ISRAEL JOURNAL OF
VETERINARY MEDICINE
REVIEW: USE OF AMOXYCILLIN + CLAVULANIC
ACID COMBINATION IN VETERINARY MEDICINE
Vol. 57 (2) 2002
AND POSSIBLE ANTIBIOTIC RESISTANCE OF
HUMAN PATHOGENS:
S. P. Pozzi1 and Z. Ben-David2
1. Pfizer AHG, Ussishkin 56/2, 94541 Jerusalem;
2. Vet-Magen Ltd, POB 76, 60910 Bney-Zyion,
Abstract
Amoxycillin and clavulanic acid combination is used in veterinary medicine since 1980 for treating
livestock and companion animals. Different presentations are in use: injectable, intra-mammary, oral
tablets and bolus and oral drops.
Doubts have arisen concerning the possibility of antibiotic resistance occurrence in bacteria of
animal origin and possible transfer of resistance to human pathogens.
A retrospective and worldwide investigation failed to reveal the occurrence of decreased susceptibility
of human pathogens to amoxycillin and clavulanic acid
Introduction
ß-lactamines are the bactericidal antibiotics inhibiting the formation of the bacterial cell wall by
interfering with final stage of peptido-glycan synthesis. Bacteria in growing phase cannot complete
cell wall structure, thus the cell wall is compromised and bacteria die.
Gram positive (G+) and negative (G-) bacteria have walls constructed in different way, so far
showing higher or lower affinity to different classes of ß-lactamines. Resistance to ß-lactamines, may
be linked either to lack of receptors on the cell wall for specific ß-lactamine (as in G-) or to the
production of enzymes inactivating ß-lactamines (both types of bacteria).
These enzymes, the ß-lactamases, are produced by bacteria and reversed outside the bacteria in
extracellular space (G+) or in peri-plasmatic space of bacteria (G-). When ß-lactamase enzymes
interact with ß-lactamines, they bind to each other. The binding causes opening of ß-lactamines
structure and loss of their bactericidal activity, as illustrated in Figure 1.
ß-lactamase plasmid-mediated is responsible for the rapid spread and diffusion of resistance in
bacterial populations and results in the significant reduction of activity of aminopenicillins because of
ability to transfer the gene encoding the mechanism of antibiotic resistance to other bacteria (2a).
Chromosome-induced resistance is less important because of slow and gradual appearance and
changes mainly linked with bacteria cell structure, and are not inducible (2b).
Clavulanic acid produced by Streptomyces clavuligenus, has a chemical structure similar to some ßlactamines, e.g. penicillin. When clavulanic acid is present in extra-cellular space of bacteria it
competitively binds with (2b) and inactivates ß-lactamases belonging to PCI class. Thus, bacteria
become sensitive again to ß-lactamine (5).
Clavulanic acid, with sulbactam (2a,b) and tazobactam (3), belong to a group of at least three
substances with ß-lactamase inhibition activity. Slight differences with respect to pharmacology,
potency and activity, are considered of little therapeutic significance (3).
Clavulanic acid has good affinity for ß-lactamases plasmid-mediated and chromosome-induced,
while it has a low affinity for chromosome induced cephalosporinases (2a).
In veterinary medicine, a combination of amoxicillin + clavulanic acid (amoxi-clav) was designed in
1980 to overcome resistance to amoxycillin-mediated by ß-lactamases, produced by bacteria of
relevant veterinary interest; among these, in particular Staphylococcus species.
The mechanism of action of clavulanic acid is to form an irreversible link with ß- lactamase (2a, 4).
Clavulanic acid prevents ß-lactamase inhibiting bactericidal activity of ß-lactamines (4). Because of its
irreversible link and inactivation of ß-lactamases, clavulanic acid is able to make ß-lactamaseproducing bacteria sensitive again to a large number of penicillin and cephalosporin -class antibiotics
(2a)
Figure 1: mechanism of action of ß-lactamase enzymes
According to Richmond and Sykes (1, modified) there are 5 classes of ß-lactamase enzymes:
1.
Chromosome induced: Cephalosporinase by P. aeruginosa; C. freundii; acting on
cephalosporin as substrate
2.
chromosome induced and plasmid mediated (DNA transduction) - PCI by S. aureus; acting
on penicillin as substrate
3.
