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Antimicrobial Agents and Chemotherapy, September 1998, p. 2375-2379, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vivo Activities of Amoxicillin and
Amoxicillin-Clavulanate against Streptococcus pneumoniae:
Application to Breakpoint Determinations
D.
Andes* and
W. A.
Craig
University of Wisconsin, Madison, Wisconsin
Received 20 January 1998/Returned for modification 25 March
1998/Accepted 10 June 1998
 |
ABSTRACT |
The in vivo activities of amoxicillin and amoxicillin-clavulanate
against 17 strains of Streptococcus pneumoniae with
penicillin MICs of 0.12-8.0 mg/liter were assessed in a
cyclophosphamide-induced neutropenic murine thigh infection model.
Renal impairment was produced by administration of uranyl nitrate to
prolong the amoxicillin half-life in the mice from 21 to 65 min,
simulating human pharmacokinetics. Two hours after thigh infection with
105 to 106 CFU, groups of mice were treated
with 7 mg of amoxicillin per kg of body weight alone or combined with
clavulanate (ratio, 4:1) every 8 h for 1 and 4 days. There was an
excellent correlation between the MIC of amoxicillin (0.03 to 5.6 mg/liter) and (i) the change in log10 CFU/thigh at 24 h and (ii) survival after 4 days of therapy. Organisms for which MICs
were 2 mg/liter or less were killed at 1.4 to 4.2 and 1.6 to 4.1 log10 CFU/thigh at 24 h by amoxicillin and
amoxicillin-clavulanate, respectively. The four strains for which MICs
were >4 mg/liter grew 0.2 to 2.6 and 0.6 to 2.3 logs at 24 h
despite therapy with amoxicillin and amoxicillin-clavulanate,
respectively. Infection was uniformly fatal by 72 h in untreated
mice. Amoxicillin therapy resulted in no mortality with organisms for
which MICs were 1 mg/liter or less, 20 to 40% mortality with organisms
for which MICs were 2 mg/liter, and 80 to 100% mortality with
organisms for which MICs were 4.0-5.6 mg/liter. Lower and higher doses
(0.5, 2, and 20 mg/kg) of amoxicillin were studied against organisms
for which MICs were near the breakpoint. These studies demonstrate that a reduction of 1 log10 or greater in CFU/thigh at 24 h
is consistently observed when amoxicillin levels exceed the MIC for 25 to 30% of the dosing interval. These studies would support amoxicillin (and amoxicillin-clavulanate) MIC breakpoints of 1 mg/liter for susceptible, 2 mg/liter for intermediate, and 4 mg/liter for resistant strains of S. pneumoniae.
| |
INTRODUCTION |
Infections caused by
Streptococcus pneumoniae with reduced susceptibility to
beta-lactam antimicrobial agents are an increasingly encountered
problem in clinical practice. The incidence of infection with
penicillin-resistant pneumococci now exceeds 30% in most areas of the
United States (22). There have been reports of failure of
conventional antimicrobial regimens in acute otitis media and
meningitis caused by highly penicillin-resistant pneumococci (2,
3, 11, 19, 22). These therapeutic failures suggest that the
current standards for predicting effective therapy of infection with
these organisms may need to be altered.
Amoxicillin and amoxicillin-clavulanate are orally administered
beta-lactams, with thrice daily dosing in humans commonly used to treat
infections caused by S. pneumoniae. Although these agents
have the lowest MICs for S. pneumoniae among currently available oral beta-lactams, the precise MIC breakpoint separating effective and noneffective in vivo activity is currently unknown. The
use of animal models has become integral in the evaluation of the
therapeutic efficacies of antimicrobial agents. Animal models can
describe the time course of in vivo antibiotic therapy and
dose-response relationships and determine the influence of antimicrobial agent resistance in vitro on various in vivo outcomes observed during the treatment of these infections (5, 10, 13,
24).
The goals of these studies were (i) to stimulate the human
pharmacokinetic profiles of amoxicillin and amoxicillin-clavulanate in
the murine infection model in order to appropriately compare these
results to those that might be expected in humans and (ii) to
characterize the in vivo activities of amoxicillin and
amoxicillin-clavulanate against strains of S. pneumoniae for
which penicillin and amoxicillin MICs vary. By observing efficacy
against organisms with a range of in vitro activity, we hoped to
identify in vivo MIC breakpoints of amoxicillin and
amoxicillin-clavulanate for S. pneumoniae. These studies
would also enable us to determine if clavulanate enhances the in vivo
activity against strains of S. pneumoniae with various
susceptibilities to penicillin.
