fluoroquinolones to replace parenteral administration as long as there is no contraindication for oral administration. Peak serum concentrations of most of the quinolones are achieved in 1 to 3 hr after an oral dose. The presence of food in the gastrointestinal tract has little influence on the absorption of quinolones causing only serum peaks to appear only slightly later and to be somewhat lower (35). The concomitant administration of food may, however, help minimize any gastrointestinal distress associated with these drugs (17). Distribution The fluoroquinolones have good penetration into various fluids and tissues of the body except for the central nervous system. After oral administration, the fluoroquinolones produce serum levels that are well in excess of those required for efficacy against infections in many areas of the body (36). Drug levels significantly higher than serum are achieved in the kidney, prostate, liver and lung whereas the levels in saliva, bronchial secretions and prostatic fluid are lower than in serum (37-40). They are especially concentrated in the respiratory tract thus providing good activity against pathogens located there. Their penetration into the cerebrospinal fluid (CSF) is usually poor, although the CSF levels of ofloxacin and ciprofloxacin reached 40 to 90 percent of serum levels when the meninges were inflamed (13,41). Urine drug concentrations are high and remain above the MIC concentrations for most of the common urinary pathogens, and fecal levels are also high and sufficient to inhibit most GI pathogens. Bone concentra- 166 American Journal of Pharmaceutical Education Vol. 66, Summer 2003

4 anaerobes which limits their use in the treatment of intraabdominal infections (4,17,18). Of the available quinolones, only trovafloxacin demonstrates significantly improved in vitro activity against Bacteroides fragilis one of the most commonly encountered anaerobes in intra-abdominal infections. In addition to being active against B. fragilis, trovafloxacin has good activity against other anaerobes including Clostridium perfringens, C. difficile and Peptostreptococci (4,14,19,20). MECHANISM OF ACTION The fluoroquinolones have a rather unique mechanism of action for antimicrobial agents. They are now known to interact with two related but distinct targets within the bacterial cell, DNA gyrase (or topoisomerase II) and topoisomerase IV (21). Topoisomerase enzymes maintain cellular DNA in an appropriate state of supercoiling in both replicating and nonreplicating regions of the bacterial chromosome. For DNA replication to occur the two strands of double-helical DNA must be separated. However, separation of the strands results in excessive positive supercoiling or overwinding of the DNA in front of the separation point. To avoid this the bacterial enzyme DNA gyrase is responsible for continually introducing negative supercoils into DNA in an ATP-dependent reaction. Both strands of the DNA are cut during this process thus allowing passage of a portion of the DNA through the break which is then resealed. All of the quinolones inhibit bacterial DNA gyrase but they possess no activity against the mammalian type II enzyme, which is the target of several anticancer drugs, such as etoposide. Evidence that the quinolones also target DNA topoisomerase IV has only been recently established (22). This enzyme is also a bacterial II DNA topoisomerase but unlike the gyrase it cannot supercoil DNA. Topoisomerase IV carries out the ATP-dependent relaxation of DNA and is a more potent decatenase than DNA gyrase. Thus, it helps separate the daughter DNA molecules after DNA replication. It is well accepted that fluoroquinolone inhibition of these two enzymes are important components in their mechanism of action. However, it is not clear how quinolones bind to the topoisomerases or precisely how the enzyme inhibition kills the cells. The drugs apparently bind to a complex of the gyrase and the DNA. This stabilizes the complex and causes the lethal effect of these drugs as it leads to induction of DNA strand breaks and freezing of the replication fork or both (23). Complexes of DNA, quinolone and active topoisomerase IV appear to form physical barriers to DNA replication. Most recently, a quinolone-induced complex of DNA and topoisomerase IV has also been shown to inhibit the activity of several DNA helicases in E. coli, including the DnaB helicase, which is one component of the replication complex (24). Also blocks in the passage of RNA polymerase leading to premature termination of transcription occur with quinolone-gyrase DNA complexes (25). However, both of these complexes appear to be insufficient