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Antibiotic Selection and Dosing for the

Treatment of Acute Exacerbations of
Jerome J. Schentag and Glenn S. Tillotson

Chest 1997;112;314S-319S
DOI 10.1378/chest.112.6_Supplement.314S
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1997 by the American College of Chest Physicians

Pharmaceutical Division. MS (CHEST 1997.3 Mis¬ use or inappropriate use of these agents can lead to *From the Clinical Pharmacokinetic Laboratory (Dr. In this review.4 with infection. West Haven. In simplistic terms. These are Hae¬ estimated that only half of acute exacerbations are mophilus infiuenzae.1 Its COPD impact in terms of morbidity and mortality is considerable. it is evident that three bacterial prior to a decision on which antibiotic to use.3 the infected bronchial tree. Schentag. Morgan Lane. only recently that the extent of this resistance has become an issue. clinical material available from each year for infections associated with COPD. it is developed for nosocomial pneumonia treatment and how it may be applied to COPD by guestChallenges on April in1. health-care expenditures. Schentag). process. Together these three exacerbations may be due to host responses to viral species account for >70% of bacteria isolated. M catarrhalis was regarded as a commensal organ¬ years. Millard Fillmore Hospital. nevertheless. not the least of which is Division (Dr. has accelerated recently. as all too collected From the numerous clinical trials undertaken in frequently respiratory specimens are not chronic bronchitis. CT 06516 office visits. Our knowl¬ Pseudomonas aeruginosa.Pulmonary 2011 Medicine: Beating Bronchitis 1997 by the American College of Chest Physicians . Thus. The antibiotics prescribed are various in physicians be aware of the antibiotic resistance levels that no single agent or class is the clear empiric either nationally or. we will affects almost 15 million Americans. $4 billion annually. yet now it accounts for >20% colonizing upper respiratory flora in the infections of COPD infections (Table 1). Again.78 There does seem to be a need for informa¬ antibiotics.chestpubs. we will compare the approach tarrhalis have been acknowledged for >20 years. the remaining Streptococcus pneumoniae. Tillotson. 400 Rayer Corporation. the remainder consisting of Staphylococcus aureus. further course(s) of an- 314S Downloaded from chestjournal. Moraxella catarrhalis.2 and al¬ investigations. It is species currently predominate.5 it is evident that virtually all physicians In addition to being aware of the most likely treat such acute exacerbations with a course of causative pathogens. and the Pharmaceutical many different outcomes. it is the reason for focus on the bacteria that have been isolated from the expectorated sputum of COPD patients. or some other pathophysiologic process. allergic reactions to environmental stimuli. who pneumococci in the United States are now consid¬ sees most of the acute infections. and the specialist ered intermediate or resistant to penicillin. and definitely due to bacterial infection. One of the more contentious issues in recent years Antibiotic Selection has been the role of bacteria in initiating acute exacerbations of COPD.Antibiotic Selection and Dosing for the Treatment of Acute Exacerbations of COPD* Jerome f. Conn. Virtually all of these are written empirically.913 The current levels of antibiotic resistance among community-acquired respiratory Bacterial Etiology of COPD pathogens in the United States are shown in Table 2. more especially. Ampicillin-resistant H infiuenzae and M ca¬ organisms. 112:314S-319S) tory tract flora is under investigation. MS. therapy failure and a patient's condition becoming worse. hospitalization. controversy flares over the value of such specimen 10 million physician office visits annually. Over 25% of tion to assist both the primary care physician. Tillotson. West Haven. Finally. The balance between colo¬ Antibiotics account for a large proportion of nization and infection by the normal upper respira. Other outcomes can include repeat physician S. Tillotson). and members of the en- edge of the bacterial pathogens implicated in COPD infections has improved significantly over recent terobacteriaceae such as Klebsiella. Buffalo. we will discuss the otic resistance among other respiratory pathogens etiology of COPD infections and analyze the various has been recognized but rarely publicized for some factors of the antibiotic classes with respect to these time.6 The attention given to this costly decision in emergence of penicillin-resistant pneumococci. Reprint requests: G. and Glenn S. locally.4 Although there is still debate over the role of ism until 10 years ago. recent disease management guidelines has been which are typically resistant to several additional scant. relevant. NY. Curiously. it is essential that prescribing antibiotics.9 Antibi¬ pulmonologist. PharmD. The choice. etc. Bayer Corporation. it is still the most easily most 1 million antibiotic prescriptions are written obtained.

