Antibiotic Update 1998: Part 1The Antimicrobial Armamentarium
Author: Gideon Bosker, MD, FACEP, Associate Clinical Professor, Department of Emergency Medicine, Oregon Health Sciences Center, Portland, OR. Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine.
Peer Reviewers: Norman C. Christopher, MD, Director, Emergency and Trauma Services, Children’s Hospital Medical Center of Akron, Akron, OH; Stephen P. Ernst, PharmD, Clinical Pharmacy Coordinator, Columbia Terre Haute Regional Hospital, Terre Haute, IN; Jonathan Edlow, MD Clinical Director, Beth Israel and Deaconess Medical Center, Boston, MA; Instructor in Medicine, Harvard Medical School, Cambridge, MA; Albert Weihl, MD, Emergency Medicine Residency Program Director, Yale-New Haven Medical Center, Section of Emergency Medicine, Department of Surgery, Yale University School of Medicine.
Editor’s NoteThis issue begins the first of a two-part series on Antibiotic Update 1998. Part I deals with issues of compliance, resistance, and the advantages and disadvantages of the newer agents in the antibiotic armamentarium. Part II will focus on achieving optimal clinical outcomesmatching the bug with the drugfor most common conditions that face the primary care physician.
Selecting antibiotics in the primary care setting is a confusing, critical, and controversial exercise with formidable financial and clinical implications. Not surprisingly, with the introduction of so many new antimicrobial agents, the noise level in the "antibiotic of choice" arena has become almost deafening. There are claims and counter-claims for the superiority of one drug over another or of one class over another, with many of these opinions being rendered on the basis of personal anecdotal experience and selective interpretation of clinical trials. Because precise delineation of an etiologic agent is often impractical or unnecessary in the outpatient environment, antibiotic selection is almost always empiric and rarely benefits, at least initially, from microbiologic identification or susceptibility results.
But there are other pitfalls as well. Many patients may not require antibiotic therapy, although distinguishing among patients who do and do not require antimicrobial intervention can be a formidable clinical challenge. Even if an antibiotic with an appropriate spectrum of coverage is identified, there is always the issue of medication compliance, which can be woefully inadequate in the case of agents requiring multiple daily dose administration and prolonged courses of therapy. Aside from ensuring targeted spectrum of coverage, the issues of palatability, toleration, side effects, and convenience are fundamental to maximizing cure rates in the real-world environment.
With the recent explosive growth of the antibiotic pharmacopoeia, appreciating subtle but clinically important differences among antimicrobials has become increasingly difficult. In this regard, newer quinolones have become available that have expanded indications for community-acquired pneumonia (CAP), and one advanced generation macrolide is now indicated for parenteral therapy in hospitalized patients with lower respiratory tract infections. It may be difficult for clinicians to keep abreast of new indications, new agents, and their clinical implications.
Unfortunately, the selection process is never easy, even for well-educated practitioners at the front lines of clinical practice. Experienced clinicians, especially those who work in a managed care environment, are particularly aware of the debate: To choose a new, more conveniently dosed and, usually, more costly, antimicrobial with documented patient-friendliness and more predictable coverage or to choose a less expensive, vintage, warhorse drug with undesirable side effectsone that is "report card" and formulary-friendlyand which requires a 30-dose course of therapy. That is the question.
The fact is, no matter how we frame the issue, nothing seems to produce more debate among health care practitioners than selection strategies for outpatient antibiotic therapy. In addition, it should be stressed that in clinical environments that are patient volume-driven and that are dominated by capitated reimbursement arrangements, there are powerful incentives to "cure" infections the first time around (i.e., within the framework of the first prescription generated in the initial visit).
Although optimizing cure rates with so-called convenient, dose- and duration-friendly branded agents that provide appropriate coverage may be perceived as costly on a course of therapy basis, it is important to stress that antimicrobials with these properties can also help avoid the unnecessary costs of patient re-evaluations, return visits, treatment failures, patient dissatisfaction, and the pharmacological reservicing cost associated with initiating a second course of antibiotics. In this sense, antibiotics that lower barriers to clinical cure can be seen as "productivity" tools that improve efficiency of clinical care and, potentially, reduce the overall costs associated with outpatient management of infections.
Clearly, coverage of implicated pathogens is critical for cost-effective care. Making matters worse is the difficulty of identifying an appropriate, cost-effective antibiotic that is "smart" enough to provide coverage against the most likely offending organisms in a particular patient. For example, in children with otitis media, a so-called "high-performing" antibiotic must be "smart" enough to cover appropriate species of Streptococcus pneumoniae, Haemophilus influenzae, and M. catarrhalis. In adults with CAP, the corral of coverage must be expanded to include atypical organismsMycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniaewhich are now implicated in about 22% of cases with CAP.
In the real world, the road from the clinician’s prescription pad to clinical cure depends on a constellation of factors (i.e., beyond spectrum of coverage) including prescription, patient, drug, and in the case of suspensions, parent-resistance (PPD factors). The PPD approach to antimicrobial selection in the emergency and primary care setting attempts to account for all the factorsand potential barriersthat go into the equation for clinical cure. These include cost of the medication, compliance profile, palatability issues, duration of therapy, gastrointestinal side-effect profile, convenience of dosing, and spectrum of coverage.
Overcoming these barriers to clinical cure is essential for enhancing clinical outcomes and reducing the costs of therapy and complications of the disease. The goal, of course, is to identify an antibiotic that will simultaneously manage cost, manage coverage, and manage compliance, so that, ultimately, the clinician can manage care of the patient in an outcome-effective manner.
Although primary care physicians mainly prescribe oral antibiotics, parenteral antibiotics are commonly used to initiate therapy for hospitalized patients, who will then continue oral treatment in the outpatient setting. An understanding of how initial selection of intravenous antibiotic therapy in the hospital may affect subsequent choices for completing the treatment course with oral agents has become an important cost and clinical consideration for the primary care practitioner.
