more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.
Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.
Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.
PK/PD relationship
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.
Mechanisms of resistance
The two main mechanisms of resistance to amoxicillin/clavulanic acid are:
• Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.
• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.
Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
Breakpoints
MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST)
Organism
Susceptibility Breakpoints (μg/ml)
Susceptible
Intermediate
Resistant
Haemophilus influenzae1
≤ 1
-
> 1
Moraxella catarrhalis1
≤ 1
-
> 1
Staphylococcus aureus 2
≤ 2
-
> 2
Coagulase-negative staphylococci 2
≤ 0.25
> 0.25
Enterococcus1
≤ 4
8
> 8
Streptococcus A, B, C, G5
≤ 0.25
-
> 0.25
Streptococcus pneumoniae3
≤ 0.5
1-2
> 2
Enterobacteriaceae1,4
-
-
> 8
Gram-negative Anaerobes1
≤ 4
8
> 8
Gram-positive Anaerobes1
≤ 4
8
> 8
Non-species related breakpoints1
≤ 2
4-8
> 8
1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l.
2 The reported values are Oxacillin concentrations.
3 Breakpoint values in the table are based on Ampicillin breakpoints.
4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant.
5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.
The preva lence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local preva lence of resista
