Dosing of Amoxicillin/Clavulanate Given Every 12 Hours Is as Effective as Dosing Every 8 Hours for Treatment of Lower Respiratory Tract Infection
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Dosing of Amoxicillin/Clavulanate Given Every 12 Hours Is as Effective as
Dosing Every 8 Hours for Treatment of Lower Respiratory Tract Infection
Alistair D. Calver, Niall S. Walsh, Patrick F. Quinn, From the West Vaal Hospital, Orkney, South Africa; Longford Centre,
Constantin Baran, Val Lonergan, Krishan P. Singh, County Longford, Ireland; Health Centre, Sligo, Ireland; private
practice, Dachau, Germany; Health Centre, Graignamanagh, County
Wendy S. Orzolek, and the Lower Respiratory Tract
Kilkenny, Ireland; and SmithKline Beecham Pharmaceuticals,
Infection Collaborative Study Group Collegeville, Pennsylvania, USA
In this double-blind study, 557 patients with lower respiratory tract infection were randomly
assigned to receive amoxicillin/clavulanate orally either every 12 hours (875/125 mg) or every 8
hours (500/125 mg) for 7 —15 days. For the 455 patients evaluable for clinical efficacy at the end of
therapy, clinical success was similar in the two groups: 93% and 94% in the 12-hour and 8-hour
groups, respectively (P = .42). Bacteriologic success at the end of therapy was also comparable:
97% and 91% in the 12-hour and 8-hour groups, respectively (P = .86). The occurrence of adverse
events related to treatment was similar for the two groups, but fewer patients in the 12-hour group
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reported moderate or severe diarrhea. Amoxicillin/clavulanate (875/125 mg) given every 12 hours
is as effective and safe as every-8-hours administration of the combination (500/125 mg) for the
treatment of lower respiratory tract infection.
Bacterial pneumonia and acute exacerbation of chronic bron- Amoxicillin/clavulanate (Augmentin; SmithKline Beecham
chitis remain among the most common infections treated in the Pharmaceuticals, Philadelphia) is a combination product con-
community. In the United States up to 3.3 million people de- taining the semisynthetic penicillin amoxicillin and the 0-lacta-
velop community-acquired pneumonia each year [1], and 50% mase inhibitor clavulanate potassium. The established oral-
to 90% are treated as outpatients [2]. Because of the relatively dose regimen for lower respiratory tract infections in adults is
high frequency of individuals whose host defenses are compro- 500/125 mg (amoxicillin/clavulanate equivalent) given every
mised by age or coexistent disease, along with increasing bacte- 8 hours [5].
rial resistance, careful selection of antimicrobial therapy is war- In recognition of the fact that compliance is a major factor
ranted. in the outcome of outpatient treatment of many infections, it
The microbiology of community-acquired lower respiratory is necessary to determine the most convenient dose regimen
tract infection is changing with the emergence of resistant that is effective. The objective of this study was to compare
pathogens. This is partially attributable to changing characteris- the safety and efficacy of amoxicillin/clavulanate given every
tics of the general population [3, 4]. There are now greater 12 hours (875/125 mg) to that of the combination given every
numbers of people over age 65 years and of ambulatory patients 8 hours (500/125 mg) for the treatment of lower respiratory
with compromised immune function. New lower respiratory tract infections (community-acquired pneumonia and acute
tract pathogens have emerged (such as Legionella species), bacterial exacerbation of chronic bronchitis).
and f3-lactamase-producing organisms (such as Haemophilus
influenzae and Moraxella catarrhalis) are increasingly com-
mon. In addition, antibiotics tend to be used early in infectious Methods
episodes, leading to a high proportion of patients with unidenti- Study design. This was a multinational, multicentered
fiable pathogens. study with 87 participating centers in the United States, Repub-
lic of Ireland, Canada, Australia, United Kingdom, Italy, Ger-
many, Belgium, The Netherlands, Switzerland, and South Af-
rica. Treatment was randomized and administered in a double-
Received 26 April 1996; revised 23 September 1996. blinded, double-dummy manner to two parallel treatment
This study was supported by a grant to each center by SmithKline Beecham
Pharmaceuticals.
groups.
