Can

Fluoroquinolones Once-Daily Harold

Fluoroquinol concentrations, the available

Be Considered Therapy? C. Neu,

MD,

FACP

one

antimicrobial agents inhibit most Enterobacteriaceae at extremely low O.5 ,zg/mL. The half-lives of the agents range from 4to 18 hours. Most of fluoroquinolones can be administered once daily to treat urinary tract and diarrheal infections. Newer agents with long half-lives that inhibit gram positive organisms at lower concentrations than the older fluoroquinolones, 1 zg/mL, and have a long postantibiotic effect have the potential to be used once daily as treatment of respiratory, skin-structure and selected bone infections as well. Careful clinical studies are needed to establish the efficacy of once daily use of fluoroquinolones, to determine that clinical efficacy is equivalent to multiple doses, and that once-daily dosing does not select more resistant bacteria. Single-dose therapy with quinolones would be an improvement in cost and patient compliance.

I

n the last several years there has been great interest in developing ways to administer antimicrobial agents less frequently both in the hospital and in the community setting.’ A reduction in the number of administrations in the hospital has major cost-saving potential.5 In the community, it has been shown that in the treatment of diseases such as tuberculosis, single daily administration of a drug is associated with a much higher degree of compliance by patients.6 For many years antimicrobial agents have been administered orally on a four times a day basis irrespective of their pharmacokinetic profiles. Penicillin, with a blood half-life of 1 hour, was administered four times daily, as was tetracycline with a blood half-life of 9 hours.7 Parenteral agents such as the aminoglycosides were administered three times daily, although in many situations it was realized that a twice a day or single daily dose was adequate to treat infections, particularly in areas such as the urinary tract.8 As our understanding of infectious diseases has improved, there has been greater attention to the pharmacokinetics and pharmacodynamic properties of antimicrobial agents.9’1#{176}Alternate forms of therapy have been constructed for many infectious diseases. Diseases such as streptococcal pharyngitis will

From the College of Physicians & Surgeons, Columbia University, New York, New York. Address for reprints: Harold C. Neu, MD, FACP, College of Physicians & Surgeons, Columbia University, 630 West 168 Street, New York, NY 10032.

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#{149} J CIIn Pharmacol

1992;32:692-697

respond to twice-daily therapy with an oral beta-lactam that has a half-life of only 1 hour. Similar responses of streptococcal pharyngitis have been seen with twice daily administration of erythromycin. Fluoroquinolone antimicrobial agents have recently become available.11’12 These agents are the offspring of nalidixic acid, which was synthesized in the early 1960s. Nalidixic acid had a number of pharmacologic disadvantages such as high protein binding, extensive metabolism, and lack of activity against many important pathogens. With the advent of drugs such as norfioxacin, ciprofloxacin, ofloxacm, and pefloxacin, which have been in use for a number of years, it has been possible to delineate many areas of use for fluoroquinolone antimicrobials.11’12 Fluoroquinolone antimicrobial agents vary in half-life from 4 hours for compounds such as norfloxacin to prolonged half-lives of 18 hours with newer agents such as sparfloxacin.13 The compounds also differ in their antimicrobial activity and degree of metabolism. It is reasonable to investigate situations in which it may be feasible to use fluoroquinolones on a one-daily basis. ANTIMICROBIAL

ACTIVITY

The current fluoroquinolones inhibit most of the Enterobacteriaceae, Haemophilus, Neisseria, and Moraxella species at low concentrations.11’12 They inhibit some gram-positive organisms such as Staphylococ-

