Review

How

can we predict

bacterial

eradication?

Michael R. Jacobs@)
Antimicrobial efficacy is measured in vitro by determination of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of antimicrobials, but these values do not account for fluctuations of drug concentrations within the body or the time course of the drugs in vivo antibacterial activity. However, in vivo bacteriologic efficacy can be predicted by pharmacokinetic/pharmacodynamic (PKPD) parameters, such as the time for which the serum drug concentration is above the MIC (T >MIC), the ratio of peak serum concentration to the MIC, and the ratio of the area under the 24-h serum concentration-time curve to the MIC (AUC/MIC). Different patterns of antibacterial activity correlate with different PK/PD parameters. For example, a T >MIC of 40-50% of the dosing interval is a good predictor of bacteriologic efficacy for penicillins, cephalosporins, and most macrolides, and an AUCYMIC ratio of at least 25 is required for efficacy with fluoroquinolones and azalides. The PK/PD breakpoint for susceptibility of an organism to a specific dosing regimen of an agent can be determined as the highest MIC met by the relevant PK/PD parameter for bacteriologic efficacy for that agent. These parameters have been validated extensively in animal models, as well as in many human studies where bacteriologic outcome has been determined. The PK/PD breakpoint of an agent is determined primarily by the dosing regimen, and generally applies to all pathogens causing disease at sites where extracellular tissue levels are similar to non-protein-bound serum levels. On this basis, many parenteral p-lactams are active against almost all strains of Streptococcus pneumoniae, including penicillin-non-susceptible strains, in all body sites except for the central nervous system. Application of PK/PD breakpoints to standard dosing regimens of oral P-lactams predicts that agents such as cefaclor and cefixime will have efficacy only against penicillin-susceptible strains of S.pneumoniae, while cefuroxime axetil, cefpodoxime and cefdinir will be effective against all penicillin-susceptible as well as many penicillin-intermediate strains. However, the most active oral p-lactams, amoxicillin and amoxicillin-clavulanate, have predicted efficacy against all penicillin-susceptible and -intermediate pneumococci, as well as against most penicillin-resistant strains, at amoxicillin doses of 45-90 mg/kg per day in children and 1.75-4.0 g/day in adults. These predictions are supported by evidence from animal studies of bacteriologic efficacy. The use of PK/PD parameters to predict bacterial eradication therefore allows an evidence-based approach to the selection of appropriate antimicrobial therapy.
Int J Infect Dis 2003; 7: S13-S20

INTRODUCTION

The introduction of antimicrobial agents, more than 50 years ago, considerably reduced morbidity and mortality among patients with respiratory tract infections (RTIs). However, the problem of antimicrobial resistance among the major respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) has been increasing rapidly in many regions, with the potential to reduce the efficacy of some oral antimicrobials. Consequently, there is an ongoing need to re-evaluate therapeutic choices in RTIs, to ensure that the primary goal of antimicrobial therapy-maximum bacterial killing-is met. This paper considers the various issues relating to optimal bacterial eradication in RTIs, including: accurate prediction of bacteriologic

efficacy, optimized dosing regimens, novel antimicrobial formulations, and pharmacokinetic (PK)/pharmacodynamic (PD)-based susceptibility breakpoints.
EVALUATING ANTIMICROBIAL EFFICACY

(l)Case Western Reserve University Cleveland, Cleveland, Ohio, USA. Address correspondence University Hospitals Ohio 44106, USA. E-mail: mrj6Qpo.cwru.edu

and

University

Hospitals

of

to: Dr M. R. Jacobs, Department of Pathology, of Cleveland, 11100 Euclid Avenue, Cleveland,

