parameters were enhanced to develop new antimicrobial formulations CONSIDERATIONS IN ANTIMICROBIAL SELECTION Using animal models and human data, PK an

Overview of Newer Antimicrobial Formulations for Overcoming Pneumococcal Resistance William A Craig, MD The pharmacokinetic (PK) and pharmacodynamic (PD) profile of an antimicrobial agent provides important information that can be used to maximize bacteriologic and clinical efficacy, minimize selective pressure for the development of antimicrobial resistance, and determine an optimal dosing regimen Judicious selection of an antimicrobial based on local susceptibility data and PK and PD parameters is imperative in this era of increasing resistance among Streptococcus pneumoniae, a leading cause of community-acquired respiratory tract infections The 13-lactam antimicrobials display time-dependent bacterial killing with minimal to no persistent effects Ketolides and fluoroquinolones display concentration-dependent bacterial killing, and tetracyclines and macrolides display time-dependent killing All have prolonged persistent effects (eg, postantibiotic effect) that retard or prevent bacterial regrowth when free drug levels fall below the minimum inhibitory concentration (MIC) New high-dose and/or extended-release formulations of traditional antimicrobials have been added to the current armamentarium for treatment of community-acquired respiratory tract infections These formulations include amoxicillin-clavulanate potassium powder for oral suspension 90/6 4 mg/kg per day divided every 12 hours (Augmentin ES-600 ; GIaxoSmithKline, Research Triangle Park, NC), amoxicillin-clavulanate potassium extended-release tablets 2 x 1,000 mg/62 5 mg every 12 hours (Augmentin XR ; GIaxoSmithKline), clarithromycin extended-release tablets 2 x 500 mg once daily (Biaxin XL ; Abbott Laboratories, North Chicago, IL), and cefaclor extended-release tablets 375 mg or 500 mg every 12 hours (Ceclor CD ; Eli Lilly Pharmaceuticals, Indianapolis, IN) Of these agents, only amoxicillin-clavulanate potassium powder for oral suspension and amoxicillin-clavulanate potassium extended-release tablets were designed to treat infections caused by penicillin-resistant pneumococci (penicillin MIC _<2 µg/ml) Extended-release clarithromycin does not provide higher daily doses than its immediate-release counterpart ; rather, it allows for once-daily dosing of this agent because of its slower absorption following oral administration Extended-release cefaclor is considered clinically equivalent to 250 mg of immediate-release cefaclor From the Department of Medicine, University of Wisconsin, William S Middleton Memorial VA Hospital, Madison, Wisconsin, USA Correspondenc e should be addressed to William A Craig, MD, William S Middleton Memorial VA Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705-2254 pulvules administered 3 times daily ; it cannot be used interchangeably with 500 mg 3-times-daily dosages of other cefaclor formulations Thus, despite providing a similar or higher total daily dose than its immediate-release counterpart, extended-release cefaclor is indicated only for the treatment of patients with mild to moderate infections caused by susceptible strains of certain organisms Am J Med 2004 ;1 17(3A) : 1 6S-22S 2004 by Elsevier Inc The emergence and subsequent increase in antimicrobial resistance among common communityacquired respiratory pathogens (e g, penicillinresistant Streptococcus pneumoniae [PRSP]) have led researchers to develop antimicrobials that can maintain activity against these resistant strains ' Data from the Alexander Project, an international surveillance study of antimicrobial susceptibilities of bacterial pathogens from patients with community-acquired respiratory tract infections, suggest that the worldwide prevalence of penicillin resistance (penicillin minimum inhibitory concentration [MIC] >_2 µg/ml) among 8,882 isolates of S pneumoniae obtained between 1998 and 2000 was 182% 2 Among pneumococcal isolates obtained in the United States (N = 2,432), the prevalence of penicillin resistance was 25 0% Thus, the need for antimicrobials with activity against penicillin-resistant pneumococci is imperative in this era Antimicrobial susceptibility