FLUOROOEJINOLONES

AS

aureus and some coagulase-negative staphylococci at readily achievable concentrations. They differ in their activity against organisms such as Streptococcus pneumoniae, beta-hemolytic streptococci, such as Streptococcus pyogenes and S. agalactiae. Agents such as norfioxacin, enoxacin, fleroxacm, and lomefloxacin do not inhibit these streptococci at fluid or tissue concentrations. Ciprofloxacin, ofloxacin, and temafloxacin have MICs for pneumococci and streptococci that are near the peak serum levels.12 Compounds such as sparfioxacin and tosufloxacin inhibit gram-positive species at much lower concentrations than did the earlier agents.14’15 In vitro activity always must be correlated with pharmacologic properties, but fluoroquinolones have several important microbiologic properties that allow less frequent dosing. This includes the fact that they have a prolonged post-antibiotic effect (PAE) on both grampositive and gram-negative bacteria.16 Organisms may not resume growth until 2 to 6 hours after having been exposed to a fluoroquinolone. Fluoroquinolones also have the ability to inhibit bacteria that are growing slowly as well as rapidly dividing organisms. This is of importance since many organisms in an infectious population may not be dividing at a rapid rate as would be needed for compounds involved in killing bacteria by inhibition of cell-wall biosynthesis such as with the beta-lactam and glycopeptide compounds. Further factors that are important in infrequent administration of a drug resolve around the development of resistance. Resistance development for most of the Enterobacteriaceae is infrequent, with rates of single-step increases in MICs of four- to eightfold occurring at a level of b_b to 10-11.17 However, for some species such as methicillin-resistant S. aureus and Pseudomonas aeruginosa, the frequency of this resistance development may be lower, that is in the range of iO- to iO. With fluoroquinolones, bactericidal concentrations usually are within a dilution of the inhibitory concentration for both gram-positive and gram-negative bacteria. Due to the low inhibitory concentrations against Enterobacteriaceae, Haemophilus, Neisseria, and Moraxella, and the low protein binding of these compounds, serum concentrations frequently remain above the inhibitory concentrations for prolonged periods. In addition to the prolonged plasma concentrations, tissue concentrations and interstitial fluid concentrations are high as are intracellular phagocytic concentrations in both polymorphonuclear cells as well as concentrations in circulating and fixed macrophages such as the alveolar macrophage and Kuppfer cells in the liver.18 GUS

SYMPOSIUM

ON

ONCE-DAILY

ORAL ANTIMICROBIAL

THERAPY

ONCE-DAILY

THERAPY

Obviously, it is important that the prolonged plasma and tissue concentrations do not increase hematologic, neurologic, hepatic, renal, or gastrointestinal adverse effects of these agents. What factors affect the use of fluoroquinolones as once-daily oral therapy? The factors that are clearly important in oral therapy are the degree of the absorption of the drug, variation and absorption among different ethnic and genetic populations, the length of time the agent will remain at a concentration above the MIC or the organisms causing a particular infection being treated, and above all, the concentration of agent at the infection site. The ability to use once-daily oral therapy is highly dependent on the microorganisms involved in the infection and the location within the body.19 If organisms are in a sequestered area into which there would be poor perfusion of drug, single daily therapy might promote resistance or increase the likelihood of clinical failure. The severity of illness clearly is another important factor. Single daily therapy would be of risk in life-threatening infections, and in these kinds of situations it is obvious that one could not risk the chance of error in administration of the drug. One would be concerned whether the disease state in terms of the host protective elements is placing the entire burden on the fluoroquinolones. This means that in a markedly immunocompromised patient lacking white cells, adequate antibody, and complement, single dose therapy would not be advisable. Currently fluoroquinolones are used to treat a number of different infectious states. Urinary tract infections, gastrointestinal infections, skin and skinstructure infections, bone and joint infections, and respiratory infections have all been successfully treated with various members of the fluoroquinolone class.11’12 It seems appropriate to examine each indication and determine those clinical situations in which single daily therapy is appropriate or to be preferred to multiple doses. URINARY

TRACT

INFECTIONS

The concentration currently available Japan, irrespective in urine is above

of virtually all fluoroquinolones in the United States, Europe, and of their plasma half-life, present the MICs of the important Enterobacteriaceae, P. aeruginosa, and Staphylococcus saprophyticus which account for the majority of urinary tract infections.20’21 In many situations urine bactericidal concentrations are present for over 48 hours. Single dose therapy with fluoroquinolones has not been as successful as has been therapy for 3 or 5 days irrespective of the agent examined.20 However, sin-

693

NEU

gle daily doses administered for 3 or 5 days with agents such as lomefloxacin and fleroxacin in recent studies has shown cure rates comparable to those achieved with cotrimoxazole administered twice daily for 7 to 10 days.21 Even in acidic urine, fluoroquinolones are bactericidal due to their high concentrations and their ability to decrease the attachment of bacteria to epithelial surfaces. Thus it is reasonable at the present time to administer a fluoroquinolone on a single daily basis for 3 to 5 days to treat uncomplicated urinary tract infections. It is not reasonable to continue programs administering fluoroquinolones at low doses three times a day as is the

currently

larly

in

program

in

some

countries,

particu-

Japan.