by themselves to generate double-strand DNA breaks which are thought to be necessary for quinolone produced bacterial lethality (23). RESISTANCE The emergence of pathogens resistant to the fluoroquinolones has been increasing thus potentially compromising the usefulness of these drugs. Resistance to these drugs has now been found to be considerably more complicated than previously thought (26). Bacterial resistance to the fluoroquinolones can occur by two main mechanisms, alterations in the target mole- cule (e.g., DNA gyrase or topoisomerase IV) or by reduced intracellular accumulation of the quinolone antibiotics (27,28). Reduced accumulation in turn could result from a decreased uptake of the antibiotic into the cell or by an increased efflux of antibiotic from the cell through multidrugresistant efflux systems (29,30). Although both mechanisms have been shown to play a role, increased efflux seems to be the most important of the two. in a clinical setting resistance by either of these mechanisms occurs most likely from genomic mutations. No specific quinolone-modifying ordegrading enzymes have been found as a mechanism of bacterial resistance to fluoro-quinolones (29). The fluoroquinolones are an attractive group of drugs to use for the therapy of an extensive range of conditions. As a result, there has been a heavy and indiscriminate use of these drugs in some areas which has resulted in fluoroquinolone resistance emerging more rapidly than anticipated in certain pathogens, especially those that were formerly only marginally susceptible (31). There is a widespread concern that resistance will soon develop to some of the more potent quinolones that have been recently released. As a result, it is very important that these drugs be reserved for situations where they are drugs of choice and that drugs that have a lower likelihood of resistance be used (32). PHARMACOKINETICS Absorption The fluoroquinolones as a group exhibit rapid but not always complete absorption following oral administration. The oral bioavailability varies with the individual members of this class. It is approximately 30 to 50 percent for norfloxacin, and 70 to 85 percent for ciprofloxacin. With the newer members of this group such as ofloxacin and fleroxacin it approaches 100 percent (33,34). This excellent bioavailability allows oral dosing with fluoroquinolones to replace parenteral administration as long as there is no contraindication for oral administration. Peak serum concentrations of most of the quinolones are achieved in 1 to 3 hr after an oral dose. The presence of food in the gastrointestinal tract has little influence on the absorption of quinolones causing only serum peaks to appear only slightly later and to be somewhat lower (35). The concomitant administration of food may, however, help minimize any gastrointestinal distress associated with these drugs (17). Distribution The fluoroquinolones have good penetration into various fluids and tissues of the body except for the central nervous system. After oral administration, the fluoroquinolones produce serum levels that are well in excess of those required for efficacy against infections in many areas of the body (36). Drug levels significantly higher than serum are achieved in the kidney, prostate, liver and lung whereas the levels in saliva, bronchial secretions and prostatic fluid are lower than in serum (37-40). They are especially concentrated in the respiratory tract thus providing good activity against pathogens located there. Their penetration into the cerebrospinal fluid (CSF) is usually poor, although the CSF levels of ofloxacin and ciprofloxacin reached 40 to 90 percent of serum levels when the meninges were inflamed (13,41). Urine drug concentrations are high and remain above the MIC concentrations for most of the common urinary pathogens, and fecal levels are also high and sufficient to inhibit most GI pathogens. Bone concentra- 166 American Journal of Pharmaceutical Education Vol. 66, Summer 2003