With these issues in mind, this 1998 Antibiotic Update article, which presents a thorough discussion of recent advances, new indications, intravenous/oral treatment combinations, and controversies, outlines a rational, systematic approach to antimicrobial selection in the primary care setting, with a special emphasis on indications and rational guidelines for day-to-day use.
The Antimicrobial Armamentarium: Uses and Abuses
In addition to the older, so-called "standard" antibioticsmost notable among them, the penicillins and sulfa drugsthere are many newer oral agents, particularly cephalosporins, quinolones, and macrolides, that play a role in treating bacterial infections commonly encountered in the primary care setting. Typically, antibiotics have been evaluated by comparing spectrum of activity, clinical efficacy, toxicity (adverse drug reactions and interactions), pharmacokinetics (convenience and compliance with dosing), and cost. In addition to these parameters, there are at least two additional factors that must be taken into account when comparing antibiotics: 1) the selective pressure for the emergence of resistant organisms; and 2) the overall cost-effectiveness or outcome cost.
The newer antibiotics, although possessing variable increases in the spectrum of activity over older agents, have uniformly been shown in clinical trials to be equally, but rarely more efficacious, than standard therapy. It should be stressed, however, that within the context of clinical trials, patients are frequently given incentives through counseling and pill counts to comply with their regimens. Notably, outcomes in these studies may deviate from those seen in the "real world," where noncompliance with antibiotics is a major barrier to clinical cure. Consequently, it may be difficult to extrapolate from cure rates published in idealized clinical trials to the front lines of emergency medicine practice.
Generally speaking, most advantages associated with newer drugs are typically found in parameters other than spectrum of coverage. For example, some of the newer agents have a significantly improved toxicity or drug interaction profile compared with conventional therapy. One drawback of newer agentseven those that belong to familiar classes of antibioticsis limited information regarding specific toxicity issues. In this regard, temafloxacin, a fluoroquinolone antibiotic, was withdrawn from the worldwide market just four months after approval in the United States because of subsequent reports of serious hemolysis, with or without other organ system dysfunction. This adverse reaction (temafloxacin syndrome) was not recognized in patients participating in the clinical trials but became evident when nearly 200,000 prescriptions were written after approval.1,2
Outcome Considerations in Antibiotic Selection
Barriers To Clinical Cure for Oral Antibiotic Therapy. In the best and most cost-effective of all worlds, the antibiotic selection process for common infections such as pneumonia, acute otitis media, cystitis, and PID would be based on an outcome-oriented assessment of the total cost of cure associated with managing these conditions. This review will underscore the importance of identifying therapeutic agents that, because of favorable cost, compliance, safety, and pathogen coverage features, are able to reduce barriers to clinical cure. In general, antimicrobial agents that satisfy these criteria will improve "first time around" cure rates and thereby reduce overall outcome costs.
Among the factors that would be included in an outcome analysis (i.e., the total costs associated with diagnosis, management, and cure of outpatient infection) are the following: cost of the medication(s) used for the initial course of antibiotic therapy; cost of the initial physician visit; human resource time (telephone time, revisits, etc.) required to service queries regarding the drug and/or its side effects; the cost of practitioner re-evaluations for treatment failures; hospitalization costs due to treatment failure; the cost of additional courses of therapy to achieve therapeutic endpoints (clinical improvement or bacterial eradication); the economic opportunity cost sustained by patients (or parents) because of time lost from work to care for themselves or their child; the cost of medications or other devices (diapers, etc.) to service the gastrointestinal side effects (diarrhea) of the medications; and the short- and long-term sequelae of treatment failures or repeated episodes of infection.
Although comprehensive, outcome-directed studies addressing all of these variables for most outpatient infections are not currently available, other outcome-sensitive drug therapy assessment tools can be pressed into service for the purpose of drug selection. In this regard, the prescription, patient, and drug resistance (PPD) approach to drug selection permits emergency physicians to evaluate and compare the clinical success profiles of one antibiotic vs. another. These comparisons are based on a synthetic approach constructed according to established specifications and parameters such as price, daily dose frequency, duration of therapy, palatability, side-effect profile, and spectrum of coverage. 3-15
From the perspective of prescribing antibiotics in the outpatient setting, it must be emphasized that each of the PPD resistance barriers is important, and that if one or more of these barriers (cost, side-effect profile, lack of convenience, inadequate coverage of pathogens) is of sufficient magnitude, it may influence the overall real-world cure rate.9,11,14,16 These barriers are discussed in the following sections.
Prescription Resistance, Patient Resistance, and Drug Resistance (PPD System)
PPD Resistance Barriers for Oral Antibiotic Therapy. The prescription, patient, and drug (PPD) resistance approach to drug selection permits physicians to evaluate and compare the clinical success profiles of one antibiotic vs. another according to established specifications and parameters, such as price, daily dose frequency, duration of therapy, side-effect profile, and spectrum of coverage.3-5
In this regard, having a patient achieve a favorable outcome requires negotiating several real-world PPD resistance barriers. Using this outcome-based, cost-effectiveness-oriented, "real-world" approach, some antibiotics will fare better than others. From the perspective of prescribing antibiotics in the hospital, it must be stressed that each of these three resistance barriers is equally important in determining whether clinical cure is likely. These barriers are discussed in the following sections.
Prescription Resistance. Prescription resistance refers to the likelihood that patients will actually fill their prescription. Studies show that up to 25% of patients given a prescription for an antibiotic never even fill their prescription, and the risk of non-filling increases with the cost of the medication.3,5 Accordingly, the primary determinant of prescription resistance is the cost of the medication.
In addition to the cost of the antibiotic, other factors affecting the patient’s propensity for filling the prescription include: 1) The clinical provider’s persuasiveness in convincing the patient he or she needs the antibiotic as part of their therapeutic program; 2) "word of mouth" about the drug (i.e., is it perceived by the community as a tolerable, or poorly tolerated, medication?); 3) previous experiences with the medication; and 4) the patient’s perception of the seriousness of his or her condition.
When the cost of a course of therapy is high, if the physician has not taken the time to persuade the patient of the importance of filling his or her prescription, or the patient perceives his or her illness as mild, the prescription resistance barrier is high and, therefore, will affect clinical outcomes.