breakpoints that integrate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of an antimicrobial with its in vitro activity (i e, MIC) have been suggested 2-4 These new breakpoints more accurately predict the bacteriologic and clinical efficacy of an antimicrobial than traditional NCCLS (formerly National Committee for Clinical Laboratory Standards) breakpoints Further, PK and PD parameters also may be used in the selection of an appropriate dosing regimen 5 Recently published guidelines on the treatment of acute bacterial rhinosinusitis use PK and PD breakpoints as the basis upon which recommendations are made 4 Although treatment guidelines for community-acquired pneumonia (CAP) are based on NCCLS breakpoints, 6- " a large segment of infectious disease experts advocate the use of PK and PD breakpoints when treating all respiratory tract infections (-3 '5 The purpose of this article is to review the PK and PD parameters used in the selection of an appropriate antimicrobial and to describe how these 1548-2766/04/$22 00 doi :1 0 101 6/j amjmed 2004 07 004

parameters were enhanced to develop new antimicrobial formulations CONSIDERATIONS IN ANTIMICROBIAL SELECTION Using animal models and human data, PK and PD effects have been studied both in vitro and in vivo " ' Data gathered from animal models demonstrate consistent results across several species that are also similar to results obtained in human studies Therefore, results from animal studies can be predictive of antimicrobial activity and clinical efficacy in humans and can be used to determine optimal dosage regimens In addition, animal studies provide important information in situations where collection of sufficient clinical data is difficult, such as those involving emerging resistant pathogens or rare infections The PK Parameters PK involves the absorption, distribution, metabolism, and elimination of a drug The PK parameters of primary importance in the selection of an appropriate antimicrobial are the area under the serum concentration versus time curve (AUC), the maximum plasma concentration (C m1 ), and the duration of time that effective drug concentrations persist 1U Free drug levels provide a more accurate determination of amount of drug available to elicit a response than total drug levels because protein binding reduces antimicrobial activity Therefore, free drug levels should be used when comparing the PK profiles of several antimicrobials within the same class Because several of the most common infectious respiratory pathogens (e g, S pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) are located primarily in the interstitium, drug concentration in the interstitial fluid may be considered more important than serum drug concentration Fortunately, interstitial and serum concentrations of free drug are approximately equivalent As a result, serum drug concentrations are typically used to monitor peak and trough levels and in PD calculations Drug concentration in tissue homogenates is typically not obtained because it often does not accurately reflect interstitial drug concentrations The PD Parameters With regard to antimicrobials, PD is the relation between drug concentration and antimicrobial activity One PD parameter of primary importance in the selection of an appropriate antimicrobial is the MIC, 1 ' which is the minimum concentration of antimicrobial needed to inhibit pathogen growth Although this parameter is a good indicator of the potency of antimicrobial activity, alone it does not provide information about the time course of antimicrobial activity (ie, whether an agent displays time-dependent or concentration-dependent killing, or whether the antimicrobial effects are persistent) All antimicrobials belong to 1 of 3 categories : concentrationdependent killing with prolonged persistent effects, timedependent killing with minimal or no persistent effects, or time-dependent killing with moderate to prolonged persistent effects Persistent Effects Several factors may prolong the activity of an antimicrobial beyond the point where drug concentration at the site of infection falls below the MIC 9 '' ' "' The postantibiotic effect of an antimicrobial is defined as continued suppression of bacterial growth that