The study was conducted following the guidelines of the Declaration of Patients. Inpatients or outpatients at least 18 years of age
Helsinki and was approved by an institutional review board/ethics committee presenting with a community-acquired lower respiratory tract
at each site. Informed consent was obtained from each patient prior to study infection who could be treated with an oral antimicrobial were
initiation.
Reprints or correspondence: Wendy S. Orzolek, SmithKline Beecham Phar- enrolled. We ensured that —50% of the patients had commu-
maceuticals, 1250 South Collegeville Road, P.O. Box 5089, UP4330, Col- nity-acquired pneumonia and —50% had acute exacerbation of
legeville, Pennsylvania 19426-0989. chronic bronchitis.
Clinical Infectious Diseases 1997; 24:570-4 Patients with community-acquired pneumonia were required
© 1997 by The University of Chicago. All rights reserved.
1058-4838/97/2404 — 0006$02.00 to have clinical symptoms (e.g., chest pain, shortness of breath)CID 1997;24 (April) Amoxicillin/Clavulanate Every 12 vs. Every 8 Hours 571
and features suggestive of community-acquired pneumonia peared after treatment that did not contribute to the symptoms
(e.g., fever, crackles on auscultation, bronchial breathing, dull- and signs of infection); superinfection (sputum culture showed
ness on percussion), cough productive of sputum, and infiltrates a significant number of colonies of an organism that was differ-
evident on a chest roentgenogram. Patients with acute exacer- ent from pretreatment pathogens, that contributed to the symp-
bation of chronic bronchitis were required to have a history of toms and signs of the infection, and that required additional
a cough productive of sputum on most days of the week for 3 antimicrobial therapy); failure (noneradication of the initial
months in each of the 2 preceding years, with an increase in pathogen); or inevaluable. Proven eradication, presumed eradi-
quantity and/or purulence of sputum in the 48 hours before cation, and colonization were judged to be evidence of bacterio-
enrollment. logic success.
Patients included in the assessment of bacteriologic response The safety of the regimen was determined for all randomized
were required to have an organism identified from a sputum patients by interview at each visit. Clinical chemistry and he-
sample collected within 2 days prior to the start of treatment. matology screening tests were performed at the start of treat-
The pretreatment gram stain must have contained >25 poly- ment and then, if clinically indicated, at the end of treatment
morphonuclear leukocytes and < 10 epithelial cells per low- and 2-4 weeks after completion of treatment.
power field. Identification of organisms was confirmed by a Data analysis. The study was designed to enroll at least
central study laboratory. 150 evaluable patients per treatment regimen (300 patients to-
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Antimicrobial treatment. Patients were randomly assigned tal) to determine with 80% power (/3 = 0.20) that the lower
to receive either oral amoxicillin/clavulanate every 12 hours confidence limit of the two-sided 95% confidence interval
(875/125 mg) plus an oral placebo (identical in appearance to (a = 0.05) of the difference in the clinical success rates be-
the active treatment) every 8 hours or amoxicillin/clavulanate tween the two treatment groups was not below —10%, with
every 8 hours (500/125 mg) plus an oral placebo every 12 the assumption that the clinical response rate in the two groups
hours. Each regimen was administered for 7-15 days. Use of was 90%.
additional antimicrobials or probenecid was not permitted. Continuous data (age and duration of therapy) were analyzed
At the end of treatment, compliance was assessed to ensure by Student's t-test, while categorical data were analyzed with
that patients had received a minimum of 80% and a maximum the x 2 test. The difference in the success rates between treat-
of 120% of the prescribed medication doses. ment groups was assessed by analyzing a linear model with
Evaluations. Patients were evaluated for clinical and bacte- effects due to center and treatment (Statistical Analysis System,
riologic efficacy of treatment 48-96 hours after its initiation version 6.07; SAS Institute, Cary, NC). The equivalence of the
and then 2-4 days after its completion. In addition, assessment two treatment groups was also assessed by determining the
was performed by telephone 5-9 days after the start of treat- two-tailed 95% confidence interval of the difference in the
ment. Patients returned for clinical and bacteriologic evaluation proportions of patients with clinical and bacteriologic success.