Patient Resistance. Patient resistance refers to the likelihood that the patient will actually take the medication for the entire course of therapy, assuming, of course, that the prescription-resistance barrier was low enough to induce the patient to actually fill the prescription. Once filled, however, there are a number of factors that determine whether patient resistance will be high or lowor, put differently, how likely the patient is to be compliant with his or her medication.
The principal factors determining patient resistance are the daily dose frequency of the medication, the duration of therapy, the side-effect profile, and the discontinuation rate of the drug. Not surprisingly, the antibiotic with the lowest patient resistance profile would be characterized by a well-tolerated, single-dose therapy administered under supervision. Examples of low patient resistance regimens include a single 2 g dose of metronidazole for trichomoniasis, single-dose therapy for gonorrhea, a single 1 g dose of azithromycin for uncomplicated chlamydial cervicitis, or a single 150 mg dose of fluconazole for the treatment of candida vaginitis.
These approaches satisfy the criteria for Universal Compliance Precautions (UCP) because, in general, administration of single-dose therapy especially when given under supervision prevents noncompliance-mediated therapeutic failures from undermining the success of a drug regimen. Generally speaking, patient resistance is acceptable, but still less than perfect, for therapeutic courses based on antibiotics dosed on a once-daily basis and given for five or fewer days, and that have a low incidence of side effects (usually gastrointestinal in origin). Patient resistance becomes an important barrier to clinical cure for medications given on a bid or greater daily dose frequency, those given for seven days or more, and for agents that have gastrointestinal side effects that are severe enough to produce drug discontinuation.4,5
Special considerations apply to antibiotic suspensions for the pediatric age group. Because children do not self-administer medications, compliance in the pediatric age group depends, to a great extent, upon the parent’s willingness and motivation to give the antibiotic. Similarly, medications that require refrigeration, must be administered by day care or school personnel, or require special timing requirements with respect to food intake, increase parent resistance and, therefore, may compromise proper, timely administration.16,17 In particular, drugs with gastrointestinal side effectsespecially diarrheacreate a "clean-up" factor that may discourage parents from completing the entire course of therapy as prescribed. This can be called "parent" resistance. In this regard, at least one study has shown that poor medication compliance is the most common cause of antibiotic treatment failures.17
The effect of patient resistance (i.e., compliance profile) barriers on clinical outcomes in outpatient infections should never be underestimated. Even when the cost of the medication is sufficiently low to encourage prescription fulfillment, if patient resistance factors are sufficiently imposing, clinical cure rates will be compromised.
Drug Resistance. Drug resistance refers to the spectrum of coverage (i.e., antimicrobial activity) provided by the antibiotic against the most likely organisms encountered in the specific infection against which the drug is directed. For example, organisms targeted for empiric therapy in community-acquired respiratory infections include Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, and Moraxella catarrhalis. Chlamydia pneumoniae is also cited as an increasingly common etiologic agent.
An antibiotic with proven activity against all these organisms would provide optimal coverage and, therefore, would be associated with a low drug-resistance barrier. On the other hand, an antibiotic with activity against only three (or fewer) of these organisms might produce therapeutic failures in a significant percentage of cases and, therefore, would be associated with a drug-resistance barrier obstructing the outcome highway. The risk of infection caused by specific organisms is often related to patient characteristics. H. influenzae is unusual in nonsmoking patients without COPD, and M. pneumoniae is less frequent outside the youngest adult age group.
Naturally, drug resistance must always be considered when selecting an antibiotic. Even when the medication is inexpensive and well-tolerated (i.e., prescription- and patient-resistance barriers are low), if the drug fails to provide optimal activity at the "business end" (it has poor spectrum of coverage against anticipated organisms at the site of infection), cure rates will be compromised.
Optimal PPD Profiles. Optimal PPD profiles are characterized by antibiotics with low prescription, patient, and drug resistance. In this regard, the most desirable agentin other words, the antibiotic producing the greatest likelihood of clinical success in the real-world patient encounteris inexpensive enough to encourage prescription filling, well-tolerated enough by the patient to promote compliance, and active against all the anticipated pathogens so that its empiric use will provide appropriate coverage without the necessity for retreatment due to resistance organisms.
Recent Advances in Antibiotic Therapy: New Agents, Formulations, Treatment indications, and Antimicrobial Combinations
Overview and General Principles. Among the most important advantages of the newer antibiotics is improved pharmacokinetics, which permits less frequent dosing, increased convenience, shorter duration of therapy, and increased compliance. Azithromycin is one important example of a newer agent with these features. In general, compliance is thought to be enhanced by once- or twice-daily dosing compared to more frequent administration.3,4 Although this has been confirmed by "science of compliance" studies, other factors such as a good doctor-patient relationship reinforcing the importance of taking medications as prescribed may also be important in generating improved compliance.5
As a rule, the advantage of less-frequent dosing must always be weighed against the generally higher cost of newer antibiotics as well as the antibiotic’s spectrum of activity. In this regard, although newer antibiotics are generally more expensive compared to established agents, there is considerable variability among the newer agents. (See Table 1.)