occurs after brief exposure (e g, 1-2 hours) to bactericidal or bacteriostatic concentrations of an antimicrobial 10,15 " The duration of the postantibiotic effect depends on the infecting organism, the antimicrobial, the concentration at the site of infection, and the duration of exposure to the antimicrobial Growth medium, ph, and inoculum size also may influence the in vitro postantibiotic effect of an antimicrobial Neutrophils have been shown to enhance in vivo postantibiotic effects in animal models through a phenomenon known as postantibiotic leukocyte enhancement, which enhances the natural host immune defense mechanism The mechanisms of postantibiotic effect are unknown ; however, suggested hypotheses include nonlethal damage to the bacteria by the antimicrobial or persistence of the drug at the bacterial drug-binding site In theory, antimicrobials with a longer postantibiotic effect require less frequent dosing than antimicrobials with little or no postantibiotic effect, because it is less likely that the bacteria will start to regrow during the period of subinhibitory tissue concentration 9 PATTERNS OF ANTIMICROBIAL ACTIVITY The determination of NCCLS breakpoints for antimicrobial susceptibility is based on population distributions, known mechanisms of bacterial resistance, PK parameters (primarily peak levels), and clinical outcomes Recently, PD has become a parameter considered for breakpoint determinations In considering antimicrobials with activity against pneumococci, virtually all antimicrobials are bactericidal The differentiating criterion is the time course of antimicrobial activity, which is based on 2 factors : the patterns of bactericidal activity (concentration dependent versus time dependent) and the presence of persistent effects after antimicrobial exposure Concentration-Dependent Killing with Prolonged Persistent Effects Ketolides and fluoroquinolones display concentrationdependent killing with prolonged persistent effects 9 ' 7 I7 The rate and extent of bacterial eradication depend largely on the amount of drug administered, not on the length of exposure to the antimicrobial Therefore, these antimicrobials are administered in high doses once or August 2, 2004 THE AMERICAN IOURNAL or MEDICINE Volume 117 (3A) 17S

twice daily to maximize peak serum drug concentration as well as the AUC The prolonged persistent effects associated with the use of these antimicrobials also support 0 wide dosing intervals because they prevent pathogen regrowth when the concentration at the site of infection E falls below the MIC The AUC/MIC,,, (the concentration < at which 90% of the isolates are inhibited) ratio provides a more accurate estimation of the efficacy of these antimicrobials than the C,,,a,/MIC,,, ratio because AUC takes into consideration serum drug concentration as well as length of exposure to the antimicrobial, an important feature of drugs possessing a long half-life Results from several animal studies suggest that, for fluoroquinolones, a 24-hour AUC/MIC ratio of <30 is associated with >50% mortality, whereas a ratio of X100 is associated with little to no mortality (Figure 1) 1) Similar results were observed in human studies "" 9 Lower ratios, in the range of 30 to 35, are required for pneumococci in immunocompetent animals and in non-neutropenic patients 20,21 Time-Dependent Killing with Minimal or No Persistent Effects The (3-lactam antimicrobials display time-dependent killing with minimal to no persistent effects In general, pathogen eradication begins once drug concentration at the site of infection exceeds approximately 4 times the MIC ; subsequent increases in concentration do not cause further or faster elimination 9 ' 10 Rather, duration of antimicrobial exposure (time above MIC) is the primary determinant of pathogen eradication and clinical cure with these agents Because regrowth begins once serum levels drop below the MIC, antimicrobials that demonstrate time-dependent killing and have no persistent effects must be dosed frequently throughout the day to maintain the serum drug concentration above the MIC for an extended time For cephalosporins, concentrations must exceed the MIC for at least 40% to 50% of the dosing interval "' Data suggest that lower