2-4 weeks after the end of treatment. The treatment groups were considered equally effective if the
Clinical response (cure, improvement, failure, or inevaluable lower 95% confidence limit was not below —10%.
because of poor compliance or extenuating circumstances) was
determined 2-4 days after completion of treatment. Cure was
defined as complete resolution of signs and symptoms of infec- Results
tion, with no additional antimicrobial therapy required. Im-
provement was defined as incomplete resolution of the signs Patients. Five hundred and fifty-seven patients were ran-
and symptoms of infection, with no additional antimicrobial domized to receive study medication: 273 received amoxicillin/
therapy required. Failure was defined as no diminishment of the clavulanate every 12 hours, and 284 received it every 8 hours.
signs and symptoms of infection and/or the need for additional A total of 472 patients (85%) were evaluated at all four visits,
antimicrobial therapy. Cure and improvement were judged to and 455 (80%) were considered evaluable for clinical efficacy
be evidence of clinical success. at the end of therapy. No significant differences were detected
Sputum samples were collected for gram stain, culture, and (P > .05) with respect to any of the baseline characteristics
susceptibility testing within 2 days prior to the start of treatment of patients (table 1).
and then during therapy, at the end of therapy, and 2-4 weeks One hundred and two patients were excluded from the per-
after treatment if the sputum was available. Serological tests protocol evaluation of clinical efficacy at the end of therapy
were not routinely performed to identify atypical pathogens. because of protocol violations (17% of the 12-hour group and
Bacteriologic response was determined by presence or ab- 20% of the 8-hour group). Two hundred and thirty-seven pa-
sence of an organism 2-4 days following completion of treat- tients (52%) had community-acquired pneumonia and 218
ment and was assessed as proven eradication (elimination of (48%) had acute exacerbation of chronic bronchitis. Compli-
the pathogen documented by culture); presumed eradication ance with the antibiotic regimen (^, 80% and 120% of doses
(symptomatic response was cure or improvement and a culture taken) was similar for the 12-hour and 8-hour groups (96%
was not clinically indicated); colonization (an organism ap- and 94%, respectively; P = .22).572 Calver et al. CID 1997; 24 (April)
Table 1. Characteristics of the 455 evaluable patients from among the 557 with lower respiratory tract infection who were enrolled in the
study.
No. of patients or other data per amoxicillin/
clavulanate dosing schedule
Variable Every 12 h Every 8 h P value
Patients enrolled 273 284
Patients who completed therapy
and were clinically evaluable 227 228
Patients withdrawn from the study 41 44 .38
Age (y)
Mean ± SD 56.2 ± 18.0 57.1 ± 17.1 .41
Range 19-93 18 —89
Gender (male/female) 143/84 148/80 .92
Race
White 204 213 .06
Black
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19 13
Asian 1 0
Other 3 2
Duration of therapy (d)
Mean ± SD 11.0 ± 3.0 10.8 ± 2.9 .19
Range 2 —15 4 —15
Patients with
Community-acquired
pneumonia 120 (53%) 117 (51%)
Acute exacerbation of chronic
bronchitis 107 (47%) 111 (49%)
Clinical response. Clinical response at the end of therapy were — 7.1% —4.0% for community-acquired pneumonia and
was similar for the two treatment groups, with success rates — 7.2%— 6.7% for acute exacerbation of chronic bronchitis.
of 93% and 94% in the 12-hour and 8-hour groups, respectively Clinical success was maintained at the time of the follow-up
(P = .42; 95% CI for the difference was — 5.3% —3.5%) (table visit for 89% (193 of 216 patients) and 86% (185 of 215 patients)
2). Clinical response was similar between the groups when of the clinical successes at the end of treatment (P = .30) in the
community-acquired pneumonia and acute exacerbation of 12-hour and 8-hour groups, respectively. Recurrence of infection
chronic bronchitis were considered separately (table 2). The was observed in 8 patients (3.7%) and 17 patients (7.9%) in the
95% confidence intervals for the differences between regimens 12-hour group and 8-hour group, respectively (P > 0.05).