Furthermore, the appropriateness of broad-spectrum antibiotic therapy in a setting in which narrower-spectrum therapy would suffice must be questioned, especially because of the selective pressure for resistance exerted. There are currently numerous examples of resistant organisms in both the community and hospital settings, including methicillin-resistant staphylococci, VISA, VRE, penicillin- and cephalosporin-resistant pneumococci, penicillin- and tetracycline-resistant gonococci, Beta-lactamase-producing H. influenzae associated with amoxicillin resistance, and multiple antibiotic-resistant gram-negative bacilli.6,7,18
It appears that the increasing incidence of antibiotic resistance is in large part due to antibiotic prescribing and misuse.19 Despite increased worry over antibiotic resistance, physicians are prescribing more expensive, broad-spectrum antibiotics (especially cephalosporins and quinolones) in the United States.20 Because of uncertain benefits, there has recently been a plea to decrease inappropriate antibiotic use, especially in patients with acute bronchitis who do not have associated chronic obstructive pulmonary disease (COPD).21 Patients with acute bronchitis that is unrelated to COPD probably do not benefit from antibiotic therapy. It should be stressed, however, that in patients with COPD, antibiotics do appear to have a role in the treatment of exacerbations caused by bacterial bronchitis.22
Although the newer antibiotics have a wide variety of approved indications (See Table 2), these agents should be used more judiciously in patients in whom bacterial resistance, allergy, intolerance, or a significant opportunity to simplify therapy exists. Although it is often said that 5-10% of penicillin-allergic patients will have a reaction to cephalosporins, the true incidence appears to be much less (about 1-2%).23 Consequently, cephalosporins may safely be given to the majority of patients with a history of penicillin allergy; however, avoid such therapy in the case of a potential IgE-mediated allergy (anaphylaxis, urticaria).24
Cephalosporins. The extended-spectrum cephalosporins include the designated "second-generation" agents cefuroxime axetil and cefprozil.25,26 The carbacephem antibiotic, loracarbef, has a spectrum of activity similar to these agents.27 A minor modification of the cephalosporin ring of cefaclor results in the carbacephem designation. These antibiotics have good activity against common gram-positive organisms except for methicillin-resistant staphylococci and enterococci. They are reliably active against H. influenzae, M. catarrhalis, and many strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. (See Table 2.)
In general, these agents offer no significant advantage over trimethoprim-sulfamethoxazole (TMP-SMX) for upper or lower respiratory tract pathogens, with the exception of Streptococcus pyogenes, which can cause pharyngitis or tonsillitis. Penicillin remains the drug of choice for pharyngitis, except in cases in which a high risk of noncompliance can be anticipated, in which case a macrolide with shorter duration of therapy should be considered. Skin and skin structure infections generally respond well to a first-generation cephalosporin or a penicillinase-resistant penicillin such as dicloxacillin. Cefuroxime axetil has been shown to be as effective as doxycycline in early Lyme disease.28
The "third-generation" cephalosporins include cefixime and cefpodoxime proxetil.29,30 These antibiotics are characterized by an extended spectrum against gram-negative organisms such as E. coli and Klebsiella; nosocomial bacteria such as Pseudomonas aeruginosa, Enterobacter, Serratia, and others are generally resistant to these agents. Cefpodoxime proxetil has moderate gram-positive activity, while that of cefixime is poor. These antibiotics have a variety of approved indications but are generally not superior to established agents for the same indications. (See Table 2.) Cefpodoxime proxetil has a lower cure rate for uncomplicated urinary tract infections than comparable agents.31 Both of these agents are effective as one dose-therapy for uncomplicated gonorrhea.32,33
Penicillins. Although no dramatic advances have been reported in the penicillin-related antibiotics, the most important recent "modifications" among antimicrobials in this category has been the the new dosing schedule approved for amoxicillin-clavulanate in the treatment of otitis media. In this regard, recent approval for BID administration of this antibiotic should be noted, although this agent does not share the full compliance-promoting benefits of once-daily administration seen with other agents such as azithromycin, cefixime, and cefpodoxime. Although palatability of the amoxicillin is quite acceptable, the incidence of diarrhea is reported in large studies to be about 16%.30 In vitro coverage of most bacterial offenders causing acute otitis media is favorable.
Amoxicillin-clavulanate. From a practical perspective, amoxicillin-clavulanate is now made in a 200 mg/5 mL and 400 mg/5 mL suspension. This new suspension has a lower concentration of clavulanate and thus has fewer GI side effects (especially diarrhea). Furthermore, dosing differs for these two new suspensions. Otitis media should be treated with 45 mg/kg bid, a more convenient dosing pattern than the previous tid recommendations, if these suspensions are used. Finally, the new suspensions contain aspartame and should not be used by phenylketonurics.
Quinolones. The currently available quinolones include levofloxacin, sparfloxacin, ciprofloxacin, ofloxacin, norfloxacin, lomefloxacin, and enoxacin.34-37 (See Table 2.) Prior to the recent introduction of the extended spectrum quinolones, levofloxacin and sparfloxacin, these antibiotics were characterized by extensive activity against gram-negative organisms including H. influenzae, M. catarrhalis, and most enteric bacilli. In addition, ciprofloxacin has good activity against P. aeruginosa. Although the quinolones have no useful anaerobic activity, they have moderate gram-positive activity, but resistance has emerged quickly in S. aureus and streptococcal activity is borderline, except in the case of the newer quinolones levofloxacin and sparfloxacin (see below). There have been breakthrough bacteremias caused by S. pneumoniae reported on ciprofloxacin.38,39 The quinolones have excellent activity against bacteria commonly causing diarrheal illnesses, including E. coli, Salmonella, Shigella, Campylobacter, and Yersinia. This class of drugs is contraindicated in pregnancy and in children less than 18 years of age.
Levofloxacin. One of the most important developments has been the introduction of the extended spectrum quinolones. In this regard, levofloxacin, the S-enatiomer of ofloxacin, is a new fluoroquinolone antibiotic recently approved by the FDA. It is an extended spectrum quinolone that, compared with older quinolones, has improved activity against gram-positive organisms including Streptococcus pneumoniae. This has important drug selection implications for management of patients with community-acquired pneumonia and exacerbations of COPD. The active stereoisomer of ofloxacin, levofloxacin is available in a parenteral preparation or as a once daily oral preparation that is given for 7-14 days.
Levofloxacin is indicated for the treatment of adults (> 18 years of age) with mild, moderate, and severe infections including acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia, uncomplicated skin and skin structure infections, and complicated urinary tract infections including acute pyelonephritis.40 This antimicrobial is active against many gram-positive organisms including S. pneumoniae, Enterococcus faecalis, Staphylococcus aureus, and S. pyogenes, and it also covers atypical pathogens including Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. It is also active against gram-negative organisms including Enterobacter cloacae, E. coli, H. influenza, H. parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa.