Are there situations in which single daily dose therapy of uncomplicated urinary tract infection could be hazardous? It is unlikely that uncomplicated urinary tract infections will be a problem for single daily dose therapy except for the rare compound that produces exceedingly low urinary concentrations. Consider the situation of a compound such as sparfioxacin which produces peak urinary concentrations of 20 tg/mL in the first 8 hours and concentrations of 5 to 7 tg/mL at 48 hours after a 400-mg dose. These concentrations would still inhibit an Escherichia coli, which would be the major cause of uncomplicated urinary tract infection. However, these concentrations might well not be as successful with an organism such as S. saprophyticus or a less common cause of uncomplicated urinary tract infection such as Klebsiella pneumoniae or Proteus mirabilis since the MICs in acidic urine might well be near the urinary concentration. In acute pyelonephritis which is also most frequently caused byE. coli, most of the currently available qumnolone agents could be administered once daily after the acute period of illness, that is the first 48 hours in which the patient has become afebrile. In complicated

urinary

tract

infections

some

caution

must be exercised about the use of once daily administration of a fluoroquinolone. In complicated urinary tract infections organisms such as P. aeruginosa, Serratia marcescens, Klebsiella pneumoniae, and multiple resistant E. coli are the major pathogens. In recent years the MICs of these organisms to the fluoroqumnolones have been increasing, particularly in patients who have had indwelling urethral catheters. Thus it would seem that it is critical to know the MIC when considering single daily therapy with a fluoroquinolone. To treat complicated urinary tract infections, it would be preferable to have a drug that is highly absorbed, produces high urinary concentrations, and has a long plasma and urine

694

#{149} J Clin Pharmacol

1992;32:692-697

half-life above tion in urine.

RESPIRATORY

the

minimal

TRACT

bactericidal

concentra-

INFECTIONS

There has been great concern about the use of fluoroqumnolones in respiratory tract infections. In spite of fairly impressive results in the therapy of bacterial exacerbations of chronic bronchitis and bacterial pneumonia,22 many infectious disease physicians have reservations about the use of the drugs in these particular situations. The major pathogens involved in bacterial exacerbations of bronchitis are Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, Streptococcus pneumoniae, and less frequently Haemophilus parainfluenzae and Neisseria species. Of these organisms, with the exception of S. pneumoniae, all are inhibited by the currently available or under study quinolones at concentrations of 0.12 g/mL. There are no controlled studies that have been done to establish how long a half-life is necessary to treat these organisms in exacerbations of bronchitis. Should the half-life be 4, 7, 8, 10, or 18 hours? Review of clinical studies of respiratory tract infections has indicated that although the eradication of H. inJ1uenzae and Moraxella exceeds 90%, eradication of S. pneumoniae frequently is only at 70%.22 In the treatment of pneumonia with ciprofloxacin at doses of 500 mg twice daily, inadequate levels above the MIC may be present if the organisms have MICs of 2 g/mL as some isolates do. This may explain the occasional breakthrough bacteremia and extrapulmonary infection due to S. pneumoniae that have been reported.23 With the currently available drugs, it would seem that acute bacterial exacerbations of bronchitis should be treated twice daily with compounds such as ciprofloxacin and ofloxacin. The lack of activity against S. pneumoniae of agents with longer half-lives such as lomefloxacin and fleroxacin would prevent their use as single agents to treat any infection in which S. pneumoniae was a pathogen. Temafloxacin at doses of 600 mg produces blood levels above the MIC of most pneumococci for periods up to 6 hours. Nonetheless, this agent also would not be considered as single dose therapy for S. pneumoniae. Sparfioxacin has been shown to inhibit Haemophilus at concentrations as low as 0.007 zg/mL, S. pneumoniae at 0.25 tg/mL, and organisms such as K. pneumoniae at 0.25 g/mL. At higher doses of sparfloxacin, this agent could inhibit these organisms on a once-daily basis given its 18-hour half-life, but clinical studies are needed to establish this. There are a number of intracellular pathogens that