PK and PD characteristics both influence antimicrobial efficacy. Traditional predictions of antimicrobial efficacy have focused on in vitro activity (i.e. MIC) and pharmacokinetics, particularly the serum concentration profile of a drug over time, as well as its penetration into the site of infection. Recently, PD parameters-i.e. those describing the relationship between serum concentrations and drug pharmacology and toxicology-have assumed greater importance. Today, the integration of PK and PD characteristics (i.e. the PK/PD relationship for a drug) is central to our understanding of drug dose and efficacy. The specific PK/PD parameter correlating with bacteriologic efficacy is mostly dependent on whether bacterial killing is concentration- or time-dependent (Table l).l For time-dependent agents, such as p-lactams and macrolides, it is important that the dosing regimen maximizes the duration of time above the MIC (T >MIC)

S14
Table

International
1. PWPD

Journal

of Infectious
predictive PKIPD

Diseases

I Volume 7, Supplement 1,2003

efficacy based on unbound PKIPD interval serum MIC target plasma levels. Adapted with permission Antimicrobial Carbapenems Cephalosporins Clindamycin Macrolides Monobactams Oxazolidinones Penicillins ratio or Streptogramins Tetracyclines Vancomycin Fluoroquinolones Azalides Aminoglycosides Ketolides l class

parameters effect

of antimicrobial parameter

Antimicrobial

Time-dependent killing and minimal/moderate persistent effects

Proportion of dosing for which unbound drug level is above (T>MIC)

Unbound serum concentration present for approximately 40% of the dosing interval

Time-dependent killing and prolonged persistent effects Concentration-dependent killing and prolonged persistent effects

Unbound 24-h serum AUC/MIC ratio Unbound 24-h serum AUUMIC ratio or peak/MIC ratio

Unbound serum 24-h AUUMIC 225-30 (immunocompetent) >I00 (immunocompromised) Unbound serum 24-h AUCIMIC ratio >25-30 or peak/MIC 23 (immunocompetent) or Unbound serum 24-h AUClMlC ratio >I00 or peak/MIC >I2 (immunocompromised) drug concentration-time curve.

MIC, minimum

inhibitory

concentration;

AUC, area under

serum

of the agent against the target pathogen2 The unbound drug serum concentration present for >40-50% of the dosing interval is predictive of bacteriologic efficacy (bacterial eradication), and can be used to determine a PK/PD breakpoint for that specific dosing regimen.3 It has been argued that, for macrolides, tissue rather than serum concentrations determine efficacy; however, the major RTI pathogens are located in the extracellular rather than the intracellular compartment. Thus, the high intracellular concentrations of macrolides may actually decrease their therapeutic potential in these infections.4 Successful bacteriologic efficacy predictions for p-lactams and for macrolides, such as erythromycin and clarithromycin, are based on unbound serum concentrations present for 40-50% of the dosing interval. For agents with concentration-dependent killing, such as fluoroquinolones and azalides (e.g. azithromycin), the 24-h unbound serum AUC/MIC ratio and the peak unbound serum concentration/MIC ratio both correlate with outcome.1,2 For concentration-dependent killing, the unbound serum 24-h AUC/MIC ratio needs to be 2 25 for less severe infections or in immunocompetent hosts, and 2 100 in severe infections or in the immunocompromised patient.3 For concentration-dependent agents, therefore, the PK/PD breakpoint can be calculated using the following formula: unbound serum AUc~25.~ Consequently, if a penicillin (time-dependent killing) and a fluoroquinolone (concentration-dependent killing) had comparable in vitro activity against a specific pathogen and comparable PK, the PD characteristics determining their dosing regimen would be quite different.l
BACTERIAL ERADICATION IN HUMANSHOW PREDICTIVE ARE ANIMAL MODELS?

quently, data from experimental models of infection can predict antimicrobial activity in humans. This is particularly valuable during drug development and when there are difficulties in collecting sufficient data to demonstrate definitive bacteriologic efficacy in humans (e.g. in clinical syndromes where spontaneous recovery is high, such as otitis media and sinusitis, or when bacteriologic sampling is problematic, such as in patients with pneumonia).3
Time-dependent killing