When given orally, levofloxacin is dosed once daily, is well absorbed orally, and penetrates well into lung tissue.40 It is active against a wide range of respiratory pathogens including atypical pathogens and S. pneumoniae resistant to penicillin.37,38 In general, levofloxacin has similar activity against gram-positive organism as ofloxacin and ciprofloxacin, and it is more active than ofloxacin and slightly less active than ciprofloxacin against gram-negative organisms.41,42 In particular, it should be noted that levofloxacin is less active against Pseudomonas aeruginosa than ciprofloxacin.41,42 Reflecting this sensitivity data, levofloxacin is FDA approved for treating pseudomonal infections of the urinary tract only. In contrast, it has been reported to be more active than the older quinolones against S. pneumoniae resistant to penicillin.43 The drug is available as both an oral and parenteral form, and the oral and IV routes are interchangeable (i.e., same dose). Levofloxacin is generally well tolerated (incidence of adverse reactions, < 7%).
Levofloxacin is supplied in a parenteral form for IV use and in 250 mg and 500 mg tablets. The recommended dose is 500 mg IV or orally qd for 7-14 days for upper or lower respiratory tract infections and uncomplicated skin and skin structure infections, and 250 mg qd for 10 days for complicated UTI or acute pyelonephritis. Food does not affect the absorption of the drug, but it should be taken at least two hours before or two hours after antacids containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparation with zinc. Dosage adjustment is recommended in patients with impaired renal function (clearance < 50 mL/min).40 The drug is well-tolerated, with the most common side effects including nausea, diarrhea, headache, and constipation.40 All quinolones have been associated with cartilage damage in animal studies, and therefore, they are not recommended for use in children, adolescents, pregnant and nursing women.
Comparative trials (generally available in abstract form) suggest that levofloxacin is as effective as cefuroxime axetil, cefaclor, and amoxicillin/clavulanate in upper or lower respiratory infections.44-46 In patients with community-acquired pneumonia, IV levofloxacin with step-down to oral therapy was superior to ceftriaxone with step-down therapy to cefuroxime axetil.47 About 22% of patients in the cephalosporin arm required the addition of erythromycin or doxycycline due to the presence of atypical respiratory pathogens. The clinical response rates (cure plus improvement) were 88-97% for levofloxacin. Microbiological eradication was reported to be 94-98%; however, a large number of patients (32-43%) were not evaluable for this end point.44,46,47
Levofloxacin, ofloxacin, and another recently approved drug, sparfloxacin, are the only quinolones approved by the FDA for respiratory tract infections, in particular for empiric therapy for community acquired pneumonia. Currently, such macrolides as azithromycin or clarithromycin are recommended for pneumonia in ambulatory, otherwise healthy adults. For older patients, an oral cephalosporin such as cefuroxime axetilwith or without the addition of a macrolide to provide coverage of atypical pathogensmay be considered.43 In this patient subgroup, levofloxacin provides an effective, safe, and cost-attractive outpatient alternative to two-drug combinations, especially in the elderly patient who is deemed well enough to be treated out of hospital and in whom coverage of gram-negative organisms in addition to coverage of Streptococcus pneumoniae and atypical pathogens are desirable. (Please refer to "Community-Acquired Pneumonia" section below for a more detailed analysis of drug options in CAP).
Sparfloxacin. The second of two extended-spectrum fluoroquinolone antibacterial agents recently approved by the FDA, sparfloxacin was developed in Japan and is a chemically unique quinolone, with an amino substituent in the five-position and a fluorine substituent in the eight-position of the quinolone nucleus. The amino substituent enhances gram-positive activity,48 while the fluorine substituent increases plasma half-life49 but also appears to increase the risk of phototoxicity (e.g., lomefloxacin).
Like levofloxacin, sparfloxacin is dosed once a day and provides a wide range of coverage including activity against common gram-positive and gram-negative respiratory pathogens, as well as against the atypical pathogens Chlamydia pneumonia and Mycoplasma pneumonia. Importantly, sparfloxacin shows excellent activity against penicillin-resistant pneumococcus and multidrug-resistant H. influenzae and M. catarrhalis.
Sparfloxacin is indicated for the treatment of adults (> 18 years old) with the following infections caused by susceptible strains of the designated microorganisms: Community-acquired pneumonia (CAP) caused by Chlamydia pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, or Streptococcus pneumoniae, and; acute bacterial exacerbation of chronic bronchitis caused by Chlamydia pneumoniae, Enterobacter cloacae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, or Streptococcus pneumoniae.49 In comparative trials, sparfloxacin was as effective as amoxicillin/clavulanate, cefaclor, erythromycin, amoxicillin, ofloxacin, or amoxicillin plus ofloxacin for clearing community-acquired pneumonia.48,49,50-52 Sparfloxacin is more active than ciprofloxacin against Mycobacterium tuberculosis, but is less active against P. aeruginosa than ciprofloxacin with a median MIC90 two- to four-fold higher.48
Given this drug’s excellent and appropriate spectrum of coverage for CAP and bacterial exacerbations of COPD, one issue that will clearly play a determining role in the acceptance of sparfloxacin among emergency medicine and primary care practitioners is the reported incidence of photosensitivity reactions, which, in selected individuals (i.e., active, young, outdoor-oriented individuals who are not ill enough from their CAP to require bedrest indoors) can affect patient satisfaction, and potentially, be problematic.