Table 2. Summary of clinical responses to treatment among the 455 evaluable patients.
No. (%) of patients per amoxicillin/clavulanate dosing schedule and disease category
Every Every
Every 12 h Every 8 h 12h 8h
Variable Pneumonia AECB Pneumonia AECB Total Total
Evaluable patients 120 107 117 111 227 228
Clinical outcome at end of therapy
Cure 78 (65) 81 (76) 80 (68) 74 (67) 159 (70) 154 (68)
Improvement 35 (29) 18 (17) 32 (27) 29 (26) 53 (23) 61 (27)
Overall clinical success (cure or improvement) 113 (94) 99 (93) 112 (96) 103 (93) 212 (93) 215 (94)
Failure 7 (6) 8 (7) 5 (4) 8 (8) 15 (7) 13 (6)
Clinical outcome at follow-up
Recurrence 4 (4) 4 (4) 4 (4) 13 (12) 8 (4) 17 (8)
Failure 7 (6) 8 (8) 5 (5) 8 (8) 15 (7) 13 (6)
NOTE. AECB = acute exacerbation of chronic bronchitis.CID 1997;24 (April) Amoxicillin/Clavulanate Every 12 vs. Every 8 Hours 573
The reason for the difference in the recurrence rates could every-8-hours regimen (P = .86; 95% CI for the difference,
not be ascertained. Recurrence was more frequent in the 8-hour —2.5%-14.7%). Colonization was observed in five patients
group with acute exacerbation of chronic bronchitis (12.3% of in the every-12-hours group and no patients in the
patients), but differences between subgroups were not tested every-8-hours group (this difference was not tested since it
since these subgroup comparisons were not part of the study was a subgroup analysis that was not included in the proto-
design. col design). The responses were similar when patients with
Bacteriologic response. One hundred and thirty-nine or- pneumonia and those with acute exacerbation of chronic
ganisms were reported for the 122 patients (59 in the 12-hour bronchitis were considered separately. At the follow-up
group and 63 in the 8-hour group) who were evaluable for visit, bacteriologic success was maintained in 95% and 87%
bacteriologic efficacy. Most patients (108 of 122) had one or- of patients in the 12-hour and 8-hour groups, respectively
ganism isolated at presentation. The pattern of organisms iso- (P = .15).
lated was similar for the two treatment groups (table 3) and Adverse events. One hundred and thirty-two of 557 patients
for the two indications for treatment, with the exceptions that (24%) reported 179 adverse events related or possibly related
M catarrhalis was isolated more frequently with acute exacer- to the study medication (P = .39 between groups). The most
bation of chronic bronchitis (17 of 58 patients [29%], vs. 9 of common adverse event was diarrhea (11% of patients). Most
64 [14%] with pneumonia) and Streptococcus pneumoniae was of the diarrhea was mild (defined as easily tolerated by the
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isolated more frequently with pneumonia (28 of 64 patients patient, causing minimal discomfort, and not interfering with
[44%], vs. 13 of 58 [22%] with acute exacerbation of chronic everyday activities).
bronchitis). Of all patients who reported moderate or severe diarrhea
There were no significant differences between treatment (moderate diarrhea was defined as sufficiently discomforting
groups in the frequency of isolation of S. pneumoniae, Staphylo- to interfere with normal everyday activities, while severe diar-
coccus aureus, or gram-negative bacilli (P > .05). All isolates rhea was defined as incapacitating enough to prevent everyday
of the four most common pretherapy organisms (S. pneumo- activities), 50% fewer were in the 12-hour group (2.9%) than
niae, H. influenzae, M catarrhalis, and S. aureus) were suscep- in the 8-hour group (4.9%) (P = .28). Thirty-eight patients
tible to amoxicillin/clavulanate. Three of 31 H. influenzae iso- reported 58 adverse events that led to withdrawal from the
lates (10%) and 19 of 26 M catarrhalis isolates (73%) were study (5.9% of the 12-hour group and 7.7% of the 8-hour
ampicillin-resistant and 0-lactamase-positive. All S. pneumo- group; P = .38). Gastrointestinal disturbances were the most
niae isolates were susceptible to ampicillin. common adverse events leading to withdrawal.