Many studies indicate that the magnitude of the PK/PD parameter required for antimicrobial efficacy is similar in various animal species and in humans.5,6 Conse-

Craig reported on the relationship between T >MIC and bacterial eradication in animal models infected with S. pneumoniae, in which mortality was used as the endpoint.5T7 The infected animals were treated for several days with either a penicillin or a cephalosporin. The mortality rate was almost 100% if unbound serum levels were above the MIC for ~20% of the dosing interval; however, once the T >MIC exceeded 40-50%, survival was 90-100% (Figure 1). Clinical support for this principle has been obtained from numerous studies of sinusitis and otitis media.8 Using data collected from patients with these infections, the investigators calculated the T >MIC for each of the dosing regimens from mean serum concentrations and MICs for different pathogens (Figure 2). High rates of bacteriologic cure (>80%) were achieved once the T >MIC exceeded 40% of the dosing interval. The relationship between T >MIC and bacterial eradication was investigated by Berry et al in a rat model of experimental pneumococcal pneumonia.9 Pneumococcus is a difficult pathogen to work with in rodents, as it is not naturally virulent in these animals. In order to establish infection, it is necessary to introduce agar beads containing lo6 CFU ,S.pneumoniae intrabronchially into each animal. Dosing is then initiated to simulate the human serum pharmacokinetics obtained with different dosing regimens.

How can we predict bacterial eradication? I Jacobs

s15

100

.
i?? 802 is 60oc%A : II II 0 A Penicillins Cephalosporins

A
03;

k d
: % 2 -ifi % *o%P 40-

: I I
I I

Otitis media (circles)

Maxillary sinusitis (squares)

0 n
@ 0

PSSP PISP-PRSP

%P
ct+b c+&b I

H. influenzae

: A
40 T> MIC $0 (%) 8b do 0 t, l20 40 T> MIC $0 (%) i0 ItlO

O-

I 0 0

, I
20

Figure 1. Relationship between the length of time for which serum levels of p-lactams exceed the MIC (T>MIC) and survival in animal models infected with 5. pneumoniae. Reproduced with permission.7

Figure 2. Relationship between T >MICgo and bacteriologic cure for 5. pneumoniae and H. influenzae in the treatment of otitis media and acute maxillary sinusitis. Reproduced with permission.8 PSSP, penicillin-susceptible 5. pneumoniae; PISP, penicillin-intermediate 5. pneumoniae; PRSP, penicillin-resistant 5. pneumoniae.

Antimicrobial treatment begins 24 h after infection and is continued for 3 days, after which the animals are killed and the lungs removed for the enumeration of viable bacteria. Berry et al simulated the human PK profiles of different oral amoxicillin-clavulanate formulations (500/125 mg t.i.d., 875/125 mg b.i.d. and t.i.d., 10001125 mg t.i.d., and the new pharmacokinetically enhanced formulation, 2000/125 mg b.i.d.) by intravenous infusion of doses calculated using a linear one-compartment absorption model.9 The new pharmacokinetically enhanced 2000/125 mg b.i.d.

formulation of amoxicillin-clavulanate achieved significant reductions in bacterial load against three S. pneumoniae strains with amoxicillin MICs of 4 mg/L and three with MICs of 8 mg/L. The efficacy of amoxicillin-clavulanate 2000/125 mg b.i.d. was superior to that of the other formulations against all three S. pneumoniae strains with amoxicillin MICs of 8 mg/L. This is consistent with predictions based on T >MIC.9 Other formulations were effective against strains of S. pneumoniae with amoxicillin MICs of 2-4 mg/L (Figure 3).

(a) 6-

875/125 mg b.i.d. or 500/125 mg t.i.d.

(b) 6-

90 mg/kg/day

(4

2000/125

mg b.i.d.