5 Table I. Dosage and therapeutic uses of approved fluoroquinolones Fluoroquinolone Common therapeutic uses Dose Ciprofloxacin Gastroenteritis, traveler's diarrhea, UTIs, venereal diseases, mg bid, oral osteomyelitis, anthrax Enoxacin UTIs 200mg bid,oral Galifloxacin Community-Acquired pneumonia, chronic bronchitis 400 mg qd,oral or intravenous Levofloxacin Community-acquired pneumonia, UTIs 500 mg qd.oral or intravenous Lomefloxacin Acute diarrhea 400 mg qd,orally Moxifloxacin Community-Acquired pneumonia Norfloxacin Traveler's diarrhea, UTIs 400 bid.oral Ofloxacin Community-Acquired pneumonia, gastroenteritis, traveler's 400 bid.oral or intravenous diarrhea, UTIs, venereal diseases, osteomyelitis Sparfloxacin community acquired pneumonia 400 mg on day one. then 200mg qd, oral Trovafloxacin/ Alatrolloxacin Community -acquired pneumonia 200 mg once/day, oral or intravenous Grepailoxacin Chlamydial infections mg qd tions of ciprotloxacin and ofloxacin are excellent and are usually above the MICs for infecting bacteria. Biliary concentrations of the quinolones are five to eight times the simultaneous serum levels(42). In contrast to nalidixic acid which is 95 percent bound to protein, the newer fluoroquinolones bind to a relatively small degree (about 30 percent) and consequently serum protein will have relatively little effect on their antimicrobial activity(43). Metabolism and Excretion The fluoroquinolones differ widely in the degree to which they are eliminated by metabolism in the liver or by renal excretion. They are eliminated by both renal and nonrenal routes, but the primary route of elimination of most fluoroquinolones is by the kidney(44). A number of quinolones are cleared almost exclusively by glomerular filtration and tubular secretion and these require dosage modification when there is significant renal impairment and in the elderly(44,45). The fluoroquinolones are poorly cleared by both peritoneal dialysis and hemodialysis (<20 to30 percent)(17,35,45). THERAPEUTIC USES The fluoroquinolones have many favorable properties including broad spectrum of activity, excellent bioavailability when given orally, good tissue penetrability and a relatively low incidence of adverse effects. As a result they are widely used clinically and the number of uses is constantly growing. Although they are approved for use in the treatment of many different types of infections they are the drug of choice for only a few. They are often considered alternatives when patients are allergic or intolerant to first line drugs or if the patient does not respond to first line agents. Table II lists the approved fluoroquinolones and their therapeutic uses. In the treatment of urinary tract infections and prostatitis they are superior to nalidixic acid in their antibacterial spectrum and activity, with efficacy similar to or better than traditional antimicrobial agents, such as cotrimoxazole or amoxicillin (46). The fluoroquinolones are therefore excellent drugs for the treatment of UTIs of all types and urinary drug levels are maintained at many times the bactericidal concentrations for most uropathogens. Furthermore, their excellent tissue penetrability ensures that adequate concentrations necessary to eradicate most pathogens associated with UTIs are achieved in serum, kidney, prostate and urine (17). The long serum halflives of the newest fluoroquinolones enables them to be given once daily and a three to seven-day regimen of these drugs seems to be more effective in comparison to single dose treatment. The fluoroquinolones are highly effective in uncomplicated urinary tract infections and are drugs of choice when bacterial resistance compromises routine therapy with β-lactams. The fluoroquinolones were shown to be suitable agents for the treatment of complicated UTIs caused by P. aeruginosa or other gram-negative bacteria that are multi-drug resistant. The orally administered fluoroquinolones were found to be as efficacious as standard parenteral aminoglycoside therapy in the treatment of complicated UTIs thereby reducing the length of hospitalization and hence overall costs(47). As a result of excellent antibacterial activity and the high concentrations achieved in the bowel mucosa and in biliary fluid the fluoroquinolones are very useful in the treatment of GI infections, in contrast to the beta-lactams, tetracyclines and chloramphenicol. Many of the quinolones have now been used extensively for the prophylaxis and treatment of acute diarrhea (48). The quinolones have been shown to be very effective for the treatment of typhoid fever which is very important in light of the advent of increased resistance to drugs such as chloramphenicol and TMP-SMX. A ten day course of therapy for example, is the treatment of choice for the oral management of typhoid fever in both adults and children, reducing associated complications and relapse rates to a greater extent than other antibiotics(49,50). Quinolones such as ciprofloxacin and nor-floxacin have also become the treatment of choice for eradicating the carrier state of this disease. In most cases of non-typhoid salmonellosis, antibiotics are usually not employed. However, when certain disorders are complicated by Salmonella caused gastroenteritis, quinolones such as ciprofloxacin and norfloxacin appear promising. Among these disorders are lymphoproliferative diseases, malignant disease and immunosuppressive conditions such as AIDS, thus the quinolones are the drugs of choice in the management of invasive salmonellosis in AIDS patients. The most common health problem encountered in international travelers to tropical and subtropical areas is diarrhea. Even though it is not a life-threatening condition, it may influence greatly the quality of a vacation or the success of a busi- American Journal of Pharmaceutical Education Vol. 66, Summer