levels may be acceptable for penicillins 22 ' 3 A compilation of results from several animal studies demonstrates that treatment of pneumococcal infections with penicillins or cephalosporins at doses that produce serum levels above the MIC for 20% or less of the dosing interval are associated with almost 100% mortality Alternatively, mortality fell 22,2 2s to between 0% and 10% with dosing regimens that produced serum levels above the MIC for at least 40% to 50% of the dosing interval Mortality rates were comparable in infections caused by penicillin-susceptible or penicillinresistant strains ; thus, the need for higher MICs does not increase the length of time required above the MIC Clinical studies have produced results similar to those found in animal studies `' 4 ' 2 `''`' Studies conducted in patients with acute otitis media (AOM) or acute maxillary sinusitis caused by S pneumoniae demonstrated that bac- 18S August 2, 2004 Tiie AMERICAN lot RNAI ~)r MFDIC] NE Volume 117 (3A) 100- O 80 - %P 60-0 O (D 0-0 O I I I I I I 0 10 30 100 300 1000 AUC/MIC at 24 Hours Figure 1 Relation between the 24-hour area under the concentration versus time curve and the minimum inhibitory concentration (AUC/MIC ratio) and survival among animal models infected with a variety of gram-positive and gram-negative pathogens and treated with a fluoroquinolone The 24-hour AUC/MIC ratio is the sum of the AUCs for all doses administered every 24 hours divided by the MIC Solid circles = data obtained in the thigh-infection model ; open circles = data obtained in other animal models (Reprinted with permission from Clin Infect Dis 10 ) Time Above MIC (%) Figure 2 Relation between time above the minimum inhibitory concentration (MIC) and bacterial eradication with various f3-lactams against Streptococcus pneumoniae in patients with acute otitis media (circles) or acute maxillary sinusitis (squares) PISP = penicillin-intermediate S pneumoniae ; PRSP = penicillin-resistant S pneumoniae ; PSSP = penicillin-susceptible S pneumoniae (Adapted with permission from I Antimicrob Chemothcr " ) teriologic cure with 0-lactam antimicrobials is dependent on time above the MIC, with longer durations above the MIC conferring greater efficacy (Figure 2) Bacteriologic eradication occurred in >80% of cases when serum levels were above the MIC for at least 40% to 50% of the

Table 1 Time Above the MIC,, (Minimum Concentration Necessary to Inhibit 90% of Isolates) for Orally Administered /3-Lactam Antimicrobials Against Penicillin-Susceptible, Penicillin-Intermediate, and Penicillin-Resistant Streptococcus pneumoniae Susceptible Intermediate Resistant Drug Regimen MIC,,, T>MIC MIC,,, T>MIC MIC,,, T>MIC Amoxicillin ± clavulanate 500 mg tid' 0 06 100 1 55 2 43 Cefaclor 500 mg tid 0 5 60 16 0 64 0 Cefuroxime 500 tng bid 0 12 75 2 35 8 0 Cefprozil 500 tng bid 025 75 4 32 16 0 Cefpodoxime 200 mg bid 0 25 83 2 21 4 0 Cefixime 400 mg qd 05 59 16 0 64 0 MIC = minimum inhibitory concentration; T>MIC = duration of time ('is) that serum levels exceed the minimum inhibitory concentration during the dosing interval 'Dose expressed in terms of amoxicillin component (Reprinted with permission from Diagn Microbial Infect Dis ' s ) dosing interval Drug levels above the MIC for 60% to 70% of the dosing interval were associated with nearly 100% bacterial eradication A comparison of time above MIC,, values achieved with standard dosing regimens of several orally administered f3-lactam antimicrobials reveals that, although these agents achieve serum levels above the MIC for >40% of the dosing interval against penicillin-susceptible S pneumoniae (Table 1), only amoxicillin with or without clavulanate achieves serum levels above the MIC for >_40% of the dosing interval against penicillin-intermediate and many, but not all, penicillin-resistant S pneumoniae ' s Time-Dependent Killing with Moderate to Prolonged Persistent Effects Tetracyclines, macrolides, and clindamycin display timedependent killing with prolonged persistent effects For all these drugs, the AUC/MIC ratio, rather than time above the MIC, is the primary determinant of bactericidal activity and clinical efficacy ' 3 This is perhaps attributable to the prolonged in vivo postantibiotic