(Part of this research was presented at the 35th Interscience
Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September 1995.)
| |
MATERIALS AND METHODS |
Bacteria, media, and antibiotics.
S. pneumoniae ATCC
10813 and 49619 and 15 clinical isolates (provided by Fred Tenover of
the Centers for Disease Control and Prevention and Gary Doern of the
University of Iowa) were used for these experiments. Organisms were
grown, subcultured, and quantified in Mueller-Hinton broth (MHB) (Difco
Laboratories, Detroit, Mich.) and on sheep blood agar plates (Remel,
Milwaukee, Wis.). Amoxicillin and amoxicillin-clavulanate were provided
by SmithKline Beecham, Philadelphia, Pa.
In vitro studies.
MICs of amoxicillin and penicillin for the
various isolates were determined by standard National Committee for
Clinical Laboratory Standards (NCCLS) microdilution methods with
geometric two-fold serial dilutions in cation-adjusted MHB supplemented
with 3% lysed horse erythrocytes. Each well contained 100 µl (50 µl of inoculum plus 50 µl of drug-containing MHB). The final
inoculum was 1 × 105 to 5 × 105.
MIC endpoints were determined by visual inspection after
CO2 incubation (Forma Scientific Incubator, Marietta, Ohio)
at 37°C for 18 to 24 h. Final results were expressed as
geometric means of two to four determinations.
Mouse preparation and infection.
Six-week-old,
specific-pathogen-free, female ICR/Swiss mice weighing 23 to 27 g
(Harlan Sprague-Dawley, Madison, Wis.) were rendered neutropenic
(neutrophils, <100/mm3) by injecting cyclophosphamide
(Mead Johnson Pharmaceuticals, Evansville, Ind.) intraperitoneally 4 days (150 mg/kg of body weight) and 1 day (100 mg/kg) before
experimental infection. Previous studies have shown that this
regimen produces neutropenia in this model for 5 days
(6). Renal impairment was produced by one intraperitoneal
injection of uranyl nitrate (10 mg/kg) 3 days before therapy with an
antimicrobial agent. This intervention causes a reversible acute
tubular necrosis and a subsequent significant stable reduction in renal
function for at least 7 days (6, 14, and data not
shown). Broth cultures of freshly plated bacteria were grown to
logarithmic phase overnight to an absorbance of 0.3 at 580 nm
(Spectronic 88; Bausch and Lomb, Rochester, N.Y.). After a 1:10
dilution into fresh MHB, bacterial counts of the inoculum ranged from
105 to 106 CFU/ml. Thigh infections with each
of the S. pneumoniae strains were produced by injection of
0.1 ml of inoculum into each of the ether-anesthetized mice 2 h
before therapy with an antimicrobial agent was begun.
Treatment with an antimicrobial agent.
Mice were treated
with amoxicillin administered by subcutaneous injection every 8 h
at a dose of 7 mg/kg. Lower doses (0.5 and 2 mg/kg) and a higher dose
(20 mg/kg) were used with some strains (673, 145, 1293, 1329, and 1285)
to vary the duration of time that serum levels exceeded the MICs for
the infecting strains. Amoxicillin-clavulanate was administered
subcutaneously every 8 h at a dose of 7 mg of amoxicillin per kg
and 1.75 mg of clavulanic acid per kg. These dosing intervals were
chosen to simulate one of the commonly used regimens in humans. Control animals received subcutaneous injections of 0.85% saline. Antibiotic treatment was administered in 0.2-ml volumes 2 h after thigh
infection for a total duration of 24 h. Pairs of mice were used
for each dosing regimen and sacrificed at the end of therapy. Untreated control mice were sacrificed just after thigh infection
(n = 1), just before drug treatment (n = 2), and after 24 h (n = 2).
After sacrifice, thighs were removed and homogenized (Polytron tissue
homogenizer; Kinematica, Lucerne, Switzerland) in 10 ml of iced 0.85%
saline. Ten-microliter aliquots of four serial 10-fold dilutions were
plated on sheep blood agar for CFU determinations. Efficacy in these
studies was calculated by subtracting the log10 CFU per
thigh of each mouse at the end of therapy with an antimicrobial agent
from the mean log10 CFU per thigh of control mice just
before therapy (0 h). The lower limit of detection in the
antibiotic-treated mice was 102 CFU/thigh.