6 ness trip. Most cases of travelers diarrhea are due to bacterial pathogens (51). Fluoroquinolones are effective for both the treatment and prophylaxis of travelers diarrhea (52). For those patients receiving chemoprophylaxis for travelers diarrhea, fluoroquinolones taken once a day while in the area at risk produce the highest protection rate (up to 95 percent) (51,53). However, most authorities do not recommend routine prophylaxis for travelers diarrhea. In addition to prophylaxis, quinolones are now the drug of choice for the treatment of this disease. Ciprofloxacin has been shown to decrease the duration of diarrhea to about one episode per day, relieve associated symptoms (abdominal cramps) and minimize the number of liquid stools passed (54). As a result of drug resistance, drug toxicity and the lack of broad spectrum single agents that work against multiple genital pathogens, the role of the fluoroquinolones has been expanding in the treatment of sexually transmitted diseases(17,55). These drugs have demonstrated excellent clinical efficacy in numerous trials for the treatment of uncomplicated gonorrhea, including infections by both penicillinase-producing and non-penicillinase producing strains. They also appear to be effective in rectal and/or pharyngeal gonococcal infections (56). Trovafloxacin has shown high efficacy at low single doses in gonorrhea and after multiple dosing for chlamydial sexually transmitted disease (57,58). The fluoroquinolones are also very useful for the therapy of common respiratory infections, including communityacquired pneumonia, hospital-acquired pneumonia and acute exacerbations of chronic bronchitis (59,60). The major limitation for the use of the fluoroquinolones in respiratory infections has been their poor activity against Streptococcus pneumoniae and anaerobic bacteria. There have been several reports demonstrating therapeutic failures and serious lifethreatening complications including bacteremia and bacterial meningitis in patients with S. pneumoniae while receiving ciprofloxacin. The newer quinolones like sparfloxacin, levofloxacin, trovafloxacin, moxifloxacin, gatifloxacin and grepafloxacin, however, are very active against S. pneumoniae and appear to be effective for the treatment of communityacquired pneumonia including that caused by multidrugresistant pathogens (60-62). They have proved to be more effective than the older fluoroquinolones, as well as other antibiotics such as the beta-lactam antibiotics (60). A major advantage of these newer quinolones is their good in vitro activity against the penicillin-resistant pneumococci in contrast to the cephalosporins, β-lac-tam/β-lactamase inhibitor agents and the macrolides (59). One disadvantage of the new quinolones is that they have a broad spectrum of activity including activity against gram-negative organisms that are rare in community-acquired pneumonia and thus their widespread use may accelerate the emergence of quinoloneresistant organisms. The fluoroquinolones also appear to be useful agents in the management of acute exacerbations of cystic fibrosis and their use may obviate hospitalization and intravenous antibiotic therapy (62). The fluoroquinolones possess most of the properties necessary for the treatment of osteomyelitis and other deep seated bone and joint infections (13,63). Several studies have now shown very satisfactory results for the fluoroquinolones (particularly ciprofloxacin) in osteomyelitis due to Enterobacteriaceae (64,65). Good results have also been seen in staphylococcal and P. aeruginosa infections, but selection or development of resistant strains is more likely to occur in patients infected with these organisms, particularly if the response to therapy is not rapid (66,67). The fluoroquinolones also appear to be very useful in infections due to multi-resistant gram negative bacilli and in clinical situations in which prolonged courses of therapy are indicated, such as infections of prosthetic joints. The fluoroquinolones are effective in the treatment of various kinds of skin and skin structure infections, especially when these are caused by gram-negative organisms. When the