effect, which allows dosing regimens similar to those used for concentration-dependent antimicrobials (i e, high doses administered at wide intervals) A 24-hour AUC/MIC ratio of at least 25 for free drug is required for efficacy against susceptible strains of S pneumoniae The low AUC/MIC ratio of macrolides and tetracyclines against macrolide-resistant or tetracycline-resistant S pneumoniae (i e, <2) predicts poor efficacy against this pathogen NEWER ANTIMICROBIALS USED TO TREAT RESPIRATORY INFECTIONS Several new high-dose and/or extended-release formulations of traditional antimicrobials have been introduced in recent years to treat respiratory tract infections These include amoxicillin-clavulanate potassium powder for oral suspension 90/6 4 mg/kg per day divided every 12 hours (Augmentin ES-600 ; GlaxoSmithKline, Research Triangle Park, NC), amoxicillin-clavulanate potassium extended-release tablets 2 X 1,000 mg/62 5 mg every 12 hours (Augmentin XR; GlaxoSmithKline), clarithromycin extended-release tablets 2 X 500 mg tablets once daily (Biaxin XL; Abbott Laboratories, North Chicago, IL), and cefaclor extended-release tablets 375 mg or 500 mg every 12 hours (Ceclor CD ; Eli Lilly Pharmaceuticals, Indianapolis, IN) The extended-release formulations of amoxicillin-clavulanate potassium, clarithromycin, and cefaclor provide extended absorption after oral administration Extended-release clarithromycin provides lower and later steady-state peak plasma concentrations, but the same total daily dose and AUC as immediate-release clarithromycin tablets '' Extended-release cefaclor differs pharmacokinetically from the suspension formulation, and the 2 formulations cannot be used interchangeably 30 It is, however, considered clinically equivalent to 250 mg of immediate-release cefaclor pulvules administered 3 times daily Much like extended-release clarithromycin, extended-release cefaclor provides lower and later steady-state peak plasma concentrations than equivalent doses of immediate-release cefaclor pulvules ; however, it also provides a lower AUC Extended-release formulations are an appealing option for treatment of respiratory infections because they can help increase patient adherence by offering once- or twice-daily administration of these agents However, the PK and PD profiles of extended-release clarithromycin and extended-release cefaclor do not provide any enhanced activity against resistant pneumococci Thus, these agents are indicated only for the treatment of patients with mild to moderate infections caused by susceptible strains of certain organisms, including S pneumoniae 29,i0 In contrast, 2 new high-dose formulations of amoxicillin-clavulanate, extended-release tablets (adult formulation) and powder for oral suspension (pediatric formulation), have been developed to overcome pneumococcal resistance on the basis of PK and PD parameters August 2, 2004 Ttis AMERICAN IOURNAL or MEUtcINE C ' Volume 117 (3A) 19S

-u- Extended-Release Amoxicillin-Clavulanate ---0 Immediate-Release Amoxicillin-Clavulanate 4 ltg/ml 2 2 6 Time (hr) 8 10 12 Figure 3 Mean plasma concentration-time profile for amoxicillin after oral administration of extended-release amoxicillinclavulanate (2,000 mg/125 mg) compared with that of immediate-release amoxicillin-clavulanate (2,000 mg/125 mg) (Reprinted with permission from Clin Ther 32 ) Amoxicillin-Clavulanate Potassium Extended- Release Tablets Amoxicillin-clavulanate potassium extended-release tablets (2 X 1,000 mg/62 5 mg every 12 hours) provide both immediate and sustained release of amoxicillin and immediate release of clavulanate through a bilayer tablet formulation and have excellent in vitro activity against major respiratory pathogens, including S pneurnoniae with penicillin MICs of 2 µg/ml and 4 µg/ml 3 ` A single dose of extended-release amoxicillin-clavulanate (2,000 mg/125 mg) exceeds an amoxicillin concentration of 4 µg/ml for 49 4% of a 12-hour dosing interval, a value not achievable with a comparable dose of immediate-release amoxicillin-clavulanate (Figure 3) 3' Thus, based on PK and PD considerations alone, the results of this study suggest that extended-release amoxicillin-clavulanate would be an effective treatment for bacterial infections caused