To gain an accurate, balanced assessment of the photosensitivity dimension of this new antimicrobial, it is important to look at the rate of photosensitivity reactions in detail and their frequency in specific patient subgroups. First, it should be stressed that photosensitivity reactions were the most common adverse reaction observed, with an overall rate of 7.9% reported among patients enrolled in all clinical trials (126 of 1585) for the drug. Moderate to severe phototoxic reactions occurred in 3.9% of patients. It should be stressed, however, that these adverse event rates were generated from initial trial data that included a wide variety of active, minimally ill, younger individuals with infections such as UTI and sinusitis, (two indications for which the drug is not FDA-approved or being marketed) that were not severe enough to prevent participation in normal daily activities, including outdoor exposure to sun or ultraviolet (UV). However, in patients with community-acquired pneumoniaa subgroup which, because of the morbidity and debilitation associated with this condition, is less likely to encounter sun or UV light exposure during their treatment coursethe incidence of photosensitivity reaction diminished by almost 50%, to 4.1%. Moreover, there were no severe (i.e., blister-forming reactions) in CAP group, and the discontinuation rate from photosensitivity problems was only about 1%.49
Based on these findings, it appears as if patient selection can play a pivotal role in identifying clinical situations that will maximize the benefits of sparfloxacin, while reducing the potential side effects. In this regard, homebound patients and individuals who are not active in outdoor activities, are the most suitable candidates. All patients must be instructed to avoid exposure to the sun, bright natural light, and UV rays throughout the entire duration of treatment and for five days after treatment is stopped. Phototoxic reactions have occurred even with the use of sun screens and can occur following a single dose.49
A moderate prolongation of the QTc interval (approximate 2% incidence) occurs with sparfloxacin. The mean prolongation is about 10 msec. A small percent of patients (0.7%) had a clinically significant QTc interval prolongation of more than 500 msec. Torsades de pointes has been reported in patients receiving sparfloxacin with disopyramide and amiodarone. Consequently, the drug is contraindicated in patients who are taking agents (including terfenadine, disopyramide, amiodarone, and others) known to prolong the QTc interval, and in individuals with a known QTc prolongation.49 Other side effects include diarrhea (4.6%), nausea (4.3%), and headache (4.2%).49
Sparfloxacin is supplied in 200 mg tablets. The initial dose is 400 mg on the first day as a loading dose, then 200 mg every 24 hours for a total of 10 days. In patients with renal impairment (creatinine clearance < 50 mL/min), the 400 mg loading dose is used, but the maintenance dose should be reduced to 200 mg every 48 hours for a total of 10 days.49 Sparfloxacin can be taken with food but not with sulcrafate or antacids.
Both sparfloxacin and levofloxacin may be considered for the treatment of respiratory infections caused by penicillin-resistant Streptococcus pneumoniae.53 Sparfloxacin has greater in vitro activity against this organism as well as more favorable pharmacodynamics (i.e., plasma levels relative to minimum inhibitory concentrations) than levofloxacin,54 but the potential for phototoxicity and prolongation of QTc must be weighed against the potential advantages in selected patient subgroups. Prudent use of these new agents are essential. With the emergence of drug-resistant Streptococcus pneumoniae, the rational use of antibiotics is paramount in limiting the spread of this organism. These new fluoroquinolones, if used appropriately, can provide a useful alternative to older agents against this organism. Sparfloxacin is priced in the same range as levofloxacin, clarithromycin, and cefuroxime axetil and somewhat more than azithromycin.
Non-Extended Spectrum Quinolones. The older quinolones still constitute the primary treatment modality for bacterial infections of the urinary tract. The non-extended spectrum quinolones such as ciprofloxacin still play a very important role in and can be considered reasonable first-line agents for the following conditions: prostatitis in older men, invasive bacterial diarrheas with prolonged duration of symptoms, complicated urinary tract infections, otitis external, diabetic vasculopathic ulcers, one-dose therapy for gonorrhea, and selected cases of osteomyelitis. Ciprofloxacin and ofloxacin have a wide variety of indications, while norfloxacin, lomefloxacin, and enoxacin are generally used only for infections of the urinary tract. More frequent use of quinolones has resulted in increasing resistance, which has been observed predominantly in methicillin-resistant staphylococci and P. aeruginosa.55
The quinolones are not presently recommended for use in patients younger than 18 years old or in pregnant or lactating women due to concerns over cartilage toxicity.56 However, the quinolones may enjoy increased use in children if European safety data are further substantiated.57 Because divalent and trivalent cations decrease quinolone absorption, concomitant antacids, calcium, sucralfate, iron, and zinc need to be avoided. The quinolones may decrease theophylline and caffeine metabolism by inhibiting the hepatic cytochrome P-4P-450 system, with enoxacin, ciprofloxacin, and norfloxacin being most often implicated.55 Phototoxicity may occur most frequently with lomefloxacin and sparfloxacin.
Phosphonic Acids. Fosfomycin (Monurol®), a new single-dose antibiotic has been approved by the FDA for the treatment of uncomplicated urinary tract infections in women, but not in men. This new synthetic antibiotic inhibits cell synthesis by inactivating the enzyme enolpyruvyl transferase, which catalyzes one the early steps in cell wall synthesis. Extensively used in Europe since 1988, fosfomycin tromethamine represents the first in a new class of antibiotics that are derivatives of phosphonic acid. The drug is bactericidal against a wide range of common urinary tract pathogens and is well absorbed orally. A single dose results in high serum levels, which provides concentrations above the MIC for common urinary pathogens for up to 3.5 days. Supplied as a package of soluble granules that is mixed with water, fosfomycin is indicated for the treatment of uncomplicated UTIs (acute cystitis) in women, due to susceptible strains of Escherichia coli and Enterococcus faecalis, and there is generally little cross resistance between fosfomycin and other antibiotics.59 It should be stressed, however, that in vitro data suggests that Staphylococcus saprophyticus, a common urinary pathogen, is resistant to fosfomycin.60
Fosfomycin received a Pregnancy Category B (i.e., no documented evidence of risk in humans), the same as amoxicillin and nitrofurantoin, while TMP/SMP and quinolones are in category C (i.e., risk cannot be ruled out and use in pregnancy not recommended). The most common side effect of fosfomycin is diarrhea (9%) which, on average, last for about two days.61 Although the bacteriologic eradication rate with a single dose of fosfomycin (82%) is inferior to that of a seven-day course of ciprofloxacin (98%) or a 10-day course of TMP/SMX (98%), it is comparable to eradication rates seen with 3-day courses of commonly used antimicrobials.59 Because metoclopramide lowers the serum concentration and urinary excretion of fosfomycin, coadministration of these drugs is not recommended.