primary pathogen is a gram-positive organism, betalactams and macrolides are preferred. For those patients who require prolonged therapy and are infected with gramnegative organisms or mixed flora, the fluoroquinolones play a major role either alone or in combinations. Mycobacterial diseases are often difficult to treat and require prolonged therapy with multidrug regimens. Fluoroquinolones have excellent bactericidal activity against many mycobacteria and achieve effective serum, tissue, and intracellular levels following oral administration and have relatively few adverse effects (68-70). Ofloxacin, ciprofloxacin, and sparfloxacin, all have shown good clinical efficacy against several mycobacterial diseases, especially tuberculosis and leprosy (71,72). The fluoroquinolones are also being effectively used in combination regimens for the treatment of multiple drug resistant tuberculosis. Disseminated infections caused by Mycobacterium avium complex (MAC) are often seen in patients with advanced AIDS. Although they have demonstrated only modest in vitro activity against MAC, the fluoroquinolones have been used in regimens to treat infections due to this organism usually in combination with macrolides, ethambutol, rifampin or amikacin. Since the quinolones have a strong bactericidal activity against gram-negative bacteria they have been extensively evaluated as prophylactic agents in neutropenic patients. Early trials demonstrated that quinolones used as prophylactics during periods of neutropenia were effective in preventing gram-negative bacteremia, but that streptococcal bacteremia occurred with increased frequency, particularly in bone marrow transplant recipients (20). For the treatment of neutropenic cancer patients with fever the combination of a fluoroquinolone with an aminoglycoside has been found to be comparable to the beta lactam-aminoglycoside combination but has the advantage of less nephrotoxicity (73). However, when used alone for this condition the quinolones were found to be less effective (74). As a result of recent threats of anthrax it has become known that naturally occurring strains of anthrax bacillus are usually susceptible to ciprofloxacin and other fluoroquinolones as well as penicillin and other antibiotics. Ciprofloxacin is one of several drugs recommended for post-exposure prophylaxis of anthrax after inhalation of spores. However, treatment after symptoms develop is probably ineffective. It is also a drug of choice for the treatment of cutaneous anthrax. ADVERSE EFFECTS Overall, the quinolones are fairly well tolerated. Even prolonged use of these compounds has been well tolerated. The pattern of adverse effects is comparable for most fluoroquinolones. However, certain structural properties of the quinolones seem to correlate with certain types of adverse effects especially with the third and fourth generation compounds. For example, quinolones with a halogen at the C- 8 position seem to cause frequent phototoxicity. The most common adverse effects associated with the fluoroquinolones are gastrointestinal upset (nausea, vomiting and 168 American Journal of Pharmaceutical Education Vol. 66, Summer 2003

7 diarrhea) ( percent)(75). These effects tend to be mild, transient and dose-dependent and are less common after intravenous administration. A wide spectrum of neurotoxic effects have been seen with the quinolones and the potential for them is an important difference from most other antibiotics. With the older nonfluorinated quinolones neurotoxic symptoms such as dizziness occurred in about 50 percent of the patients while most other quinolones produced these effects at rates below 10 percent. So far, the mechanism of CNS toxicity of quinolones is unknown. However, seizures induced either by quinolones or by magnesium deficiency can be antagonized by the NMDA-antagonist MK-801 (76,77). Mild neurotoxic reactions may occur in the form of headache, dizziness, tiredness, or sleeplessness. Abnormal vision, restlessness and bad dreams have also been reported in some instances. Severe neurotoxic side effects are seldom seen (<0.5 percent) but they have occurred with most of the quinolones developed so far and have to be considered when a patient is taking these drugs. These could include psychotic reactions, hallucinations, depression and grand mal convulsions. Typically these reactions start only a few days after the beginning of therapy and stop when the medication is terminated(13,78). Major psychiatric disturbances are also common with ofloxacin and lomefloxacin. In the case of lomefloxacin, convulsions have occurred significantly more frequently than with other fluoroquinolones, often