Other groups of five mice were similarly infected with a subset of 13 strains, including penicillin-susceptible, -intermediate,
and
-resistant pneumococci, for evaluation of survival after 96
h of
therapy. Mice received either a regimen with amoxicillin
(7 mg/kg) or
amoxicillin-clavulanate (7/1.75 mg/kg) administered
at 8-h intervals,
with a total of 12 doses.
Drug pharmacokinetics.
Single-dose serum pharmacokinetic
studies were performed with thigh-infected mice given amoxicillin at
doses of 7, 20, and 48 mg/kg. For each of the doses examined, one or
two groups of three to four mice with normal and impaired (uranyl
nitrate) renal function were sampled four times at 15- to 60-min
intervals. Blood was obtained by retro-orbital puncture with
heparinized capillary tubes (Fischer Scientific Co., Pittsburgh, Pa.)
in ether-anesthetized mice. Following collection, the samples were
centrifuged (model MB; International Equipment Co.) for 3 to 5 min at
10,000 × g, and drug levels in plasma were determined
by agar-well microbiologic assay with standard media and by standard
methods, with Staphylococcus aureus ATCC 6538P as the test
organism. Standard samples were prepared in pooled normal mouse serum.
Pharmacokinetic constants, including elimination rate constant,
half-life, volume of distribution, area under the concentration-time
curve (AUC), and peak level, were calculated with a one-compartment
model with zero-order absorption and first-order elimination by
nonlinear squares techniques (MINSQ; Micromath Inc., Salt Lake City,
Utah).
Statistical analysis.
A Mann-Whitney test was used to
compare differences in in vivo activity of amoxicillin-clavulanate
between each of the strains. A sigmoid dose-effect model
(Emax model) was used to characterize in vivo
antimicrobial activity. The model is derived from the Hill equation
E = (Emax × TN)/(P50N + TN), where E is the observed effect
(change in log10 CFU per thigh compared with untreated
controls at 24 h or percent mortality), T is the
percentage of time serum levels were above the MIC,
Emax is the maximum effect,
P50 is the time above MIC needed to achieve 50%
of the maximum effect, and N is the slope of the response relationship (16). Emax,
P50, and N were calculated by
nonlinear least-squares regression (MINSQ). R2
(the coefficient of determination) was used to estimate the fraction of
the total variance in the effect of the antimicrobial agent that could
be attributed to its linear regression with the pharmacokinetic parameter.
| |
RESULTS |
MIC determinations.
The MICs of amoxicillin and penicillin G
for the 17 study strains are shown in Table
1. The MICs varied 500-fold for
amoxicillin and 1,000-fold for penicillin. In general, AUCs for
amoxicillin were similar or two- to fourfold lower than AUCs for
penicillin G. Based on NCCLS breakpoints, the organisms studied
included one strain susceptible to penicillin (MIC, 0.1 mg/liter),
eight strains with intermediate susceptibility (MICs, 0.1 to 1.0 mg/liter), and eight strains resistant to penicillin (MICs, >2.0
mg/liter).
Pharmacokinetics.
Pharmacokinetic profiles for amoxicillin
following doses of 7, 20, and 48 mg/kg resulted in peak/dose ratios of
0.7 ± 0.3 (mean ± standard deviation) and 1.5 ± 0.4 and elimination half-lives of 21 ± 3 and 65 ± 13 min in
mice with normal and impaired renal function, respectively. The peak
level was twofold higher in renally impaired mice compared to that in
mice with normal renal function. The elimination half-life was
increased 3.1-fold in the renally impaired mice, approximating that
observed in humans with normal renal function. The serum concentrations
following a subcutaneous dose of 7 mg of amoxicillin per kg in renally
impaired mice and a 500-mg oral dose in normal human volunteers are
shown in Fig. 1. Although both doses
produced similar mean peak levels (12.0 mg/liter in mice and 10.9 mg/liter in humans), peak levels occurred much earlier in the murine
model. Since the rates of elimination were very similar in mice and
humans, the duration of time that drug levels in serum would exceed the
MIC would be 1 to 1.5 h longer in humans than in the murine model.
Organism growth in thighs.