by strains with an amoxicillin MIC of <_4 µg/ml These results are supported by the results of a study in rats that simulated the PK of humans 33 '34 in which extended-release amoxicillin-clavulanate was found to be highly effective against all strains of S pneurnoniae (amoxicillin MI(',s of 4 or 8 µg/ml) and was comparable to or more effective than 3 other amoxicillin-clavulanate formulations, azithromycin, and levolloxacin A total of 9 clinical studies including >4,100 patients evaluated extended-release amoxicillin-clavulanate in patients with respiratory infections caused by S pneumonia, including strains with penicillin MICs of 2 to 16 µg/ ml 35 The studies showed that patients treated with ex- tended-release amoxicillin-clavulanate had successful bacteriologic and clinical outcomes after 7 to 10 days of antimicrobial therapy Of the 56 patients infected with PRSP (penicillin MIC?2 tg/ml), 55 (98%) had successful bacteriologic eradication Extended-release amoxicillin-clavulanate is indicated for the treatment of patients with CAP or acute bacterial sinusitis caused by S pneurnoniae with a penicillin MIC of 2 µg/ml and J3-lactamase-producing pathogens (i e, H influenzae, M catarrhalis, Haemophilus parainfluenzae, Klebsiella pneumoniae, or methicillin-susceptible Staphylococcus aureus) 3 ` This pharmacokinetically enhanced formulation provides high enough levels of amoxicillin during a 12-hour dosing interval that it may help eradicate S pneumoniae with an amoxicillin MIC of :!~4 µg/ ml 3 ' Amoxicillin-Clavulanate Potassium Powder for Oral Suspension Amoxicillin-clavulanate (90/6 4 mg/kg per day) contains twice the amount of amoxicillin as the previous formulation, but the 2 are not interchangeable (i e, the 45/6 4 mg/kg per day dose of the previous formulation cannot be doubled to equal the 90/6 4 mg/kg per day formulation) because of the clavulanate concentration provided in each "' This formulation was designed to provide high concentrations of amoxicillin to eradicate S pneumoniae with penicillin MIC values of <2 pghnl As with the adult formulation (amoxicillin-clavulanate extended-release tablets), this pediatric formulation has been shown 20S August 2, 2004 hif: AhMGRIC N JOURNAL OF MEDICINF" Volume 117 (3A)

to eradicate S pneumoniae with elevated amoxicillin MICs (2 or 4 µg/ml) in a rat study simulating human PKs 37 The reduction with the 90/6 4 mg/kg per day formulation was found to be statistically significantly greater than the 45/6 4 mg/kg per day comparator (P <0 01) Furthermore, this study demonstrated that dosing regimens that achieved amoxicillin concentrations in excess of the MIC for a minimum of 34% of the 12-hour dosing interval significantly reduced bacterial load To date, 2 clinical trials have been conducted with the high-dose pediatric formulation Dagan and colleagues 38 conducted an open-label, multicenter study to evaluate the bacteriologic and clinical efficacy of high-dose amoxicillin-clavulanate in 521 children with AOM High-dose amoxicillin-clavulanate eradicated 98% (122 of 125) of the S pneumoniae isolates, including 91% (31 of 34) with penicillin MICs of 2 or 4 µg/ml Clinical success at the end of therapy was documented in 91 % of patients (96 of 105) with pneumococcal AOM Thus, high-dose amoxicillin-clavulanate was found to be highly effective in the treatment of pneumococcal AOM, including in patients most likely to fail antimicrobial therapy (e g, those infected with PRSP, or children <24 months old, who attend daycare, or who have recently been treated with an antimicrobial) Hoberman and colleagues39 conducted a multicenter, randomized, investigator-blind study comparing clinical and bacteriologic efficacy and tolerability of high-dose amoxicillin-clavulanate with that of azithromycin in children with AOM In this study, 730 children were randomized to receive amoxicillin-clavulanate (90/6 4 mg/kg per day for 10 days) or azithromycin (10 mg/kg per day for 1 day, followed by 5 mg/kg per day for days 2 to 5) Clinical cure or improvement of symptoms at all 3 visits was significantly greater with high-dose amoxicillin-clavulanate than with azithromycin (P <0 05) In addition, high-dose amoxicillin-clavulanate eradicated 96% of S pneumoniae (72 