:I $ Jo

I I I I I I I 30 35 40 45 50 55 60 65 T> MIC (% of dosing interval) @ @ @ MIC of strain (mg/L)

Cl $ -O

I I I I I , I 30 35 40 45 50 55 60 65 T> MIC (% of dosing interval)

:I E? Ao

I I I I I I I 30 35 40 45 50 55 60 65 T> MIC (% of dosing interval)

Figure 3. Efficacy dosing regimens9 regimens equivalent regimens equivalent regimens equivalent

of amoxicillin-clavulanate against 5. pneumoniae in an animal model of respiratory tract infection at various There was a ~3 loglo reduction in bacterial load: (a) when the amoxicillin MIC was 2 but not 4 mg/L at dosing to 875/125 mg b.i.d. or 500/125 mg t.i.d. formulations; (b) when amoxicillin MlCs were 2 and 4 mg/L at dosing to the 90/6.4 mg/kg per day formulation; and (c) when amoxicillin MlCs were 2, 4 and 8 mg/L at dosing to the pharmacokinetically enhanced 2000/125 mg b.i.d. formulation.9,17,18

S16

International Journal of Infectious Diseases I Volume 7, Supplement 1,2003

Concentration-dependent

killing

Berry et al also used the rat model of pneumococcal pneumonia to evaluate the predictive value of the AUCYMIC ratio for various fluoroquinolones.lO*ll A 22 loglo drop in bacterial load is associated with a significant difference compared with controls in this model. Between five and nine animals were infected for each experiment, plus saline-treated controls. When the AUCYMIC ratio was ~5, there was generally a less than 2 log10 kill, i.e. little bacterial eradication. When the AUC/MIC ratio exceeded 25, however, bacterial killing of >2 log10 was reliably achieved (Figure 4). However, it is of note that the bactericidal activity of the fluoroquinolones in this model is 1 loglo (i.e. 10 times) less than that of p-lactam antimicrobials.lOJ1 Support for these data in the clinical setting was provided by a PK/PD study performed by Preston et a1.12 These investigators prospectively quantified the relationship between plasma levels of levofloxacin and clinical outcome. The study included 134 hospitalized patients with a pathogen recovered from the primary site of infection for which the levofloxacin MIC had been determined. Patients had RTIs, skin infections, or complicated urinary tract infections (UTIs), and were treated with levofloxacin 500 mg, intravenously, o.d., for 5-14 days. Results showed that when the AUCYMIC ratio was ~25 (or peak/MIC ratio was <3), the clinical failure rate was 43% (3/7 patients). However, when the AUC/MIC ratio was between 25 and 100 (or peak/MIC ratio was 3-12), the clinical failure rate was just 11.5% (3/26 patients); and when the AUC/MIC ratio exceeded 100 (or the peak/MIC ratio was > 12) the clinical failure rate was virtually zero (l/101 patients) (Figure 5). In the case of levofloxacin, the AUC/MIC ratio of 25 or higher based on unbound plasma levels required for in vivo efficacy is equivalent to an AUC/MIC ratio of 40 or

higher based on total plasma levels, as about one-third of this agent is protein bound. Overall, these data validate many of the factors that have been seen in animal models, and indicate that the levofloxacin PK/PD parameters described in animals are relevant in humans. DOSING REGIMENS, AND ANTIMICROBIAL PK/PD BREAKPOINTS, EFFICACY

As PK/PD parameters can predict antimicrobial efficacy, an antimicrobial agent can be considered likely to be useful in the empirical treatment of RTIs if the MI& of the agent against S.pneumoniae, H. influenzae, and 44. catarrhalis is at or below its PK/PD breakpoint. Given the ongoing increase in microbial drug resistance, there is an increasing need for clinicians to question whether dosing regimens of commonly used agents achieve sufficiently high serum PD parameters for bacterial eradication. Table 2 provides an overview of common dosing regimens for cefaclor, cefuroxime axetil, amoxicillin-clavulanate, clarithromycin, and azithromycin, their MICROS against the key RTI pathogens, and the PK/PD breakpoints associated with their dosing regimens.i3-Is For cefaclor, cefuroxime axetil, amoxicillin-clavulanate, and clarithromycin, PK/PD breakpoints reflect the serum concentrations present for 40% of the dosing interval based on approved dosing regimens. For azithromycin, the PK/PD breakpoint represents the 24-h serum AUCe-25 (see previous section). For example, the most commonly used oral regimen of amoxicillin-clavulanate in adults is 875/125 mg b.i.d. The serum amoxicillin concentration that is present for