Organisms exhibited logarithmic
growth prior to therapy in all control experiments. Bacterial numbers
at the start of therapy ranged from 6.03 to 7.46 log10 CFU
per thigh. Control growth over 24 h for each organism studied is
shown in Fig. 2a. All organisms grew at
2.06 to 3.35 log10 CFU per thigh over 24 h in
untreated control animals.
In vivo efficacy.
Organism growth (positive numbers) or
killing (negative numbers) following 24 h of therapy with
amoxicillin (7 mg/kg) and amoxicillin-clavulanate (7/1.75 mg/kg) every
8 h is shown in Fig. 2b and c, respectively. Two of the most
amoxicillin-susceptible strains were not studied with
amoxicillin-clavulanate. The differences between the extent of killing
for amoxicillin and amoxicillin-clavulanate at the end of 24 h of
therapy were small and insignificant (P = 0.06 to 1.0).
In fact, the two strains (138 and 1285) for which differences were
closest to being significant (P = 0.06) gave better
results with amoxicillin, not amoxicillin-clavulanate. The magnitude of
killing ranged from 1.5 to 4.0 log10 CFU per thigh. The
extent of organism killing with both drugs was dependent on the MICs
for the organisms. Significant killing was observed with all organisms
for which MICs were 2 mg/liter or less, while growth or minimal net
change in bacterial numbers was observed with organisms for which MICs
were 4 mg/liter or greater.
Mortality following 4 days of antimicrobial therapy with amoxicillin (7 mg/kg/8 h) and amoxicillin-clavulanate (7/1.75 mg/kg/8
h) is shown in
Table
2. Mortality was 100% within 3 days in untreated
controls for all strains. The MICs for the various
study organisms
were predictive of efficacy when mortality was used as
an endpoint
as well. All animals that were infected with organisms for
which
MICs were 1 mg/liter or less survived. With the two strains for
which MICs were 2 mg/liter, 20 to 40% mortality was observed with
amoxicillin, but no mortality was observed with
amoxicillin-clavulanate.
In contrast, mortality was 80 to 100% in mice
infected with organisms
for which MICs were 4 mg/liter or greater.
Correlation between in vivo efficacy and duration of time serum
levels exceeds the MIC.
As shown in Fig.
3, there was an excellent correlation
between mortality after 4 days of therapy and the duration of time that
serum levels exceeded the MIC for both amoxicillin and
amoxicillin-clavulanate (R2 = 95%). The highest
mortality rates, 80 to 100%, were seen when serum levels exceeded the
MIC for less than 20% of the dosing interval. Maximal survival was
approached when serum levels exceeded the MIC for 40% of the 8-h
dosing interval, or approximately 3 h per dose.
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FIG. 3.
Relationship between mortality and duration of time that
serum levels exceed the MIC following doses of amoxicillin at 2, 7, and
20 mg/kg and amoxicillin-clavulanate at 7 mg/kg every 8 h. Each value
represents the mean for two thighs.
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|
The correlation between therapeutic efficacy, measured by killing or
growth of bacteria at 24 h, and the duration of time
that serum
levels exceeded the MICs of amoxicillin and amoxicillin-clavulanate
against the various organisms is shown in Fig.
4. The graph also
includes data from the
study of additional dosage regimens. Organisms
that were not killed at
7 mg/kg/8 h were killed at dosage regimens
of 20 mg/kg/8 h. Organisms
that were killed at 7 mg/kg/8 h exhibited
growth when the dose was
reduced to 2.0 or 0.5 mg/kg/8 h. An excellent
correlation between in
vivo antimicrobial activity and time above
MIC was obtained
(
R2 = 80%). A static effect or no net growth
was demonstrated when
the time above MIC was 20 to 30% of the dosing
interval. Maximum
in vivo killing was observed with time above MICs of
50 to 60%
of the 8-h dosing interval.
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FIG. 4.
Relationship between change in log10
CFU/thigh over 24 h and duration of time that serum levels exceed
the MIC following doses of 2, 7, and 20 mg of amoxicillin per kg every
8 h and doses of 7 mg of amoxicillin-clavulanate per kg every
8 h. Each value represents the mean for two thighs.