with no past predisposing factors. However, all quinolones are contraindicated in patients with a history of convulsions. Quinolones are contraindicated in epileptics and must not be used in patients with preexisting CNS lesions involving a lowered convulsion threshold, e.g., after cerebrocranial injuries or stroke. Elderly patients, especially those with pronounced arteriosclerosis, and patients with other CNS lesions involving a lowered convulsion threshold, e.g., after cerebrocranial injuries or stroke are prone to neurologic complications and should be treated with quinolones only under close supervision(79). A variety of skin reactions have occurred after fluoroquinolone therapy and include both hypersensitivity and phototoxic reactions. Hypersensitivity reactions occur only occasionally during quinolone therapy and are generally mild to moderate in severity, and usually resolve after treatment is stopped. They include erythema, pruritus, urticaria, rash and other cutaneous reactions(13,78). Only a very few cases of anaphylactic reactions have been reported. If an allergic reaction to any of the quinolones occurs, they should be discontinued. Moderate to severe phototoxicity, manifested by an exaggerated sunburn reaction, has been seen in some patients who are taking quinolones and who are exposed to direct sunlight. This probably results from absorption of light by quinolones or their metabolites in tissue, following which, the release of oxygen radicals causes damage to lipids in cell membranes(80,81). Although all the quinolones available today show this effect, it is apparently associated with fluorination at the 8-position and thus predictably more common and potentially more severe with compounds such as lomefloxacin, fleroxacin and sparfloxacin (82). Patients should avoid excessive sunlight and artificial light while taking the quinolones and should discontinue them if phototoxicity occurs. When given to immature animals, most quinolones produce permanent damage to cartilage. This is seen as erosions of cartilage in the major diarthridial joints and other signs of arthropathy. A clear-cut relationship between quinolones and arthralgia has been established only in animal experiments. Taken together, available information indicates that all quinolones induce joint cartilage lesions in immature animals from multiple species (83). Although the exact mechanism of this arthropathy is still unknown, some data indicate that the affinity of the drugs for magnesium probably is a crucial initial step, resulting in a magnesium deficiency. A possible consequence of the depletion of functionally available magnesium in joint cartilage could be the production of oxygen-derived reactive species (84,85). The risk for humans, if any, is apparently small. However, these drugs are contraindicated in prepubertal children or in pregnant or nursing women since safe use in these groups of people has not been demonstrated. Several cardiovascular effects have been seen with the quinolones such as hypotension and tachycardia. It is unclear if these are direct effects or if they are induced via histamine release (86). Sparfloxacin and grepafloxacin, but not the other quinolones, were found to produce a moderate increase in the QT interval and associated ventricular arrhythmias (87,88). However, few serious adverse cardiovascular effects have been reported with these drugs and all have occurred in patients with an underlying cardiac condition (87). However, they should not be administered to patients with a known QT prolongation, preexisting rhythm disorders, or those currently taking antiarrhythmic agents, notably disopyramide, amiodarone and sotalol. They are also contraindicated in patients receiving other drugs which may prolong the QT interval or cause torsades de pointes, such as terfenadine, astemizole, erythromycin and cisapride.' Hematologic changes associated with quinolone therapy include decreased and elevated platelet counts, leukopenia, leukocytosis, neutropenia, eosinophilia, elevated sedimentation rate, anemia and hemolysis (78,89,90). The most serious problem experienced with a fluoroquinolone has been the temafloxacin-associated syndrome of hemolysis with in some cases, uremia, coagulopathy and hyperbilirubinemia (91). This has resulted in the withdrawal of temafloxacin from the market. Although quinolones bind to DNA, it has been found that low to moderate doses of quinolones do not have genotoxic effects and do not present a mutagenic hazard to humans. Long term carcinogenicity studies in animals have shown no indication of a carcinogenic effect with these drugs after life-long exposure (76,92). Adverse