Success

0 Failure

n
12v) .G IO27 %i ij p 86420 AUClMlC >2 log kill 0% 0 6

~2 log kill

>2 log kill

11 9

I AUCYMIC 5-25 Unbound serum AUClMlC 42%

I ratio

0
1

AUC/MIC 100%

225

AUClMlC PeaklMIC Clinical failure rate 43%

~25 ~3

AUClMlC Peak/MIC 11.5%

25-100 3-12

AUC/MIC Peak/MlC

>I00 >I2

p>O.OOl for AUClMlC

ratio c5 versus

>5, and ~25 versus

>25 (Fisher exact test)

Figure 4. Fluoroquinolone unbound AUUMIC ratio and bacterial killing in the rat 5. pneumoniae pneumonia model. Only when the AUUMIC ratio exceeds 25 is reliable bacterial eradication achieved.O,ll

Figure 5. Correlation between levofloxacin PWPD and clinical outcome in 134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with levofloxacin 500 mg once daily for 5-14 days. Adapted with permission.12

How can we predict

Table 2. PWPD breakpoints of commonly used antimicrobial agents Streptococcus pneumoniae and MI& values for

bacterial

eradication?

I Jacobs

s17

common Haemophilus influenzae (MlC90mglL)

RTI pathogens13-* Moraxella catarrhalis fMIC90 mglL) PKIPD breakpoint (mglL)

Drug P-Lactams Cefaclor

Dosing regimen (pediatric; adult)

(M&o mglL)
Pen-S Pen-l 64 Pen-R 264

20-40 mglkglday (2 or 3 divided doses); 250-500 mg (t.i.d.) or 500 mg extended release axetil 30 mglkglday 500 mg (b.i.d.) (2 divided

16

16

so.5

(b.i.d.) doses); 0.12 4 8 2 2 51

Cefuroxime

AMWCAa

45/6.4 mglkglday (2 divided 875/125 mg (b.i.d.)

doses);

0.03

0.25

52

AMXICAa

90/6.4 mglkglday (2 divided doses); PK enhanced 20001125 mg (b.i.d.)

0.03

0.25

54

Macrolides Clarithromycin 15 mglkglday (2 divided 250-500 mg (b.i.d.) doses);

Susceptible 0.06

mefEb 4

ermBb 232 16 0.12 50.25

AzithromycinC

10 mg day 1 followed by 5 mg/kg days 2-5; 500 mg day 1 followed by 250 mg days 2-5 susceptible; Pen-l, penicillin intermediate;
is AUUMIC.

0.06

232

16

0.03

SO.12

Pen-S, penicillin

Pen-R, penicillin

resistant;

AMWCA,

amoxicillin-clavulanate.

a Dosing based on amoxicillin component. b Macrolide-resistant strains of 5. pneumoniae. L For azithromycin, the key PWPD parameter

PWPD breakpoint

calculated

as AUCt25.