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| |
DISCUSSION |
Escalating resistance to antimicrobial agents seen in clinical
isolates of S. pneumoniae has reduced the efficacy of many oral drugs used to treat respiratory infections such as otitis media
(2-4). Assessing the utility of different antimicrobial agents and respective dosing regimens against resistant pneumococci has
thus become a pressing priority. The use of animal models to predict
effective dosing regimens in humans is one approach to this problem
(5, 7). Despite the many positive aspects of animal models,
several criticisms, such as altered pharmacokinetics in animals, have
precluded direct application of results to clinical practice in humans.
By altering the renal kinetics of amoxicillin in the murine thigh
infection model, we have simulated the serum concentration time course
of this agent observed in humans. Doses of 7 mg/kg produced a kinetic
elimination profile similar to that seen with a 500-mg oral dose in
humans with normal renal function. However, subcutaneous absorption of
amoxicillin in mice was faster than gastrointestinal absorption of the
drug in humans. This resulted in similar peak concentrations but a
shorter time above MIC in the mice than would be observed in humans.
Prior experiments in a murine infection model have shown that the in
vivo efficacies of antimicrobial agents correlate closely with their
respective in vitro activities (6, 20, 24). Several clinical
studies have demonstrated a similar relationship between MICs and in
vivo outcomes (1, 17). In our infection experiments, the in
vivo efficacies of amoxicillin and amoxicillin-clavulanate were
inversely related to the MICs for the infecting organisms over a
wide range of susceptibilities, including penicillin-resistant organisms. At a dose of 7 mg/kg, bacterial killing was observed for
organisms for which MICs were as high as 2 mg/liter. A recent clinical
trial of augmentin in acute otitis media demonstrated equal efficacies
in patients infected with penicillin-susceptible, -intermediate and
resistant strains of S. pneumoniae (15). The highest MIC of amoxicillin observed in this study was 2 mg/liter.
Several experimental models have proven that therapeutic efficacy for
the beta-lactam class of antibiotics correlates best with the duration
of time that serum levels exceed the MIC for the infecting organism
(8, 9, 12). With the penicillins, bacteriostatic efficacy
has been achieved in the thigh infection studies when the magnitude of
this parameter reaches 25 to 30%, while maximal bacteriologic efficacy
and survival are predictably seen when serum levels remain above the
MIC for 40 to 50% of the dosing interval (8). We found that
the percentage of time above the MIC required for utility of
amoxicillin and amoxicillin-clavulanate did not differ for
penicillin-susceptible and -resistant strains of S. pneumoniae. Again, bacteriologic efficacy and survival were maximal when serum levels exceeded the MIC for 40 to 50% of the 8-h
dosing interval.
Determination of MIC breakpoints of amoxicillin and
amoxicillin-clavulanate in humans can be estimated by calculating the highest drug concentration that is maintained in serum for at least
50% of the dosing interval with standard oral doses. Following a 250- and a 500-mg dose of amoxicillin in normal volunteers, serum levels
exceed 1.0 and 2.0 mg/liter, respectively, for at least 50% of the
dosing interval. NCCLS-approved MIC breakpoints for these agents are
currently 0.5 mg/liter for susceptible, 1.0 mg/liter for intermediate,
and 2.0 mg/liter for resistant strains. Based on the simulation of
human pharmacokinetics in this animal model, estimated breakpoints of
amoxicillin and amoxicillin-clavulanate for S. pneumoniae
would be 1 dilution higher, at 1.0 mg/liter for susceptible, 2.0 mg/liter for intermediate, and 4.0 mg/liter for resistant strains. If
the recently suggested dosage escalation to 875 mg twice daily is
considered, serum levels would remain above a MIC of 1 mg/liter for an
adequate percentage of the 12-h dosing interval, making the
above-mentioned breakpoints acceptable for this regimen as well. Our
results, even in the presence of profound neutropenia and the high
clinical success with amoxicillin-clavulanate against strains of
S. pneumoniae for which amoxicillin MICs are as high as 2 mg/liter, support a reevaluation of current breakpoints.
| |
ACKNOWLEDGMENTS |
We thank Fred Tenover of the CDC and Gary Doern of the University
of Iowa for providing the clinical isolates used in these experiments.
This work was supported by a grant from SmithKline Beecham,
Philadelphia, Pa.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Wm. S. Middleton
Memorial VA Hospital, 2500 Overlook Terrace, Madison, WI 53705. Phone: (608) 262-7020. Fax: (608) 262-7685. E-mail:
drandes{at}facstaff.wisc.edu.
| |
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Antimicrobial Agents and Chemotherapy, September 1998, p. 2375-2379, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