3 plasmidium-mediated:
-
TEM 1, 2; SHV-1; Rob-1; CTX-1; CTZ-1; by Enterobacteriacee
-
PSE-1; Carb-3; by E.coli; P. aeruginosa
-
OXAI —7 by Enterobacteriacee
Figure 2: mechanism of action of clavulanic acid
In veterinary medicine, this kind of irreversible link has not been demonstrated as affected by
appearance of resistance to clavulanic Acid (2b)
Clavulanic acid is extremely active: concentrations of 0,01 to 0,08 mcg/ml inactivates 50% of ßlactamases, released by S. aureus MB9, E.coli K12R tem, P. mirabilis, K. aerogenes A (reference
laboratory strains), which would inactivate more than 40 mcg/ml of susceptible ß-lactamines (5). In
other words, concentration of 1mcg/ml of calvulanic acid is enough to “protect” 500 to 4000mcg/ml
of ß-lactamine sensitive to ß-lactamases. Therefore, pharmacological preparations containing amoxyclav at ratio 4:1 or 2:1, as in human preparations, fully ensure the quantity of clavulanic acid necessary
to inactivate all ß-lactamases responsible for ß-lactamine inactivation.
Use of “amoxi-clav” complex in veterinary medicine
Combination of amoxi-clav specifically designed for veterinary use is established in several
countries since mid 1980s, as summarized in Table 1. Veterinary preparations contain amoxi-clav at a
ratio of 4:1, while human preparations contains amoxy-clav at up to a 2:1 ratio, that means two-fold
clavulanic concentration in respect to veterinary preparations. Use of specific veterinary preparations,
instead of off-label use of human preparations, could be of utmost importance in the very rare and
theoretical case in which any bacteria from animal origin and of human relevance, would loose
susceptibility to amoxi-clav because of a lower concentration of clavulanic acid in respect to ßlactamase produced. The amoxi-clav combination is considered “useful” per os administration in
monogastric; and intra-muscular (i.m.) administration in animal food producers, in particular for
infections of the lower respiratory tract in bovine, due to Actinobacillus, Haemophilus and by
Pasteurella ß-lactamase producers (2).
Table 1: Number of countries, type of formulation and year of introduction of amoxi-clav association
designed for veterinary use (6).
Formulation
Species
Cattle
Swine
Sheep
Dogs
Cats
Injectable
X
X
X
X
X
Intramammary
X
Bolus
X
Tablets
X
X
X
No. of
Countries
Year of
introduction
38
1987
46
1986
18
1984
49
1984
Despite several years of regular use in veterinary practice the significant appearance of antibioticresistance, neither in companion animals nor livestock, have been documented.
In dogs and cats, data on antibiotic resistance patterns among staphylococcal diseases (S. aureus; S.
intermedius) have been collected at The Royal Veterinary College, London over the past 15 years. The
authors comment on the “failure to demonstrate resistance to amoxy-clav” and that “ S. intermedius
does not readily develop resistance to this substance” (7).
Out of 78 recent (1995 - 2000) canine isolates of B. bronchiseptica from 13 separate sources in UK,
all were sensitive to amoxy-clav, 13 years following its introduction (8).
A total of 318 pyoderma isolates (S. aureus131; S. intermedius 187) from dogs in France have been
tested for antimicrobial susceptibility during 1986 - 1996. The authors report “more than 95%” were
susceptible to amoxy-clav (9).
In food-producing animals, formulations of amoxi-clav are used for short-term (a few days)
treatment in acute infections. There is no indication for long-term therapy, by any route. This shorttime use in individual animals (there is no formulation suitable for group/mass treatment) is
particularly unlikely to select for resistance, since repeated and long-term therapy is not involved.
In swine, data on 1969 bacterial strains of P. multocida; A. pleuropneumoniae; H. parasuis; S. suis;
E. coli; Salmonella species, tested in Italy, during 1995-2000 did not demonstrate development of
resistance to amoxi-clav; In comparison to a progressive pattern of microbial resistance to many
antimicrobial agents, especially by P. multocida and A. pleuropneumoniae (10).
The Swedish Veterinary Antimicrobial Resistance Monitoring quotes 3 cases out of 260 of amoxyclav resistance in pigs; 0 out of 293 in cattle; 5 out of 274 in chickens (11). Furthermore “the
association amoxi-clav is already quoted as “registered for use in bovine” (2). The use in cattle is also
supported by Soback (12). The efficacy of amoxi-clav in treatment of common respiratory diseases
caused by Pasteurella (Mannheimia) haemolytica has been widely confirmed by practical experience
in the field.
Relative to intra-mammary administration, 484 S. aureus isolates from the bovine mammary gland
have been isolated in 1999 and 2000 in Italy and tested, among others, against amoxy-clav. Their
susceptibility was 99,6% in 1999 and 100% in 2000 (13).