AS

FLUOROQ[JINOLONES

ONCE-DAILY

produce respiratory tract infections. These include Mycoplasma pneumon iae, Chlamydia pneumoniae, and most importantly Legionella species. The MICs of fluoroquinolones range from 0.06 to 2 zg/mL for these species. In general, intracellular concentrations exceed plasma levels by four- to tenfold with variations among the drugs. There is inadequate data at present to determine whether single daily therapy for these organisms would be appropriate. It is conceivable that agents with half-lives in excess of 12 hours would provide continued intracellular concentrations to treat Legionella and Chlamydia. For example, at 400 mg, once-daily sparfioxacin would yield serum and intracellular concentrations 16-fold above the MIC of Legionella pneumophila. The correct use of fluoroquinolones in respiratory tract infections needs to be established with the increasing resistance of pneumococci to penicillin, primarily in the Mediterranean countries, but also occurring in other parts of the world. Studies have demonstrated sparfloxacin blood levels at 12 hours of 1.2 zg/mL, bronchial mucosal levels of 2.5 zg/mL, alveolar macrophage levels of 70.9 pg/mL, and epithehal lining fluid, in which pneumococci would be present, of 16.7 1zg/mL. This would suggest that single daily therapy with this fluoroquinolone which inhibits respiratory pathogens at low concentrations might be successful. Nonetheless one will have to view with caution serious pneumococcal disease. The mortality associated with pneumococcal bacteremia and pneumococcal pneumonia has remained at approximately 25% throughout the antibiotic era from the 1960s to the present. Another important area to consider in respiratory infections are the more complicated ones that occur within the hospital setting, particularly due to P. aeruginosa. The MICs of P. aeruginosa have been increasing yearly due to the extensive use of fluoroquinolones. Even with a 750-mg dose of ciprofloxacm administered twice daily yielding blood levels of 4 g/mL, there have been occasional failures in hospitalized patients and resistance of Pseudomonas has developed in patients with cystic fibrosis or chronic bronchiectasis.24 The MICs of many of the new fluoroquinolones with improved gram-positive activity are less than that of ciprofloxacin against gram-negative species. Thus it is questionable whether new agents that produce blood levels for long periods, albeit at lower concentrations, would prove satisfactory as once-daily therapy for Pseudomonas infections. In the hospital situation, it is not as difficult to administer a drug twice daily, and it would seem that higher concentrations would be exceedingly useful in the therapy of organisms such as P. aeru-

SYMPOSIUM

ON ONCE-DAILY

ORAL ANTIMICROBIAL

THERAPY

THERAPY

ginosa. One will probably not be able to achieve therapy of P. aeruginosa on a once-daily basis with any of the currently available fluoroquinolones. In contrast, organisms such as K. pneumoniae, Enterobacter, Serratia, and E. coli producing nosocomial respiratory tract infections could be treated once a day with qumnolones, provided that the concentrations were well in excess of those that inhibit the organisms both at the bronchial tissue and the lung parenchymal level. SKIN

AND

SOFT

TISSUE

INFECTIONS

It is unfortunate that the therapy of skin and soft tissue infections with fluoroquinolones has resulted in the rapid development of resistance in species such as methicillin-resistant Staphylococcus aureus.25 Many fluoroqumnolones have borderline inhibitory concentrations for hemolytic streptococci. Many of the fluoroquinolones also have no or poor antianaerobic activity, and when dealing with poorly perfused tissue such as in the diabetic patient or an individual with vascular insufficiency, anaerobic species are important. Clinical studies have demonstrated that ciprofloxacm, ofloxacin, and temafloxacin with varying serum concentrations and different half-lives have proven, when administered on a twice-a-day basis, to be comparable to parenterally administered thirdgeneration cephalosporins such as cefotaxime and ceftazidime.26’27 Once-daily therapy of serious Streptococcus pyogenes or S. agalactiae infections with a fluoroquinolone would have to be undertaken with extreme caution. Given the poor perfusion of tissue frequently encountered in patients with serious skin structure infections, once-daily therapy might result in a greater degree of bacterial resistance than already encountered.28 OSTEOMYELITIS The major organisms involved in osteomyehitis for which fluoroquinolones are appropriate therapy are Pseudomonas aeruginosa, Enterobacteriaceae, and Staphylococcus aureus, including methicilhin-resistant strains. Osteomyelitis has been an infection in which resistance has developed to fluoroquinolones, particularly with methicillin-resistant S. aureus and P. aeruginosa. Single daily dose therapy will only be effective if it is possible to achieve high concentrations in bone for the entire period of time that one would be treating the infection. Current results with twice-daily therapy with ciprofloxacin and ofloxacin have produced cures in the range of 60 to 80%. These