These Antibiotics are agents designed to kill bacteria patients have a reduced ability to respond efficiently while invoking minimal effects on humans. specific and fluids. and azalides have infiuenzae. Despite this litany of poten¬ tial "downsides. penicillins. cephalosporins. the scription? rates will likely pathogen but Awareness of the and local invading organisms may reside in tissues and fluids susceptibility help enormously. They rarely achieve levels comparable to serum concentrations. Table 1.3 3. The CHEST/112/6/DECEMBER. is the drug metabolized and excreted? Is the drug costly or cost-effective? Tissue Penetration No single class or individual antibiotic fulfills all of the above criteria. centrations? Is the drug tolerated by the patient? thereby creating the opportunity to relapse at a later How often is the drug taken? (For how long?) How date. Those that actively kill bacteria are known as bactericidal agents. Yet antibiotics to select an agent that has the most activity against H such as the quinolones. In addition to the established mem¬ shown that. nized pathogens.chestpubs. In some instances. Additionally. does it kill the bacteria? Does the anti¬ Agents that inhibit or stun the pathogen may not biotic get to the site of infection in adequate con¬ adequately eliminate the cause of the infection.3 25 Penicillin S* Penicillin R Chodosh24 37. antibiotics. antibiotics exert their effects in one of graphic representation of this is shown by the "ther¬ two ways. aza. consideration of some of Having considered whether an antibiotic is active them prior to prescribing may help rationalize anti¬ against the likely pathogens and if it kills the recog¬ biotic use for COPD infections. Patients Drug Tolerahility with COPD have impaired lung defenses.9 22. These regardingtissues concentrations agents include penicillins. tetracyclines. and aminoglycosides do not penetrate these developed and approved for use in these infections. cephalospo¬ bers of each class." Cefuroxime 95 99 91 0 Erythromycin 57 100 98 75 Tetracycline 99 100 97 56 tibiotics and supportive therapy. This may be the underlying cause of their disease. is it reasonable to determine whether the amount of antibiotic present at the infection site is enough to perform the required Spectrum of Activity killing? It is only since theofadvent of bronchoscopic A wide range of classes and agents may be poten¬ techniques the myriad of various availablein that a data became tial therapeutic choices for COPD infections. macrolides.5 infiuenzae catarrhalis pneumoniae Basran etal23 43. Wise and Honeybourne14 lides. and others. while those that merely inhibit apeutic ratio" (Fig l). however.Incidence of Most Common Bacterial Table 2. bacterial resistance Ciprofloxacin 99 100 94 93 *S = sensitive. Downloaded from chestjournal. it is preferable for the prescribed antibiotic to kill the putting pen to paper? Is the spectrum of activity of causative agent without the need to depend on a antibiotic appropriate? What is the mode of action of variable and potentially poor host immune response. R = resistant.1316 This utilizes the bronchial the bacterial life cycle.Susceptibilities of US Community-Acquired Pathogens Isolated From COPD Infections* Respiratory Pathogens % of Total Bacterial Isolates % Isolates Susceptible I-1 H infiuenzae M catarrhalis S pneumoniae H M Davies etal22 58.4 Amoxicillin 70 4 95 0 Aldons25 70 13 15 Cefaclor 93 99 94 0 * Adapted from Ball. providing it will also cover the two other all been shown to be well distributed throughout the dominant organisms. In view of the known etiology of COPD.4 22. respiratory tract at concentrations well in excess of the concurrent serum levels. what other factors could or should be considered before away from the normal immune system. in broad terms. trimethoprim-sulfamethoxazole. Thus. are known as bacteriostatic by guest on April 1. A Basically. 2011 1997 SUPPLEMENT 315S 1997 by the American College of Chest Physicians . it is logical tissues and fluids well. thereby allowing the host's mucosal tissue concentration divided by the typical immune system time to respond and eradicate the MIC90 for the particular agent and pathogen. new entities are continually being rins. invader. macrolides. increasing." how much time and/or thought are actually expended before writing an antibiotic pre¬ to bacteria and other stimulants. Mode of Action these concentrations exceed the minimum inhibitory concentration (MIC90) of the likely pathogens. have conducted many studies in this area and have and quinolones.5 15 16.