From a practical standpoint, fosfomycin is supplied in orange flavored granules which are dissolved in 3-4 ounces of water taken as a single 3 gram dose. The medication should not be mixed with hot water and repeated daily doses do not appear to improve clinical success, but they do increase the incidence of adverse events. Fosfomycin may be taken without regard to food.59
The bacteriological cure rate for fosfomycin generally ranges between 69% to 96% as assessed 5-11 days post-treatment. In comparative clinical trials, fosfomycin was found to be less effective than seven days of ciprofloxacin (250 mg bid) and 10 days of TMP/SMX (960 mg daily) but was comparable to a seven-day course of nitrofurantoin (Macrodantin 100 mg bid).59,60
A small, nonblinded study (n = 36) suggests that fosfomycin may be more effective than low-dose TMP/SMX (960 mg) given for three days.62 In a large, single-blind study (n =308), however, fosfomcyin was comparable to a single dose of TMP/SMX (1.92 g) and a single dose of ofloxacin (200 mg) in terms of bacteriologic rates.63
Although fosfomycin is the only FDA-approved, single-dose regimen, current clinical data indicates that it may be no more effective than a single dose of two double strength TMP/SMX. In current practice, most physicians opt for the improved cure rates associated with a three-day treatment of TMP/SMX (1 DS tablet bid ´ 3 days), which is often considered to be optimal treatment due to effectiveness and reduced relapse rates.64,65 Unfortunately, comparative studies between this regimen and fosfomycin have not been reported. Fosfomycin costs about $21.04 per treatment) and, considering the other available, short-course alternatives, this drug should be reserved primarily for patients in whom TMP/SMX is not appropriate (e.g., sulfa allergy, bacterial resistance, and third trimester of pregnancy).
Clearly, fosfomycin offers an alternative to standard therapy for UTIs in women. But because its cure rates are no better than standard therapy, even standard single-dose therapy, it is best reserved for women with multiple drug allergies or patients who are compliance risks.
Macrolides. The newer macrolide antibiotics include the erythromycin analogs azithromycin and clarithromycin.66,67 Compared to erythromycin, the major advantages of these antibiotics are significantly decreased gastrointestinal side effects, which produce enhanced tolerance, improved bioavailability, higher tissue levels, pharmacokinetic features that permit less frequent dosing and better compliance, as well as enhanced activity against H. influenzae.68,69 In particular, the long tissue half-life of azithromycin allows this antibiotic to be prescribed for a shorter duration (5 days) than comparable antibiotics given for the same indications. (See Table 1.)
Approved indications for the newer macrolides are listed in Table 2. A single 1 g dose of azithromycin has been shown to be as effective as seven days of doxycycline in the treatment of uncomplicated chlamydial cervicitis and urethritis.70 The availability of one-dose, "cure here now" therapy offers substantial compliance advantages. With the recent introduction of a 1 g sachet pack of azithromycin, which is priced at about $10-15 at many institutions and clinics, the Centers for Disease Control and Prevention (CDC) has advocated azithromycin as a drug of choice for uncomplicated chlamydia cervicitis.71 A one-time 2 g oral dose has also been approved for the treatment of urethritis and cervicitis caused by Neisseria gonorrhea.
In contrast to azithromycin, clarithromycin (and erythromycin) should not be given with terfenadine or astemizole because of the risk of ventricular tachycardia. Both erythromycin and clarithromycin may increase theophylline levels. Clarithromycin, which has a category C rating, is contraindicated in pregnancy because of fetal cardiovascular abnormalities discovered in animal toxicologic studies. Azithromycin, which has a category B rating, is appropriate for use in pregnant patients but only when clinical findings indicate that antimicrobial treatment is warranted.
Because macrolides are the fastest-growing class of outpatient antimicrobials, comparing the advantages and disadvantages of these two antibiotics is an important issue. Given the cost differences between azithromycin and clarithromycin, as well as the improved compliance patterns associated with short-duration therapy, any rational approach to distinguishing between these agents must consider prescription, patient, and drug resistance barriers.
From the outset, it is fair to say that these newer macrolides, to a great degree, have supplanted the use of erythromycin in community-acquired infections of the lower respiratory tract. Although erythromycin, in particular, has been considered by some to be the antibiotic of choice for community-acquired pneumonia, its lack of efficacy against H. influenzae, as well as its adverse gastrointestinal side effects, potential for drug-drug interactions, and poor compliance profile are now recognized as clinically important liabilities. It is, however, effective against pneumococcal pneumonia, mycoplasma pneumonia, and many atypical infections, including Legionella. Food decreases the absorption of erythromycin, which interferes with drug metabolism, and the drug should be used with caution in patients on theophylline or warfarin. It should not be used concurrently with terfenadine.
The newer macrolide antibiotics, which include both azithromycin and clarithromycin, have recently emerged as drugs of choice for outpatient management of community-acquired pneumonia, as well as otitis media.72 When used as oral agents, they play a central role in management of pneumonia in otherwise healthy individuals who do not require hospitalization. Recently, however, the intravenous formulation of azithromycin has been approved for hospitalized patients (see below). Unlike penicillins, cephalosporins, and sulfa-based agents, these drugs have the advantage of showing in vitro activity against both atypical and bacterial offenders implicated in community-acquired pneumonia. The most common side effects include gastrointestinal upset and a metallic taste in the mouth which are more common in clarithromycin.
These agents also have the advantage of a simplified dosing schedule, especially azithromycin, which is given once daily for only five days (500 mg po on day 1 and 250 mg po qd on days 2-5). Clarithromycin requires a longer course of therapy and is more expensive. In general, the decision to use a macrolide such as azithromycin rather than erythromycin is based on weighing the increased cost of a course of therapy with azithromycin against its real-world advantages, which include a more convenient dosing schedule, its broader spectrum of coverage, its favorable drug interaction profile, and its decreased incidence of gastrointestinal side effects, which occur in 3-5% of patients taking a five-day, multiple-dose regimen.73 The recent introduction of a new oral tablet formulation permits consumption of the antibiotic without regard to food ingestion.