240% of the dosing interval is 2 mg/L. This concentration represents the amoxicillin-clavulanate 875/125 mg b.i.d. PKiPD breakpoint, and predicts that this dosing regimen of amoxicillin-clavulanate will be effective against pathogens with amoxicillin-clavulanate MICs of up to 2 mg/L. Thus, amoxicillin-clavulanate 875/125 mg is likely to be effective against all of the key RTI pathogens, except for the most highly penicillinresistant strains of S. pneumoniae (Table 2).i3-15 Of the p-lactams shown in Table 2, cefaclor is the least active and is unlikely to be very effective in bacterial RTIs. Cefuroxime axetil is significantly more active, and likely to be effective against all penicillinsusceptible S. pneumoniae strains and some penicillinintermediate S.pneumoniae, H. influenzae, and M. catarrhalis strains, but not penicillin-resistant S. pneumoniae. Amoxicillin-clavulanate remains the most active of the p-lactam agents, and, in fact, is the only oral l3-lactam to exceed the MIGos of all three pathogens for 240% of the dosing interval (Table 3).3 As highlighted above, the most common dosing regimen (8751125 mg b.i.d. in adults, or its equivalent, 4516.4 mglkg per day in two divided doses in children) is associated with an amoxicillin-clavulanate breakpoint of 2 mg/L, and covers most RTI pathogens, including 70-80% of penicillin-resistant S. pneumoniae strains. Although the prevalence of strains resistant to amoxicillin and amoxicillin-clavulanate is generally low, there are some locations where penicillin-resistant S. pneumoniae strains are emerging that are associated with MICs for

amoxicillin or amoxicillin-clavulanate of 22 mg/L. To maintain the bacteriologic efficacy of amoxicillin-clavulanate, two new formulations of amoxicillin-clavulanate with improved PK/PD profiles have been developed. For pediatric use, a high-dose formulation has been developed (amoxicillin-clavulanate 90/6.4 mg/kg per day in two divided doses), with a PK/PD breakpoint of 4 mg/L (Figure 6).This covers all the key RTI pathogens, including >95% of pneumococci (Table 4).17 An oral, high-dose, pharmacokinetically enhanced bilayer tablet has been developed for adults, comprising amoxicillinclavulanate 2000/125 mg b.i.d. This new formulation consists of a layer of immediate-release amoxicillin and clavulanate and a layer of sustained-release amoxicillin in proportions such that, for an amoxicillin MIC of 4 mg/L, the T >MIC is 49% of a 12-h dosing interval.ls This formulation also provides a serum concentration of 8 mg/L for 35% of the dosing interval (Table 5; Figures 3 and 6).9 Table 2 indicates that, while both clarithromycin and azithromycin are likely to be bacteriologically effective against macrolide-susceptible strains of S. pneumoniae (MIC90 0.06 mg/L), they would be predicted to be bacteriologically ineffective against ermB- or mefEmediated resistant strains. Consequently, these agents would be inappropriate for patients living in areas with high prevalences of macrolide resistance (Table 4).19 Similarly, clarithromycin and azithromycin fail to achieve the serum PK parameters required for the eradication of H. influenzae.3~sJ3-16

S18

International Journal of Infectious Diseases I Volume 7, Supplement 1,2003

Percentage of dosing interval tract infection pathogens3 for oral p-lactams for which serum concentrations are above the MI&s of common

Table 3. respiratory

5. pneumoniae Dosing Cefaclor Cefuroxime regimen 500 mg t.i.d. axetil 500 mg b.i.d. mg b.i.d.
intermediate;

Pen-S 60 75 100
Pen-R, penicillin

Pen-l 0 35 59
resistant.

Pen-R 0 0 46

H. influenzae 0 33 41

M. catarrhalis 0 33 70

Amoxicillin-clavulanate
Pen-S, penicillin susceptible;

875/125

Pen-l, penicillin

(4

90 mg/kg/day

12 Time (h) 2000/125 mg b.i.d.

I 24

12 Time (h)
- - - Pen-R ME,, = 4 mg/L - n Pen-l MIC,, = 1 mglL - 11 Pen-S MIC,, = 0.03 mg/L PWPD BP = 4 mg/L * - * H. influenzae ME,, = 1 mg/L ..... M. catarrhalis ME,, = 0.25 mg/L