Although one can regard class members failure of therapy. Suchthean antibiotic could make life a little 3 shows some ofthe more common adverse reactions simpler for prescriber (or unless the patient has as there is no need to decrease associated with antimicrobial therapy. not all the quinolones are fore. Thus. it is desirable to prescribe an agent that has a excreted solely via the kidney. Table tinally. as a day.Pulmonary 2011 Medicine: Beating Bronchitis 1997 by the American College of Chest Physicians . thereby encouraging metabolized hepatically and also excreted transintes- the patient to complete the treatment course. particularly renal failure. and many other conditions. particularly for <14 days. diarrhea. thrush. such as those who have may terminate therapy voluntarily without consulta¬ by guestChallenges on Aprilin1. when prescribing antibiotics for a relatively sick.16 severe renal failure). patients may the pressures that drive antibiotic resistance. is quite small. These admissions give some idea of pseudomembranous colitis. etc. insomnia. rash. >54% patients antibiotic costs. Over 80% antibiotic class. the dosing unless the patient has severe renal failure. Frequency of Administration Although it is common sense to realize that pa¬ Costly and Cost-effective Treatment tients prefer drugs that are taken only once or twice The actual cost component of antibiotic therapy.I. often seen with most members of an antibiotic or not taking tablets regularly. as ciprofloxacin is low incidence of side effects.17 this survey. The implication of such action may be antibiotics. headaches. In other instances. Frequently. It is a revelation that the cost of a failed 316S Downloaded from chestjournal. nausea. an adverse event may be so severe that counter or remedial therapy or even Prescribing physicians are all taught the need to has a degree of hospitalization is necessary. hospitalization for parenteral ther¬ of agents as being similar.1 adverse events associated with many antibiotics are confessed to not completing the prescribed course of predictable. specific attention should be paid to their tion and revisit the physician for a further course of renal and liver function when considering a range of treatment. M. stop taking a course of antibiotics due to the level of inconvenience. The patient compromised patient group. discomfort. there may be exceptions to apy. The typical adverse modify dosing drugs a patient of if events seen with the common antibiotics include organ insufficiency.chestpubs. These events range from mild dis¬ said that they preferred medication to be taken once comfort or nausea to severe. or pain due to the ther¬ Drug Metabolism and Excretion apy. this logic has only part ofthe care for a COPD patient. vomiting. life-threatening or twice a day. There¬ the rule. development of bacterial resistance. For example. Therapeutic ratios of various antibiotics against three common respiratory pathogens.1 Yet recentlyIn been corroborated Gallup sur¬ byof a recent interviewed there is a disproportionate level of attention paid to vey.C Erythromycin Ratio of bronchial concentrations to MIC90 Figure 1.

