The resistance mechanisms described in this chapter typically lead to an increase in MIC value, although it should be remembered that this does not always equate to clinical failure. If the MIC value remains below the breakpoint value, which can itself be difficult to determine, then the antibiotic will remain effective in the clinic.
CLINICAL RESISTANCE—MIC VALUES, BREAKPOINTS, PHENOTYPE
AND OUTCOME
The resistance
mechanisms described in this chapter
typically lead
to an increase in MIC value, although
it should be remembered that this does
not always equate to clinical failure.
If the MIC value remains
below the breakpoint value, which can itself
be difficult to determine, then the antibiotic will remain effective in the clinic. But such arguments assume that MIC
values, which are
typically determined when the isolate is growing in complex,
sensitivity-test broth, equate
with the sensitivity of the organism
when growing in the
many subtly different
environments encountered during infection in vivo. Unfortunately, the antibiotic literature contains numerous examples of treatment failures despite apparent sensitivity in the test
tube and this
resistance is referred to as being
phenotypic. In other words, resistance is a consequence of the adaptation of the organism to grow and survive
within the in vivo environment, and subculture into conventional laboratory growth medium rarely
shows the existence of resistant
mutants. There are several key factors at play here,
particularly slow/no
growth, nutrient depletion and mode of growth. There are numerous
papers showing a tendency
for nutrient
depletion, i.e. restricted or non-availability
of an important nutrient,
and slow/no growth to be associated with reduced susceptibility to
antibiotics and biocides.
There is now increasing concern over the
role played by microbial biofilms in infection (see Chapter 8). These
include the well-known examples
of medical devicerelated infections, such as those associated with artificial
joints, prosthetic heart
valves and catheters. Many chronic infections,
not related to medical devices,
are also due to
bacteria either not growing and relatively dormant or growing slowly as
biomasses or adherent biofilms on mucosal surfaces. A bacterial biofilm is typically defined as a population of cells growing
as a consortium on a surface and enclosed
in a complex exopolymer matrix. Commonly in the wider
environment but less so in infections, the population is mixed and also of heterogeneous
physiologies. Growth as a biofilm
almost always leads
to a large increase
in resistance to antimicrobial agents, including antibiotics, biocides and preservatives, compared
with cultures grown
in suspension (planktonic) in conventional liquid media, but there is no generally agreed mechanism to account for this resistance. Although there is general acceptance that there are numerous planktonic phenotypes, many papers refer to ‘the biofilm
phenotype’, implicitly assuming (wrongly)
that there is only one. Those same parameters known
to influence planktonic physiology
and antibiotic susceptibility, including growth rate and/or specific
nutrient limitation, also apply to biofilm physiology and antibiotic susceptibility. The general
resistance of biofilms
is clearly phenotypic. The well-characterized resistance
mechanisms described above—lack of antibiotic penetration, inactivation, efflux and repair—make contributions in some circumstances. However, compelling evidence that they are uniquely responsible for biofilm resistance is lacking. Reduced growth
rate probably has an involvement, particularly in that it is associated with responses to stress. During stress
responses, key structures are protected and cellular
processes close down
to a state of dormancy, and it has been proposed that exceptional vegetative cell dormancy
is the basic explanation of biofilm
resistance.
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