reactions to fluoroquinolones usually become apparent within the first 7 to 10 days of therapy and are frequently noted within the first several days (75). In general, adverse reactions occur with similar frequencies in young and elderly patients. However, some side effects such as those on the CNS occur more commonly in the elderly (92,93). DRUG INTERACTIONS The quinolones interact with a number of drugs which have the potential for altering their clinical effects. Some of these interactions can reduce the intestinal absorption of the quinolones after oral administration and some can result in potentially serious problems via inhibition of various metabolic pathways. Alterations of the cytochrome P450 system in the liver is especially likely to occur upon interaction with other drugs. One major drug interaction of the quinolones is reduced absorption from the GI tract, resulting in decreased therapeutic activity. Concurrent administration of di-and tri-valent salts reduce absorption of the quinolones (13,94). These include aluminum or magnesium containing antacids, zinc in multivitamin preparations, oral preparations of iron and high-dose cal- American Journal of Pharmaceutical Education Vol. 66, Summer

8 cium supplements. Pronounced alterations of quinolone absorption have been seen with dairy products, which are rich in calcium. Allowing a four to six hour interval between the administration of antacids or sucralfate and fluoroquinolones avoids these interactions. A second major type of quinolone interaction results from inhibition of various metabolic pathways, especially the cytochrome P450 enzymes and GABA neuroinhibitory pathways. For example, one of the most clinically significant interactions between the fluoroquinolones and other drugs occurs with xanthine derivatives such as theophylline and caffeine. Inhibition of the cytochrome P450 system by the quinolones and resulting reduction in plasma clearance may cause nausea, vomiting and convulsions during coadministration of theophylline (95,96). By a similar mechanism fluoroquinolones interfere with caffeine metabolism and both sleep disturbances and upper gastrointestinal symptoms become apparent (97). Patients taking quinolones should be advised against excessive caffeine intake. Some quinolones (e.g., enoxacin, norfloxacin or ofloxacin) have been reported to enhance the effects of warfarin or its derivatives. Studies on the interactions between quinolones and warfarin indicate that enoxacin causes the prolongation of the elimination half-life of (R)-warfarin, while not affecting (S)- warfarin. Because the(r)enantiomer is much less active than the (S)-isomer, the overall enoxacin warfarin interaction may be of little clinical significance (98). However, it is generally recommended that patients have their prothrombin time or other suitable coagulation test closely monitored when they are taking the two drugs concurrently (17). Synergistic inhibition of central nervous system GABA receptors by fluoroquinolones and nonsteroidal anti-inflammatory drugs (NSAIDs) may cause neuroexcitatory phenomena. These effects are dose dependent and vary between the different groups of fluoroquinolones (99). In humans, convulsions have been reported only in patients receiving enoxacin and fenbufen. CONCLUSION The fluoroquinolones represent a relatively new group of antibiotics with a broad-spectrum of antibacterial activity and a novel mechanism of action. Although the earlier quinolones were effective only in urinary tract and gastrointestinal infections the newer drugs in this class have much wider potential applications. Overall the quinolones are considered relatively safe when compared to other commonly used antimicrobial agents. With the rate of bacterial resistance increasing among available antibiotics the quinolones will likely gain many more important indications in the future. References (1) Owens, R.C. and Ambrose, P.G., "Clinical use of the fluoroquinolones," Medical Clin. N.A., 84, (2000). (2) Andriole, V., The Quinolones, Academic Press, New York NY (1998). (3) Kuhlmann, J., Dalhoff, A. and Zeiler, H.