of75), including 92% (23 of 25) ofprsp, compared with 80% (74 of 92) and 55% (12 of 22) in the azithromycin group, respectively (P <0 01) Amoxicillin-clavulanate powder for oral suspension (90/6 4 mg/kg per day) is indicated for the treatment of pediatric patients with recurrent or persistent AOM caused by S pneumoniae with penicillin MICs of <_2 µg/ ml, H influenzae, or M catarrhalis (including (3-lactamase-producing strains of the latter 2 pathogens), characterized by antimicrobial exposure within the previous 3 months and either age of :5;2 years or daycare attendance 36 Much like with the adult formulation, data suggest that this high-dose pediatric formulation provides high enough levels of amoxicillin during a 12-hour dosing interval that it may help eradicate S pneurnoniae with an amoxicillin MIC of :f~-4 µg/ml, 37 CONCLUSION The application of PK and PD parameters to the selection of an appropriate antimicrobial agent and dosing regimen can maximize clinical efficacy and minimize selective pressure for the development of resistance The goal of therapy with (3-lactams is to maximize the length of time that free drug levels exceed the MIC of a particular pathogen Ideally, free drug levels should exceed the MIC for 40% to 50% of the dosing interval to prevent pathogen regrowth For fluoroquinolones, tetracyclines, macrolides, and azithromycin, on the other hand, the goal is to maximize serum concentration With the prevalence of pneumococcal resistance on the rise, newer high-dose formulations of traditional antimicrobials are being used to treat respiratory tract infections caused by PRSP Amoxicillin-clavulanate potassium extended-release tablets (2,000 mg/125 mg every 12 hours) and amoxicillinclavulanate potassium powder for oral suspension (90/ 6 4 mg/kg per day divided every 12 hours) have favorable PK and PD profiles, which make them appealing to use in treating respiratory infections as well as in overcoming pneumococcal resistance Despite the wealth of available data on the impact of PKs and PDs on bacteriologic and clinical efficacy of antimicrobials, additional research and education are necessary to transform this concept into a reality of daily prescribing REFERENCES 1 Appelbaum PC Microbiological and pharmacodynamic considerations in the treatment of infection due to antimicrobial-resistant Streptococcus pneumoniae Clin Infect Dis 2000 ;31(suppl 2) :S29-S34 2 Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN, for the Alexander Project Group The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents J Antimicrob Chemother 2003 ; 52 :229-246 3 Jacobs MR, Weinberg W Evidence-based guidelines for treatment of bacterial respiratory tract infections in the era of antibiotic resistance Manag Care Interface 2001 ;14 :68-80 4 Anon JB, Jacobs MR, Poole MD, et al, for the Sinus and Allergy Health Partnership Antimicrobial treatment guidelines for acute bacterial rhinosinusitis Otolaryngol Head Neck Surg 2004 ;130 :1-45 5 Drusano GL, Craig WA Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections J Chemother 1997 ;9(suppl 3) :38-44 6 Heffelfinger JD, Dowell SF, Jorgensen JH, et al Management of community-acquired pneumonia in the era of pneumococcal resistance Arch Intern Med 2000 ;160 :1399-1408 7 Mandell LA, Bartlett JG, Dowell SF, File TM Jr, Musher DM, Whitney C, for the Infectious Diseases Society of America Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults Clin Infect Dis 2003 ;37 :1405-1433 August 2, 2004 THE AMERICAN JOURNAL OF MEDICINE Volume 117 (3A) 21S

8 Niederman MS, Mandell LA, Anzueto A, et al, for the American Thoracic Society Guidelines for the management of adults with community-acquired pneumonia Am J Respir Crit Care Med 2001 ;163 :1730-1754 9 Amsden GW, Ballow CH, Bertino JS Jr Pharmacokinetics and pharmacodynamics on anti-infective agents In : Mandell GL, Bennett JE, Dolin R, eds Principles and Practice of Infectious Diseases 5th ed Philadelphia : Churchill Livingstone, 2000 :253-261 10 Craig WA Pharmacokinetic/pharmacodynamic parameters : rationale for antibacterial dosing of mice and men Clin Infect Dis 1998 ;26:1-12 11 Dagan R Achieving bacterial eradication using pharmacokinetic/pharmacodynamic principles Int J Infect Dis 2003 ; 7(suppl 