Azithromycin. Azithromycin has been approved in a palatable suspension formulation for the treatment of acute otitis media and pneumonia in children. The cost for a course of therapy is usually less than $30, and the once-daily, five-day course introduces compliance-enhancing features that, to a great degree, permit parental, day care, and grade school drug administration problems to be circumvented.74 A well-accepted palatability profile, combined with an overall discontinuation rate of about 0.9%, are favorable as far as patient resistance is concerned.75-77 When the five-day course of the suspension is used for treatment of otitis media, the reported incidences of side effects includes diarrhea/loose stools (2%), abdominal pain (2%), vomiting (1%), and nausea (1%).
From the perspective of drug resistance, the oral suspension of azithromycin is characterized by excellent in vitro coverage of beta-lactamase-producing H. influenzae and M. catarrhalis, as well as in vitro coverage of S. pneumoniae, for which the overall resistance rate is estimated to be about 5-7%.75-77 Although this second-generation macrolide has been used widely in the adult population, azithromycin oral suspension for children only recently has become available for use by pediatric specialists in the United States.
In this regard, the clinical role of azithromycin in the pediatric and primary care settings is supported by rigorous clinical studies that have been published comparing the safety and efficacy of azithromycin to amoxicillin-clavulanate for the treatment of acute otitis media in children.75,78,79 In these large trials, clinical cure rates of up to 87.5% are reported, and azithromycin was as effective as, but better tolerated than, amoxicillin-clavulanate for the treatment of acute otitis media in the pediatric age group.74,78-80 Although azithromycin does not affect a single IV dose of theophylline, caution is advised if multiple doses of theophylline are used. Accordingly, prudent clinical monitoring of theophylline levels is recommended in these patients. Monitoring of the prothrombin time is also urged in patients taking warfarin.
Like azithromycin, clarithromycin suspension also has been shown to produce comparable cure rates to amoxicillin-clavulanate.7 Finally, the potential for drug-drug interactions between clarithromycin and theophylline, terfenadine, or astemizole requires caution. From a prescription resistance perspective, the cost for a course of therapy for clarithromycin is significantly more than it is for amoxicillin, trimethoprim-sulfamethoxazole, or azithromycin. Finally, with respect to medication compliance, BID dosing is less desirable than once-daily administration,15 and unpleasant taste and palatability problems have been described for clarithromycin.10,81,82
From a practical clinical perspective, the newest and, perhaps most important, advance in the area of macrolide therapy is the availability of intravenous azithromycin for the management of hospitalized patients with community-acquired pneumonia (CAP) as well as pelvic inflammatory disease (PID).83,84 Currently, azithromycin is the only advanced generation macrolide indicated for parenteral therapy in hospitalized patients with CAP due to Chlamydia pneumoniae, H. influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Staphylococcus aureus.
The comparative trials demonstrating clinical success (patients who were cured or improved at 10-14 days post-therapy) rates of about 77%with concomitant bacteriologic response rates of about 96% for frequently isolated pathogenswith azithromycin in CAP were conducted in a wide variety of patients. These included a significant percentage who were 65 years of age or older, had an abnormal respiratory rate (> 30 breaths per minute), a PaO2 less than 60 mm Hg and and/or BUN greater than 20 mg/dL. Many of these patients had concurrent diseases or syndromes, including emphysema, chronic obstructive airway obstruction, asthma, diabetes, and/or were cigarette smokers.85
As would be expected, the efficacy of this macrolide was compared to clinical outcomes with a cephalosporin used with or without erythromycin. In a randomized comparative investigation, therapy with intravenous azithromycin alone plus oral azithromycin was as effective as intravenous treatment with the designated "second-generation" cephalosporin, cefuroxime followed by oral cefuroxime axetil, with or without the addition of oral or intravenous erythromycin.85
Azithromycin dosing and administration schedules for hospitalized patients are different than for the five-day course used exclusively for outpatient management, and these differences should be noted by the physician. When this advanced generation macrolide is used for hospitalized patients with CAP, 2-5 days of therapy with azithromycin IV (500 mg once daily) followed by oral azithromycin (500 mg once daily to complete a total of 7-10 days of therapy) is clinically and bacteriologically effective. For patients requiring hospitalization, the initial 500 mg intravenous dose of azithromycin may be given in the emergency department.
Interestingly, among all intent-to-treat patients with CAP receiving azithromycin evaluated in two studies, 24 were found to have S. pneumoniae bacteremia at baseline. Of these 24 patients, 19 (79%) achieved clinical cure, which was accompanied by eradication of the pathogen from the blood. Among the five patients considered to be clinical failures, three of the five had documented eradication of S. pneumoniae from the blood, and the remaining two did not have post-baseline cultures reported. All five patients had significant comorbid conditions that are predictive of poor outcomes, but none of the failures resulted in mortality.85
Like the oral formulation, IV azithromycin appears to be well-tolerated, with a low incidence of gastrointestinal adverse events (4.3% diarrhea, 3.9% nausea, 2.7% abdominal pain, 1.4% vomiting), minimal injection-site reactions (less than 12% combined injection-site pain and/or inflammation or infection), and a low incidence of discontinuation (1.2% discontinuation of IV therapy) due to drug-related adverse patient events or laboratory abnormalities.85
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Physician CMEQuestions
63. Currently available "extended spectrum" quinolones that have improved coverage of Streptococcus pneumoniae include:
a. ciprofloxacin and ofloxacin.
b. norfloxacin and ciprofloxacin.
c. sparfloxacin and levofloxacin.
d. none of the above.
64. Which of the following antibiotics is approved for single course therapy for uncomplicated UTI?
a. Macrovantin
b. Azithromycin
c. Fosfomycin
d. Levofloxacin
e. None of the above
65. Azithromycin is approved for community-acquired pneumonia caused by:
a. Streptococcus pneumoniae.
b. Hemophilus influenzae.
c. Moraxella catarrhalis.
d. Mycoplasma pneumoniae.
e. All of the above.
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