695

NEU

cures of chronic osteomyehitis are comparable to what has been achieved with multiple intravenous therapy for periods up to 6 weeks. Single daily dose therapy should be effective in certain situations provided that close attention is given to removal of all the devitalized bone which has been a cause of much of the resistance in the last several years. Only extensive studies with single daily dose therapy of osteomyelitis in comparison to twice daily therapy will answer the question of single daily therapy. Given the difficulties in accumulating adequate numbers of similar patients, it is doubtful it will be possible to achieve clinical studies that will establish that single daily dose therapy is effective. SEXUALLY

TRANSMITTED

DISEASE

The fluoroquinolones have been shown to be excellent therapy for traveller’s diarrhea and acute diarrheal diseases due to Shigella, E. coli, Vibrio, Aeromonas, and Salmonella species, all of which are inhibited at low concentrations.29 Only with Campylobacter has resistance been encountered, but there has been persistence of Salmonella in some individuals

treated

qumnolones

696

for

Salmonellosis.3#{176}

are excreted

#{149} J Clin Pharmacol

into

Since

the intestine,

1992;32:692-697

OTHER

the

fluoro-

it is logi-

INFECTIONS

It is probable due eus,

DISEASES

Single-dose therapy has been effective as therapy of Neisseria gonorrhoeae involving the genital organs and the rectum.2#{176}However, pharyngeal disease has been less successfully treated. Drugs that would produce high concentrations for a long period should be effective. Previous studies of Chlamydia trachomatis with norfioxacin and ciprofloxacin have been less successful than studies of agents with longer halflives such as ofloxacin and fleroxacin. Therapy of Chlamydia requires both excellent in vitro activity and that the drug be present for a long period. Single daily-dose therapy in agents with half-lives in excess of 12 hours should be successful. Studies of sexually transmitted pathogens have shown that sparfioxacin inhibits C. trachomatis at concentrations of 0.06 g/ mL, Myco plasma hominis at 0.01 g/mL, and Ureaplasma urealyticum at 0.5 tg/mL. With the exception of the ureaplasma, it would seem that sparfioxacm administered once daily should be effective single daily therapy. But how long it is necessary to have concentrations of drugs within macrophages and in the genital tissues is unknown. Studies with azithromycmn, a macrolide antibiotic, have demonstrated that a single 1-g dose is curative of chlamydial genital infection.

DIARRHEAL

cal that those with long half-lives could be administered once daily for a 3-day period and produce cures of diarrheal illness comparable to the cures that have been achieved with the present agents. Drugs such as sparfioxacin which has an extensive enterohepatic cycle and has 60% of the drug present in the feces in unchanged amounts may prove to be successful for diarrheal disease and might be less likely to result in continued fecal excretion of organisms such as Salmonella.

that

in many

postoperative

infections

to Enterobacteriaceae, P. aeruginosa, and S. aurprovided that the MICs of the organisms are less

than 0.5 tg/mL, a single daily therapy with a fluoroquinolone whose half-life exceeded 12 hours could be used. Nonetheless, there is significant risk of the development of resistance with methicillin-resistant S. aureus, P. aeruginosa, and some of the Enterobacteriaceae such as S. marcescens. Once-daily prophylaxis should be possible with many of the new fluoroqumnolones in urologic surgery since all of the pathogens are inhibited at low concentrations, and urinary and prostate levels are excellent. In vascular and proved gram-positive

cardiac

surgery, agents antistaphylococcal

with imactivity

against both S. aureus and the coagulase-negative staphylococci may provide single-daily prophylaxis. A similar rationale could be advocated for orthopedic surgery and biliary tract surgery. CONCLUSION Overall there are a number of infectious disease entities in which single daily fluoroqumnolone therapy may be reasonable. The critical aspect of the single daily dose therapy with fluoroqumnolones is whether the agents will by this route select more resistant organisms. If this does not occur, such single-dose therapy may prove to be an improvement in terms of both cost and patient compliance. REFERENCES 1.Gately MS: 1969:16:39-44. 2. Barriere Inteil Clin 3.

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