Dear Editor,
I note in the “Antibiotics: Choices for Common Infections”
booklet provided with the August 2013 edition of Best Practice Journal, that amoxicillin with clavulanic acid is recommended
as an alternative agent for treating UTI in children. I would be interested in understanding the rationale for this recommendation,
given the poor oral absorption and urinary excretion of clavulanic acid compared with amoxicillin.
In 1986, Horber, et al reported that the systemic bioavailability of oral amoxicillin was about 70% compared with that
of clavulanic acid, which was about 50%. This team also demonstrated that: “In subjects exhibiting normal renal function
the urinary excretion of unchanged amoxicillin and clavulanic acid following p.o. administration was 56 and 22%, respectively.”1
Thus, rather than the proportion of clavulanic acid to amoxicillin present in urine being approximately 25%, as is
present in oral formulations of amoxicillin/clavulanic acid combinations and as could be expected of serum concentrations,
the proportion in urine is probably reduced to less than 10%.
This pharmacokinetic difference between the two beta-lactams won’t be evident in the in vitro laboratory sensitivity
testing where adequate concentrations of both agents are tested against bacterial strains. So it is understandable that
sensitivity testing will indicate pathogen susceptibility to amoxicillin/clavulanic acid combinations. However, the significant
reduction in clavulanic acid present in urine may be clinically significant in vivo and could increase the risk of treatment
failure.
To consider this another way, given that the amount of clavulanic acid present in urine is likely to be significantly
reduced, and as a consequence its therapeutic effect is likely to be significantly reduced, why isn’t amoxicillin alone
(rather than in combination with clavulanic acid) recommended as an alternative agent for treating UTI in children? Is
clavulanic acid adding any value to amoxicillin in the treatment of UTI?
Andrew Orange
Pharmacy Advisor, MidCentral DHB
Palmerston North
The information in the “Antibiotics: Choices for Common Infections”
booklet (Jul, 2013) was derived from expert consensus. In the booklet, it is recommended that the first choice antibiotic
treatment for uncomplicated UTI in children is co-trimoxazole (due to the trimethoprim component). Cefaclor and amoxicillin
clavulanate were listed as alternative treatment options. It is common practice for amoxicillin clavulanate to be used
in the treatment of UTIs in children. In fact, current Starship Children’s Health clinical guidelines list amoxicillin
clavulanate as the most preferred oral treatment option (followed by co-trimoxazole then cefaclor).1
However, the question asked by the correspondent is whether amoxicillin clavulanate is superior to amoxicillin alone
for the treatment of UTI. Amoxicillin has fallen out of favour as a treatment option for UTI due to increasing resistance
to Escherichia coli, which accounts for the majority of uncomplicated urinary tract infections in children.2 Clavulanic
acid is a beta-lactamase inhibitor which works synergistically with amoxicillin to extend the spectrum of antibiotic
susceptibility. In theory, this means that UTIs are less likely to be resistant to treatment with amoxicillin clavulanate
than amoxicillin alone.
The objective of the Horber et al study, referred to by the correspondent, was to assess changes in the way amoxicillin
and clavulanic acid are excreted with declining renal function.3 Because of this, there were only six participants
with normal renal function in the study. After oral administration of the drugs, lower urinary concentrations of clavulanic
acid compared to amoxicillin were found in these six subjects. This suggests that the amount of bioavailable clavulanic
acid may be too low to make it clinically superior to amoxicillin alone.3 However, the surrogate values
in the study may not be representative of a large population.
Perhaps a more clinically relevant measure of antibiotic efficacy is resolution of infection. A 1986 study involving
52 elderly patients with urinary tract infection found that 87.5% of those treated with amoxicillin clavulanate had
resolution of infection, compared to 43% of those treated with amoxicillin alone.4 Five out of eight patients
who did not initially respond to amoxicillin, responded to amoxicillin clavulanate. Although this study involved elderly
subjects rather than children, and again, the number of included subjects was low, some interesting observations were
made. The authors commented that:
“It has been suggested that, because of the high concentrations attainable in urine, amoxycillin [amoxicillin] is
often effective in treating UTIs caused by organisms which are resistant to the drug in vitro. The results of our study,
however, indicate that amoxycillin-resistant organisms do not respond to amoxycillin alone. Augmentin [amoxicillin clavulanate],
on the other hand, is likely to cure urinary tract infection irrespective of the amoxycillin susceptibilty of the organism
in vitro. Of the patients infected with amoxycillin-resistant organisms, 80% were cured by augmentin. By contrast, only
10% of the patients with amoxycillin-resistant organisms were cured by amoxycillin.”
A small randomised controlled study in 1981 found that 11 out of 13 (85%) adult patients with penicillin-resistant
UTI had an absence of bacteriuria after treatment with amoxicillin clavulanate, compared to 2 out of 8 (25%) patients
receiving amoxicillin alone.5
Although both of these studies have limitations, and cannot necessarily be extrapolated to the treatment of UTI in
children, they serve the purpose of demonstrating that medicines can have a clinically important treatment effect, despite
their underlying pharmacokinetic profiles being less than ideal.
In summary, amoxicillin clavulanate is used as a second-line treatment for UTI in preference to amoxicillin alone,
because most consensus-derived guidelines recommend this, and in practice, it works. A recent Cochrane review concluded
that although antibiotic treatment for children with UTI is effective, there is not enough evidence to answer the question
of which antibiotic is superior.6
ACKNOWLEDGEMENT
Thank you to Dr Rosemary Ikram, Clinical Microbiologist, for expert review of this answer.
References
- Starship Children’s Health. Starship Clinical Guidelines. Urinary tract infection. 2012. Available from:
www.adhb.govt.nz/starshipclinicalguidelines/ (Accessed
Sep, 2013).
- White B. Diagnosis and treatment of urinary tract infections in children. Am Fam Physician 2011;83(4):409-15.
- Horber FF, Frey FJ, Descoeudres C, Murray AT, Reubi FC. Differential effect of impaired renal function on the kinetics
of clavulanic acid and amoxicillin. Antimicrob Agents Chemother. 1986;29(4):614-9.
- Gallacher G, Erwin L, Scott P, Sleigh J. Augmentin (amoxycillin-clavulanic acid) compared with amoxycillin alone
in the treatment of urinary tract infections in the elderly. J Infect 1986;12(3):229-33.
- Martinelli R, Da Silva Lopes A, De Oliveira M, Rocha H. Amoxicillin-clavulanic acid in treatment of urinary tract
infection due to Gram-negative bacteria resistant to penicillin. Antimicrob Agents Chemother 1981;20:800-2.
- Fitzgerald A, Mori R, Lakhanpaul M, Tullus K. Antibiotics for treating lower urinary tract infection in children.
Cochrane Database Syst Rev 2012;8:CD006857.