tests and involve a revisit to the of the patient. GI. Stevens-Johnson syndrome H infiuenzae (including pL+) M catarrhalis No coverage of atypical pathogens Macrolides Erythromycin S pneumoniae 4/d GI "frequent. 2011 1997 SUPPLEMENT 317S 1997 by the American College of Chest Physicians .500 64 by guest on AprilDECEMBER.0 0. therapy course is significantly higher than the "most more antibiotic therapy.02 Ofloxacin 800 133 1.Adverse Drug Reactions Associated With Antimicrobial Therapy* In Vitro Activity Against Key Antibiotic Respiratory Pathogens Dosing Adverse Events Penicillins Ampicillin.125 0. Breakpoint MIC for H M Quinolone mg/24 h mg h/L AUIC of 125 infiuenzae pneumoniae catarrhalis Norfloxacin 800 14 0.)* No coverage of atypical pathogens Amoxicillin-clavulanate S pneumoniae 2-3/d GI H infiuenzae (pL +/.006 2. rash H infiuenzae (pL.0 0." interaction theophylline and M pneumoniae terfenadine(QT interval prolongation) Legionella pneumophila Clarithromycin S pneumoniae 2/d Taste.25 Sparfloxacin 400 45 0. talizations are due to COPD and its exacerbations. tooth discoloration. AZJIC.008 2. and potentially hospitalization as it will expensive" antibiotic. hypersensitivity. *PL=P-lactam.06 Lomefloxacin 400 75 0. nausea H infiuenzae (non-pL producing) M catarrhalis Mycoplasma pneumoniae No coverage of atypical pathogens Other TMP-SMXf S pneumoniae 2/d Rash.Breakpoint.03 *Creatine clearance of 50 mL/min.40 Ciprofloxacin 1. In the United States.) M catarrhalis No coverage of atypical pathogens Cephalosporins Cefuroxime axetil S pneumoniae 2/d GI H infiuenzae (including pL+) M catarrhalis No coverage of atypical pathogens Tetracyclines Doxycycline S pneumoniae 2/d Photosensitivity.0 0.0 0.0 0.60 0.6 16. Downloaded from chestjournal. Table 3.0008 2.1 Table 4.0 0. amoxicillin S pneumoniae 3-4/d GI.0 0. AUC. additional laboratory investigations. and MIC for Fluoroquinolones in Patients* MIC* Oral Dose. interaction theophylline and terfenadine M catarrhalis (QT interval prolongation) M pneumoniae L pneumophila Marginal activity against H infiuenzae Quinolones Ciprofloxacin S pneumoniae 2/d GI.5 0. 13% of all hospi¬ physician.5 0.chestpubs.16 tTMP-SMX=trimethoprim-sulfamethoxazole.01 0.12 0.06 Levofloxacin 500 138 1. theophylline/caffeine interaction H infiuenzae M catarrhalis L pneumophila * Adapted from File.06 16. CHEST / 112 / 6 / 1.

Antimicrobial resistance among clinical isolates of Haemophilus infiuenzae would still produce an AUIC of 125. but ing organism. ratio is a combination of area under pulmonary disease. Sethi S. appropriate dos¬ netic parameters has been combined in an evaluation ing. and ofloxacin. however. this yields an AUC value. Md: National by guest on April 1. 1994. effectiveThis antibiotics in particu¬ 5 Murphy T. particularly the mental status and welfare ofthe target MIC is well above the MIC90 of these organ¬ patient. single antibiotic is ideal.Obviously. it is still prudent to guide the prescriber? A method to accomplish this consider some or all of the seven factors discussed should involve both pharmacokinetics and the infect¬ herein. et al. Tillotson G. Brueggemann AB. Epidemiology and treatment of chronic bronchitis and (AUIC) ratio has enabled us to calculate the most exacerbations. Can Med Assoc J shown in Table 4. and the data are the management of chronic bronchitis. lung and blood diseases. Previ¬ respiratory tract infections. the AUIC technique has been clini¬ Grossman. 140:S9-S18 2 Chartbook on cardiovascular. as the attitude that may impact on their choice of health-care total 24-h-mg dose of levofloxacin is approximately provider. Brueggemann AB. M catarrhalis. Clin we have shown that if the ratio is >125. some agents clearly fulfill several characteristics well. 40:1208-13 This AUC value was then evaluated to determine what MIC value would serve as the highest that 10 Doern GV. 151:7-23 9 Doern GV. however. while cip¬ employed. truth and perceptions. Pa: IMS. patients may have thesda. 106(suppl):43s-52s its dosing of various likely. 2011 1997 by the American College of Chest Physicians . Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Nelson S. Both patient types have significantly 1 Feinleib M. et al. 1995: results of a 30-center national surveillance study. et al. in comparison to the MIC90 p-lactamase-positive strains resistant to amoxicillin-clavu- values of the three significant organisms in patients lanate: results of a national multicenter surveillance study.20-21 Although intherethis article we have focused on COPD References infections. The use of the area under the inhibitory curve 1996 4 Ball P. 7 ATS Board of Directors. et al. both have high bacterial load at the site of infection. Trends in COPD morbidity and mortality in the United States. an floxacin is greater than ofloxacin. A table of this type can be antibiotic treatment. Lung and Blood Institute. Additionally. and duration will maintain their effectiveness. both require good antibiotic Respir Dis 1989. 400 q 12 h. it is in everyone's interest to with acute exacerbations of chronic bronchitis: H infiuenzae. and productivity and earning ability. Pierce G. 1991 varying degrees of renal or hepatic insufficiency. relevant fashion so as to Until these data are available. This subject has been covered by Unfortunately.21 These data are in the United States in 1994 and 1995 and detection of shown in the table. 146:1067-83 the curve (AUC) (0 to 24 h) divided by the MIC ofthe 6 D'Eugenio C. there appears to be little difference apy are sparse. Am J then the likelihood of success is even higher. then Pulmon Med (in press) ously. Am Rev compromised host defenses. Recent work be seen. Bacterial infection in chronic obstructive lar infections. It would be reason¬ acute exacerbations of COPD. No current. half that of ofloxacin (500 mg [levofloxacin] vs 800 The data relating to cost-effective antibiotic ther¬ mg [ofloxacin]). but clearly. Recommendation on encountered in COPD patients. Antibiotic therapy of pathogen (or MIC90) of the expected organism.chestpubs. 3 National Disease and Therapeutic Index. Be¬ penetration. in addition to achieving clinical constructed for any organism against any antibiotic success. only sensible prescribing. Antimi¬ crob Agents Chemother 1996. Holley HP Jr. Am Rev Respir Dis 1992. there is a good chance of success.19 cally as only in patients with nosocomial pneu¬ tested Seven factors or characteristics have been dis¬ monia. longer period. 152:s77-sl20 We applied this method to the organisms typically 8 Baiter MS. is significantly adversely affected during infec¬ isms (Table 4). Ambler. sparfloxacin tive exacerbations of COPD. all ofthe quinolones perform well against H from the United Kingdom18 has shown that the quality infiuenzae and M catarrhalis. If the ratio is >250. may be some similarities between the two infections. If these patients are provides good coverage of this organism. Chest 1995. With S pneumoniae. Antimicrobial quinoloneshadwere comparedclearance in a scenario in which the of 50 mL/min. combined in a scientific. and S pneumoniae. The use of microbiological activity and pharmacoki¬ However. as their therapeutic of life. Hyland RH. not all of these are due to infections and failed therapy. Collins JG. The antimicrobial potency of levo¬ choices mean less interruption(s) to their lifestyle. they could provide daily samples that could cussed with respect to empiric antibiotic therapy for then be quantitatively cultured. one of the main goals of between these two agents. Can any of these be able to repeat such analyses in the COPD setting. 750 bid. As can give the most effective therapy initially. a range of fluoro. In this table. resistance of Streptococcus pneumoniae recovered from outpa¬ patients a creatinine tients in the United States during the winter months of 1994 to For each drug and dose. of antibiotic treatment of nosocomial pneumonia. must be to maintain a healthy patient for a as long as there are AUC and MIC values available. Rosenberg HM. there may be a significant impact on their rofloxacin. Low DE. 318S Challenges in Pulmonary Medicine: Beating Bronchitis Downloaded from chestjournal. and in both cases. patients levofloxacin are below but reasonably close to the may feel better disposed to a physician whose antibiotic necessary MIC.20 Respir Crit Care Med 1995.