24

has only one breakpoint, and this is independent of the pathogen involved but specific for dose and even formulation, whereas NCCLS breakpoints vary according to the agent and the pathogen. The NCCLS has recognized the value of PKiPD breakpoints and the need to consider these to enable the use of optimal dosing regimens. NCCLS breakpoints for S.pneumoniae and p-lactams, issued in January 2000, reflect the importance of PK/PD relationships. However, there are still considerable discrepancies between PK/PD and NCCLS breakpoints for H. infEuenzae, particularly in the case of macrolides and some oral cephalosporins, and no NCCLS breakpoints exist for M. catarrhalis. In terms of antimicrobial selection for the empirical treatment of RTIs, PK/PD breakpoints are playing an increasingly important role. Geographic variation in susceptibility patterns is considerable, and Table 4 highlights the susceptibilities of major RTI pathogens in regions worldwide to oral agents at PK/PD breakpoints.19 Table 4 indicates that, against all three major pathogens, high-dose amoxicillin-clavulanate (90/6.4 mg/kg per day or pharmacokinetically enhanced 2000/125 mg b.i.d.) would cover 29.5% of S.pneumoniae, H. influenzae, and A4. catarrhalis strains (i.e. predictive bacterial eradication).19 CONCLUSIONS

Figure 6. Use of PWPD breakpoints to predict antimicrobial activity for two high-dose amoxicillin-clavulanate formulations: (a) 90/6.4 mg/kg per day in two divided doses; and (b) pharmacokinetically enhanced amoxicillin-clavulanate 2000/125 mg b.i.d. These dosing regimens lead to a breakpoint of 4 mg/L, and permit amoxicillin to be active against all common respiratory tract infection pathogens shown, including all penicillin-intermediate and most penicillin-resistant strains of 5. pneumoniae.7*8

COMPARING PK/PD AND CURRENT BREAKPOINTS

NCCLS

Although the National Committee for Clinical Laboratory Standards (NCCLS) is starting to take PK/PD parameters into consideration,20 there remains some degree of disagreement between NCCLS and PK/PD breakpoints. The main difference is that, for PK/PD assessment, each agent (in a particular dosing regimen)

There is a great deal of evidence to suggest that PK/PD parameters can be used to predict bacterial eradication in both animal models and humans, and can be used to derive clinically relevant susceptibility breakpoints. For the p-lactam agent amoxicillin-clavulanate, optimal bacterial killing is achieved when the serum concentration remains above the MIC for approximately 40% of the dosing interval. Oral dosing regimens of 9016.4 mg/kg per day in two divided doses in children, and 20001125 mg b.i.d. of the sustained-release formulation in adults, produce serum concentrations of 4 mg/L for at least 40% of the dosing interval. Consequently, pathogens with amoxicillin-clavulanate MICs of up to 4 mg/L are susceptible and likely to be eradicated. Additionally, the oral, adult formulation (2000/125 mg) is predicted to be potentially bacteriologically effective against pathogens with MICs as high

How can we predict bacterial eradication? I Jacobs

Table 4. Susceptibility (%) of major respiratory tract infection pathogens at PWPD breakpoints: (%) Europe MC NA NA NA NA NA NA NA NA NA NA NA NA NA NA SP 97.5 98.6 97.5 18.6 79.5 85.1 85.1 97.2 77.7 77.1 81.0 76.7 99.5 72.5 HI 99.7 100 87.6 0.4 100 12.8 79.5 100 0 0.7 NA 27.4 100 80.6 MC 100 100 26.0 8.9 100 16.3 47.2 100 0 100 NA 91.9 100 100 SP 98.4 100 97.9 6.1 27.6 52.0 53.6 93.4 33.7 33.7 69.0 24.9 94.7 58.4 Far East HI 88.0 96.3 74.1 1.0 97.3 9.0 62.1 77.7 0 2.3 NA 15.9 100 83.1 Alexander Project 2001g