Bacteriologic success (proven eradication, presumed Intent-to-treat analysis. The two regimens were similar
eradication, or colonization) was similar in the two groups: when assessed by intent-to-treat analysis of 557 patients. Clini-
97% with the every-12-hours regimen and 91% with the cal success at the end of therapy was achieved in 230 of 273
patients (84%) who received treatment every 12 hours and in
236 of 284 (83%) who received it every 8 hours (P = .71;
Table 3. Bacteria isolated from the 122 patients who were evaluable 95% CI for the difference, —5.0-7.3).
for bacteriologic efficacy of the regimen.
No. (%) of isolates per amoxicillin/
Discussion
clavulanate dosing schedule
Isolate(s) Every 12 hours Every 8 hours A major determinant of the success of an antimicrobial regi-
men in an outpatient setting is compliance, which is encouraged
Streptococcus pneumoniae 19 (27) 22 (32) when a regimen is simplified to less-frequent daily dosing.
Staphylococcus aureus 8 (11) 10 (15) Amoxicillin/clavulanate has normally been administered as a
Streptococcus group B 0 1 (1.5)
regimen of 500/125 mg (amoxicillin/clavulanate) every 8 hours
Other streptococci 2 (2.8) 2 (3)
Haemophilus influenzae 16 (23) 15 (22) for adults. In this regimen, the combination is as effective for
Moraxella catarrhalis 13 (18) 13 (19) treatment of lower respiratory tract infections as other agents
Citrobacter species 0 2 (3) such as loracarbef [6, 7], cefuroxime [8], and azithromycin
Escherichia coli 2 (3) 0 [9, 10].
Enterobacter species 3 (4) 0
The pharmacodynamic properties of amoxicillin/clavulanate
Haemophilus
parainfluenzae 2 (3) 1 (1.5) supported consideration of every-12-hours dosing. Bacterial
Proteus mirabilis 1 (1.4) 0 killing by 0-lactam antimicrobials is related to the duration of
Pseudomonas aeruginosa 1 (1.4) 1 (1.5) time the plasma concentration of the 0-lactam antimicrobial
Serratia marcescens 1 (1.4) 0 remains above the MIC [11] . A study of healthy volunteers
Pseudomonas fluorescens 1 (1.4) 0
demonstrated that amoxicillin/clavulanate given at a dosage of
Other gram-negative bacilli 2 (3) 1 (1.5)
875/125 mg every 12 hours resulted in a time above the MIC574 Calver et al. CID 1997; 24 (April)
comparable to that of a dosage of 500/125 mg given every 8 Acknowledgment
hours [12].
Within the anticipated range of MICs for organisms causing The authors thank Lorna Piora for writing the programs used
lower respiratory tract infection, the time above MIC between to analyze the data for the manuscript.
the two regimens would be comparable. Although compliance
may be influenced by every-12-hours dosing, it is unlikely that
the every-12-hours regimen will increase antimicrobial activity
References
or the time above the MIC.
This trial documents the effectiveness of an every-12-hours 1. Garibaldi RA. Epidemiology of community-acquired respiratory tract in-
regimen of amoxicillin/clavulanate (875/125 mg) in direct com- fections in adults. Incidence, etiology and impact. Am J Med 1985;
parison with the standard every-8-hours regimen (500/125 mg) 78(suppl 6B):32-7.
2. Pomilla PV, Brown RB. Outpatient treatment of community-acquired
in patients with community-acquired pneumonia or acute exac-
pneumonia in adults. Arch Intern Med 1994;154:1793-802.
erbation of chronic bronchitis, including patients infected with 3. Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994;18:
fi-lactamase-producing pathogens. The numbers of enrolled pa- 501-13.
tients in each of the two disease categories may not have been 4. Sue DY. Community-acquired pneumonia in adults. West J Med 1994;
sufficient to detect differences between treatment groups in 161:383-9.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 30, 2015
each category. 5. Augmentin prescribing information. Philadelphia: SmithKline Beecham
Pharmaceuticals, 1996.