-J., Quinolone Antibacterials, Springer-Verlag, New York NY(1998). (4) Gootz, T.D. and Brighty, K.E., "Fluoroquinolone antibacterials: SAR, mechanism of action, resistance, and clinical aspects," Med. Res. Revs., 16, (1996). (5) Eliopoulos, G.M., "In vitro activity of new quinolone antimicrobial agents," in Microbiology, (edit., Leive, L.), Amer. Soc. Microbiol., Washington DC (1986) pp (6) Wiedemann, B. and Grimm, H., "Susceptibility to antibiotics: Species incidence and trends," in Antibiotics in Laboratory Medicine, (edit., Lorian, V.), Williams & Wilkins, Baltimore MD (1996) pp (7) Gleckman, R., "What do the new antimicrobials offer?," Post Grad. Med., 109, 87-91(2001). (8) Appelbaum, P.C. and Hunter, P.A., "The fluoroquinolone antimicrobials: Past, present and future prospectives," Inter. J. Antimicrob. Agents, 16, 5-15(2000). (9) Talan, D.A., "Clinical perspectives on new antimicrobials: Focus on fluoroquinolones," Clin. Infect. Dis., 32(Suppl.1), (2001). (10) Eliopoulos, G.M., Wennersten, C.B. and Moellering, Jr R.C., "Comparative in vitro activity of levofloxacin and ofloxacin against gram-positive bacteria," Diagn. Microbiol. Infect. Dis., 25, 35-41(1996). (11) Von Eiff, C. and Peters, G., "In vitro activity of ofloxacin, levofloxacin and D-ofloxacin against staphylococci," J. Antimicrob. Chemother., 38, (1996). (12) Wolfson, J.S. and Hooper, D.C., "Fluoroquinolone antimicrobial agents," Clin. Microbiol. Rev., 2, (1989). (13) Suh, B. and Lorber, B., "Quinolones," Med. Clin. North America, 79, (1995). (14) Phillips, I., King, A. and Shannon, K., "In vitro properties of the quinolones," in The Quinolones, (edit., Andriole, V.T.), Academic Press, New York NY (1998) pp (15) Gay, J.D., DeYoung, D.R. and Roberts, G.D., "In vitro activities of norfloxacin and ciprofloxacin against Mycobacterium tuberculosis, M. avium complex, M. cheloni, M. fortuitum and M. kansasii," Antimicrob. Agents Chemother., 26, 94-96(1984). (16) Fenlon, C.H. and Cynamon, M.H., "Comparative in vitro activities of ciprofloxacin and other 4-quinolones against Mycobacterium tuberculosis and Mycobacterium intracellular," ibid., 29, (1986). (17) Von Rosenstiel, N. and Adam, D. "Quinolone antibacterials. An update of their pharmacology and therapeutic use," Drugs, 47, (1994). (18) Neu, H.C., "Major advances in antibacterial quinolone therapy," Adv. Pharmacol., 29A, (1994). (19) Spangler, S.K., Jacobs, M.R. and Appelbaum, P.C., "Activity of CP 99,219 compared with those of ciprofloxacin, grepafloxacin, metronida-zole, cefoxitin, piperacillin, and piperacillin-tazobactam against 489 anaerobes," Antimicrob. Agents Chemother., 38, (1994). (20) Hooper, D.C., "New uses for new and old quinolones and the challenge of resistance," Clin. Infect. Dis., 30, (2000). (21) Hooper, D.C., "Mechanisms of fluoroquinolone action, " Clin. Infect. Dis., 32(Suppl. 1), S9-15(2001). (22) Scholar, E.M. and Pratt, W., The Antimicrobial Drugs, 2nd ed., Oxford University Press, New York NY (2000). (23) Drlica, K. and Zhao, X.L., "DNA gyrase, topoisomerase IV, and the 4- quinolones," Mol. Biol. Rev., 61, (1997). (24) Shea, M.E., and Hiasa, H., "Interactions between DNA helicases and frozen topisomerase IV -quinolone-dna ternary complexes," J. Biol. Chem., 274, (1999). (25) Willmott, C.J., Critchlow, S.E., Eperon, I.C. and Maxwell, A., "The complex of DNA gyrase and quinolone drugs with DNA forms a barrier to transcription by RNA polymerase," J. Mol. Biol., 242, (1994). (26) Martinez, J.L., Alono, A., Gomez-Gomez, J.M. and Baquero, F., "Quinolone resistance by mutations in chromosomal gyrase genes. Just the tip of the iceberg?," J. Antimicrobial Chemotherapy, 42, (1998). (27) Weidemann, B. and Heisig, P., "Mechanisms of quinolone resistance, Infection, 22(Suppl. 2), S73-S79(1994). (28) Everett, M.J. and Piddock, L.J.V., "Mechanisms of resistance to fluoroquinolones," in Quinolone Antibacterials, (edit., Kuhlmann, J., Dalhoff, A. and Zeiler, H.-J.), Springer-Verlag, New York NY (1998) pp (29) Hooper, D.C., "Emerging mechanisms of fluoroquinolone resistance," Emer. Infect. Dis., 7, (2001). (30) Poole, K., "Efflux-mediated resistance to fluoroquinolones in gramnegative bacteria," Antimicrob. Agents Chemo., 44, (2000). (31) Drlica, K., "The future of fluoroquinolones," Ann. Med., 32, (2000). (32) Thomson, K.S., "Minimizing quinolone resistance: are the new agents more or less likely to cause resistance?," J. Antimicrob. Chemo., 45, (2000). (33) Brown, E.M. and Reeves, D.S., "Quinolones," in Antibiotic and Chemotherapy, (edit., O'Grady, F., Lambert, H.P., Finch, R.G. and Greenwood, D.), Churchill Livingstone, New York NY(1997) pp (34) Schentag, J.J., Nix, D.E. and Wise, R., "Pharmacokinetics and tissue penetration of quinolones," in The New Generation of Quinolones, (edit., Siporin C., Heifetz C. and Domagala, J.), Marcel Dekker, New York NY(1990)pp (35) Robson, R.A., "Quinolone pharmacokinetics," Intern. J. Antimicrob. Agents, 2, 3-7(1992). (36) Gerding, D.N. and Hitt, J.A., "Tissue penetration of the new quinolones in humans," Rev. Infect. Dis., 11(Suppl. 5), S1046-S 1057(1989). (37) Malmborg, A.S. and Rannikko, S., "Enoxacin distribution in human tis- 170 American Journal of Pharmaceutical Education Vol. 66, Summer 2003