1) :521-S26 12 Jacobs MR How can we predict bacterial eradication? Int J Infect Dis 2003 ;7(suppl 1) :S13-S20 13 Klugman KP Implications for antimicrobial prescribing of strategies based on bacterial eradication Int J Infect Dis 2003;7(suppl 1) :S27-S31 14 Craig WA Post-antibiotic effects in experimental infection models: relationship to in-vitro phenomena and to treatment of infections in man J Antimicrob Chemother 1993 ; 31(suppl D) :149-158 15 Blondeau JM Expanded activity and utility of the new fluoroquinolones : a review Clin Ther 1999 ;21 :3-40 16 Burgess DS Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance Chest 1999 ; 115(suppl 3) :19S-23S 17 Zhanel GG, Walters M, Noreddin A, et al The ketolides : a critical review Drugs 2002 ;62 :1771-1804 18 Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients Antimicrob Agents Chemother 1993 ;37 :1073-1081 19 Preston SL, Drusano GL, Berman AL, et al Pharmacodynamics of levofloxacin : a new paradigm for early clinical trials JAMA 1998 ;279 :125-129 20 Ambrose PG, Grasela DM, Grasela TH, Passarell J, Mayer HB, Pierce PF Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections Antimicrob Agents Chemother 2001 ;45 :2793-2797 21 Andes D, Craig WA Animal model pharmacokinetics and pharmacodynamics: a critical review Int J Antimicrob Agents 2002 ;19 :261-268 22 Andes D, Craig WA In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae : application to breakpoint determinations Antimicrob Agents Chemother 1998 ;42 :2375-2379 23 Craig WA Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid Infect Dis Clin North Am 2003 ;17 :479-501 24 Craig WA Antimicrobial resistance issues of the future Diagn Microbiol Infect Dis 1996 ;25 :213-217 25 Craig WA Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins Diagn Microbiol Infect Dis 1995 ;22 :89-96 26 Craig WA, Andes D Pharmacokinetics and pharmacodynamics of antibiotics in otitis media Pediatr Infect Dis J 1996 ;15 :255-259 27 Dagan R, Klugman KP, Craig WA, Baquero F Evidence to support the rationale that bacterial eradication in respiratory tract infections is an important aim of antimicrobial therapy J Antimicrob Chemother 2001 ;47 :129-140 28 Craig WA The future-can we learn from the past? Diagn Microbiol Infect Dis 1997 ;27 :49-53 29 Biaxin XL [prescribing information] North Chicago, IL : Abbott Laboratories ; August 2001 30 Ceclor CD [prescribing information] Indianapolis, IN : Eli Lilly Pharmaceuticals ; September 1999 31 Augmentin XR [prescribing information] Research Triangle Park, NC : GIaxoSmithKline ; November 2003 32 Kaye CM, Allen A, Perry S, et al The clinical pharmacokinetics of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate Clin Ther 2001 ;23 :578-584 33 Berry V, Singley C, Satterfield J, Woodnutt G Efficacy of a pharmacokinetically enhanced formulation of amoxicillin/ clavulanate against experimental respiratory tract infection (RTI) in rats caused by Streptococcus pneumoniae (Sp) Poster presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy ; September 22-25, 2001 ; Chicago, IL 34 Craig WA Proof of concept: performance testing in models Clin Microb Infect 2004 ;10(suppl 2) :12-17 35 File TM Jr, Jacobs MR, Poole MD, Wynne B, for the 546, 547, 548, 549, 550, 551, 556, 557 and 592 Clinical Study Groups Outcome of treatment of respiratory tract infections due to Streptococcus pneumoniae, including drugresistant strains, with pharmacokinetically enhanced amoxycillin/clavulanate Int J Antimicrob Agents 2002 ;4 : 235-247 36 Augmentin ES-600 [prescribing information] Research Triangle Park, NC : GlaxoSmithKline ; April 2003 37 Woodnutt G, Berry V Efficacy of high-dose amoxicillinclavulanate against experimental respiratory tract infections caused by strains of Streptococcus pneumoniae Antimicrob Agents Chemother 1999 ;43 :35-40 38 Dagan R, Hoberman A, Johnson C, et al Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media Pediatr Infect Dis J 2001 ;20 : 829-837 39 Hoberman A, Dagan R, Rosenblut A, et al Extra-strength amoxicillin/clavulanate (A/C-ES) vs azithromycin (AZI) for acute otitis media (AOM) in children Poster presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003 ; Chicago, IL 22 S August 2, 2004 '[ru AbIFRICAN JOURNAL 01n Me uanr' Volume 117 (3A)