As with most recent reports of community-acquired lower 6. Dere WH, Farlow D, Therasse DG, Jacobson KD, Guerra FJ. Loracarbef
respiratory tract infections, the majority of pathogens isolated (LY163892) versus amoxicillin/clavulanate in the treatment of acute
were organisms other than S. pneumoniae. M catarrhalis ac- purulent bacterial bronchitis. Clin Ther 1992;14:166-77.
counted for 19% of isolates, and 81% of these were /3-lacta- 7. Zeckel ML. Loracarbef (LY163892) in the treatment of acute exacerba-
mase-positive, while H. influenzae accounted for 22% of iso- tions of chronic bronchitis: results of U.S. and European comparative
clinical trials. Am J Med 1992; 92(suppl 6a):58S-64S.
lates, and 13% of those were /3-lactamase-positive. 8. Brambilla C, Kastanakis S, Knight S, Cunningham K. Cefuroxime and
A major difficulty in treating community-acquired pneumo- cefuroxime axetil versus amoxicillin plus clavulanic acid in the treat-
nia is that pathogens in -50% of patients cannot be identified ment of lower respiratory tract infections. Eur J Clin Microbiol Infect
[3, 13], and therapy must be initiated prior to identification Dis 1992;11:118-24.
even when this is possible. Antimicrobials effective against 9. Hoepelman AIM, Sips AP, van Helmond JLM, et al. A single-blind com-
parison of three-day azithromycin and ten-day co-amoxiclav treatment
potentially resistant pathogens must therefore be used for em-
of acute lower respiratory tract infections. J Antimicrob Chemother
pirical treatment. 1993; 31(suppl E):147 -52.
The most common pathogens identified in studies of out- 10. Balmes P, Clerc G, Dupont B, Labram C, Pariente R, Poirier R. Compara-
patients with community-acquired pneumonia were S. pneu- tive study of azithromycin and amoxicillin/clavulanic acid in the treat-
moniae and H. influenzae; S. aureus, gram-negative bacilli, ment of lower respiratory tract infections. Eur J Clin Microbiol Infect
M. pneumoniae, Legionella species, and Chlamydia species Dis 1991;10:437-9.
11. Drusano GL. Role of pharmacokinetics in the outcome of infections. Anti-
are identified with varying frequency [14]. In studies of acute microb Agents Chemother 1988; 32:289-97.
exacerbation of chronic bronchitis, M catarrhalis has gained 12. Hust MR. Comparison of the 24-hour pharmacokinetic profile of oral
prominence, particularly in the elderly and in patients with Augmentin administered with food to healthy male volunteers as 1 g 12
chronic lung diseases [15]; this pathogen is usually (3-lacta- hourly versus 625 mg 8 hourly, and as 625 mg 12 hourly versus 375
mase-producing, as are up to 40% of strains of H. influen- mg 8 hourly [report HH-1001/BRL-025000/2/CPMS-360]. Philadel-
phia: SmithKline Beecham Pharmaceuticals, 24 May 1994.
zae [16].
13. Marrie TJ. New aspects of old pathogens of pneumonia. Med Clin North
In conclusion, amoxicillin/clavulanate (875/125 mg) Am 1994;78:987-95.
given every 12 hours is at least as effective and as safe as 14. Niederman MS, Bass JB Jr, Campbell GD, et al. Guidelines for the initial
that given every 8 hours (500/125 mg) for the treatment of management of adults with community-acquired pneumonia: diagnosis,
community-acquired lower respiratory tract infection. Re- assessment of severity, and initial antimicrobial therapy. Am Rev Respir
duced frequency of administration with the every-12-hours Dis 1993;148:1418-26.
15. Wright PW, Wallace RJ Jr, Shepherd JR. A descriptive study of 42 cases
regimen should improve compliance with treatment as well of Branhamella catarrhalis pneumonia. Am J Med 1990; 88(suppl 5A):
as decrease the incidence of moderate to severe diarrhea. 2S-8S.
The per-day cost of the 12-hour regimen is comparable to 16. Pichichero ME. Assessing the treatment alternatives for acute otitis media.
that of the 8-hour regimen. Pediatr Infect Dis J 1994; 13(suppl 1):S27-34.You can also read