4:28-32 parison of amoxycillin and ciprofloxacin. Mathematical examina¬ pathogens 1992-1993: the Alexander project. Pharm Weekbl Sci 1986. Prevalence of bronchitis. 40:2884-86 20 Forrest A. Gruneberg RN. Chest 1997. 476-85 pneumonia and acute exacerbations of chronic bronchitis. et al. A comparsion of clarithromycin with ampicillin in Hosp Med by / 112 guest / DECEMBER. Antimicrob Group. New York: American Lung Association. Guidelines for the treatment of acute exacer¬ Moraxella catarrhalis in the United States in 1994 and 1995: bations of chronic bronchitis. and the Alexander Project ciprofloxacin and tobramycin. and the Alexander Project intravenous ciprofloxacin in seriously ill patients. Adelman MH. Antibiotic penetration into the exacerbations of chronic obstructive airways disease: a com¬ respiratory tract. 25 Aldons PM. Felmingham D. Infectious diseases. J Antimicrob tion of dual individualization principles. Gould IM. 8:53-59 Diagn Microbiol Infect Dis 1996. Abbas AM A. Chemother J 1995. eds. J Antimicrob Chemother 1991: use. Am J Med 1989. 2011 1997 SUPPLEMENT 319S 1997 by the American College of Chest Physicians . 24 Chodosh S. lower respiratory tract 21 Schentag JJ. Bronchitis and asthma. Ann Pharmacother 1991. 37:1073-81 susceptibility of community-acquired. Treatment of acute 14 Wise R. The quinolones in munity-acquired lower respiratory tract bacterial pathogens. Wilson C. 112(suppl):310S- results of a 30-center national surveillance study. Honeybourne D. Consumer attitudes toward antibiotic of chronic bronchitis. Maesen FPV. Results of the Alexander project: a continuing. chronic bronchitis. 25: Group. Chest 1997. et al. Brief report: respira¬ Chemother 1990. 26(suppl F): 19-24 tory tract penetration of ciprofloxacin. Relationships Chemother 1996. 112(suppl):303S-309S antimicrobial resistance among 723 outpatient clinical isolates 19 Grossman R. on/ 6April 1. Antimicrob Agents Chemother 1997. Pharmacodynamics of 12 Felmingham D. Teengs JP. 25:169-81 23 Basran GS. J Antimicrob 15 Reid TMS. 1992. I. Nix DE. et al. A multicenter. 1995 27(suppl A):101-08 CHEST Downloaded from chestjournal. Brueggemann AB. collaborative study ofthe antimicrobial Agents Chemother 1993. In: Gorbach SL. 41:292-97 18 Wilson R. Bartlett 87(suppl 5A):60S-61S JG. 13 Gruneberg RN. Nix DE. 33(suppl 2):18-25 the treatment ofoutpatients acute bacterial exacerbation with 17 Gallup Organization. et al. Blacklow NR. et al. 38(suppl A):l-57 between AUC above MIC and AUIC for cefmenoxine. mul¬ 1050-57 ticenter study of the antimicrobial susceptibility of the com¬ 22 Davies BI.chestpubs. Philadelphia: WB 16 File TM. Golder D. Joseph J. Pierce G. Ballow CH. Defining subsets of patients with chronic 11 Doern GV. New therapeutic options for community-acquired Saunders. Antimicrob 313S Agents Chemother 1996.

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