Cases of antibiotic-resistance by some Gram-negative bacteria - P. aeruginosa; Serratia; E. coli JT
414 must be related to an intrinsic mechanism of resistance, because of production of a different type
of ß-lactamase and not due to a decrease of activity of Clavulanic acid on these bacteria (2a, 5).
Amoxy-clav is not recommended for use in horses because of occurrence of diarrheal disease (2b).
In countries in which amoxi-clav is used in veterinary practice, is there an increase in resistance to
amoxy-clav in pathogens of human relevance?
There is a general lack of data to show that use of antibiotics in animals has a significant impact on
resistance in humans. This is particularly true where G +, non-zoonotic bacteria (the usual target of
the use of amoxy-clav) are concerned. A retrospective study to 1990, summarized up in Table 2,
quotes more than 50 studies (14 to 55) relative to ß-lactamines - Clavulanic acid activity in human
medicine in the period 1985-2001 in countries in which veterinary preparations of amoxy-clav are
used.
Table 2: Summary of studies relative to ß-lactamines— clavulanic acid activity in human medicine
between 1985-2001 (Ref. 14 - 55).
No. of
Countries
No. of
isolates
Type and no. of studies
Resistance or
MIC*
Pharmacolo-
Clinical observations
Susceptibility
17
>32000
31
gical models
7
8
No. of
patients
No. of
clinics
>1100
40
*Minimal Inhibiting Concentration
The review did not reveal any significant change in susceptibility of pathogens of human relevance
to ß-lactamines - Clavulanic Acid. There are no evidences of generalized decrease in susceptibility of
examined pathogens (14, 16, 24, 25, 27-29, 31, 33, 35, 39-45, 52, 53) and no increase of relative MICs
(46, 47, 49, 55).
Cases of reduced sensibility to ß lactamine- Clavulanic acid are mainly associated with G- bacteria,
in particular S. enterica serotype Typhimurium, (18); Salmonella and Shigella strains (32); E.coli (34;
36; 37); H. influenzae (50).
Apparently reduced sensibility is due to TEM-1 ß-lactamase hyper-producing isolates (36) or high
level of ß-lactamine hydrolysis rather than to the Clavulanic Acid resistance properties (18).
On the other hand, ß-lactamine- Clavulanic acid presents the lowest resistance level in E. coli (37)
while implementation of guidelines for antibiotics use (38, 39) was followed by increase of
susceptibility of E. coli (39).
In a previous wider study (42), which includes over 1500 publications over 15 years, no evidence for
any significant increase in resistance to amoxy-clav was demonstrated. With this past experience, it
appears highly improbable that the use of amoxi-clav in animals will have any influence whatsoever
on the susceptibility of human pathogens. Any concerns regarding resistance in humans would best
directed at its use in human patients (38, 39).
Conclusions
There is no evidence, either from in vitro or laboratory studies or veterinary clinical practice, of the
appearance of antibiotic resistance to Clavulanic acid. Indeed, the term “antibiotic resistance” may be
considered not fully appropriate. Clavulanic acid does not act on bacteria direct, rather on ß-lactamase,
while the real bactericidal activity is mediated by the antibiotic associated with clavulanic acid, either
amoxicillin or ticarcillin (2b).
Clavulanic acid may induce ß-lactamase production in ß-lactamine susceptible Enterobacter and
Providencia, nevertheless resistance to clavulanic acid has not yet been described in practice (2b).
There are no authors reporting contra-indications for its use in companion animals or food producing
animal because of fear of antibiotic-resistance increase. On the contrary, the association amoxy-clav is
largely and extensively recommended and registered in many countries, including the USA and the
European Union,
The combination amoxy-clav is also approved and used in several countries with different
administration routes: p.o.; i.m; sub cutaneous (s.c.); i.ma. for milk-producing cows and sheep.
Widespread use of veterinary preparations over a period of many years has shown no sign of
compromising the sensitivity of human pathogens to the action of ß-lactamines by clavulanic acid.
Moreover, the activity of the combination has been maintained despite vast numbers of humans
receiving ß-lactamines - clavulanic acid therapy, both in hospitals and in the community. This
widespread use in man gives rise to the conditions where resistance might be anticipated - yet it has
remained notably rare (42).
In parallel, about 50 publications, in countries in which veterinary amoxi-clav is used, do not quote
significant changes in antimicrobial resistance of ß-lactamines - Clavulanic acid toward a wide range
of human pathogens.
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1.