s19

Susceptibility PKIPD breakpoint @wlL) 2 4 2 0.5 1 1 1 NA 0.25 0.12 NA 0.25 2 NA Worldwide SP 96.1 98.1 96.1 15.2 66.5 76.9 77.6 96.5 69.8 69.0 82.0 69.5 98.8 66.0 HI 97.5 99.5 82.7 2.3 99.5 15.5 77.2 100 0 0.9 NA 27.6 100 76.8 MC 99.3 100 23.9 8.4 100 14.8 48.6 100 0 100 NA 92.3 100 98.6 SP 91.1 94.9 91.2 15.5 67.9 73.5 75.2 97.1 71.7 70.1 90.9 85.4 99.3 64.4 USA HI 97.6 99.8 74.2 5.5 99.8 22.5 80.3 99.8 0 0.9 NA 31.4 100 77.7

Agent AMWCA AMWCA high Amoxicillin Cefaclor Cefixime Cefprozil Cefuroxime CeftriaxoneC Erythromycin Azithromycin ClindamycitY Doxycycline Levofloxacin Cotrimoxazoled
SP, 5. pneumoniae;

MC 94.7 100 10.5 5.3 100 5.3 57.9 100 0 100 NA 94.7 100 89.5

doseaeb

Hi, H. influenzae; MC, M. catarrhalis; AMXKA, amoxicillin-clavulanate; NA, no data available. a Susceptibility based on amoxicillin component. b PWPD breakpoint of 4 mg/L applies to the 90/6.4 mglkg per day pediatric formulation and the 20001125 mg b.i.d. formulation of amoxicillin-clavulanate. c Susceptibility based on NCCLS breakpoints: for ceftriaxone, 21 mg/L for 5. pneumoniae (non-meningitis), ~2 mg/L (also used here for M. catarrhalis); for clindamycin, ~0.25 mg/L for 5. pneumoniae (H. influenzae and M. catarrhalis d Susceptibility based on trimethoprim component, NCCLS breakpoint ~0.5 mg/L.

adult for H. influenzae not tested).

Table 5. T>MIC adult formulation provide coverage

for pediatric and adult amoxicillin-clavulanate (AMXKA) (2000/125 mg) will provide coverage of pathogens with of pathogens with MlCs of 2-4 mg/L18,21

formulations, MlCs as high

The new, pharmacokinetically enhanced as 4 mg/L, while current formulations will

T > MIC for % of dosing interval AMXICA formulation Pediatric 4516.4 40/l 0 9016.4 (mglkglday) 2 divided 3 divided 2 divided t.i.d. b.i.d. t.i.d. b.i.d. doses doses doses 50 59 61 55 44 >65 270 41 44 50 43 40 55 60 Dosing regimen 1 2

amoxicillin for MlCs 4

(mg/L)

of: 8

41

Adult (mg) 500/l 2s 87Sil25 1000/l 25 2000/l 25 -, T >MIC of ~35%.

41 49

35

as 8 mg/L. Clearly, amoxicillin-clavulanate remains a key antimicrobial agent for the treatment of RTIs in both children and adults. Its availability in several optimized formulations will help to reassure clinicians about its continued efficacy against drug-resistant pathogens in areas where these organisms constitute an emerging problem. REFERENCES
1. Craig WA. Re-evaluating current antibiotic therapy. Respir Med 2001; 95(suppl A):S12-S19. 2. Frimodt-Moller N. How predictive is PK/PD for antibacterial agents? Int J Antimicrob Agents 2002; 19:333339.

3. Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbial Infect 2001; 7589-596. 4. Carbon C, Poole MD. The role of newer macrolides in the treatment of community-acquired respiratory tract infection. A review of experimental and clinical data. J Chemother 1999; 11:107-118. 5. Craig WA. Pharmacokineticipharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1-12. 6. Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 2002; 19:261-268. 7. Craig WA. Antimicrobial resistance issues of the future. Diagn Microbial Infect Dis 1996; 25:213-217.

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International Journal of Infectious Diseases I Volume

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