Discussion
Bacterial resistance to antimicrobial agents is an incessantly evolving
phenomenon which threatens one of the greatest achievements of medical
science, the effective treatment of infectious diseases. Overprescribing
and suboptimal selection of antimicrobial agents are believed to have
contributed to the acceleration of the selection of resistant strains.
Thus antimicrobial stewardship has provoked the interest of the medical
community as a multifaceted set of interventions which aim to optimise
antimicrobial use and thus stem the onset of resistant bacterial
strains.
Despite, however, the public health importance of this issue, there is a
notable lack of standardised high-quality research on the field to
provide definite answers as to which, if any, initiatives are effective
or not. We have already examined antimicrobial restrictions and audit
with feedback in two papers that were recently published[9][10.]
The absence of randomised models and the great heterogeneity in study
protocols limited the ability to draw any firm conclusions on the
aspects researched. It highlights the need for future high-quality,
reproducible research. Standardisation in study design would increase
the utility of clinical research in this field, as meta-synthesis of
studies would be possible, providing greater statistical power to detect
and map the effects of intervening to try to reduce resistance, and
guide clinicians.
Examination of the available literature on the potential efficacy of
antimicrobial cycling gives an overall impression of rather limited
success. Research papers could be roughly divided to those which
evaluated cycling versus a control group and produced conflicting
results and those that compared cycling with mixing with none of the
strategies appearing superior to the other. Lack of success becomes more
evident if one takes into account the most rigorous studies conducted by
Toltzis et al[14] as well as Van Duijn et al[23 ]both of which
failed to record any favourable results comparing cycling with a control
group and a mixing group respectively.
Fair interpretation of the relevant data must take into account some
core limitations which could influence results in either way. One such
limitation is the lack of standardization of antibiotic protocols across
intervention and control groups of different studies, though a general
tendency to increase heterogeneity of antibiotic administration in the
experimental arms was observable. It is rational to assume that the
relevant baseline practices would influence whether significant changes
in antibiotic resistance patterns would be recorded post-intervention. A
pertinent paradigm is probably provided by Nijssen et al who compared
antibiotic rotation with a control group receiving fluoroquinolones in a
highly homogeneous manner. Fluoroquinolone resistance rates were
decreased in the rotation arm, a trend not seen for cephalosporins. It
is well-known that the main mechanism of fluoroquinolone resistance
comprises point mutations in chromosomal DNA which are obviously
particularly prone to selective pressures. Radical reduction in
fluoroquinolone administration along with the main relevant mechanism of
resistance could provide a likely explanation for the observed results
further supported in the clinical literature after the application of
restrictive fluoroquinolone strategies[9].
We cannot exclude the possibility that the potential of success could be
pathogen-specific and depending on the monitoring protocol it could be
potentially missed; a pathogen-specific effect has indeed been suggested
by researchers in the past[8]. It is true that the majority of the
available positive findings in our dataset relate to P.
aeruginosa although we are not aware of any pathophysiological
mechanism that would account for such a theory.
Failure of antibiotic cycling to produce clear benefits is consistent
with the theoretical predictions generated by many mathematical models
that challenge its intuitively presumed efficacy. On the basis of the
aforementioned models, though, one would expect that antibiotic mixing
would be more effective via maximising heterogeneous antimicrobial use.
Neither assumption was confirmed in practice. Although there is high
variability in research protocols and the overall quality of our data is
far from satisfying to reach definite conclusions, we should bear in
mind that the evolution of bacterial resistance is a complex process and
the strategies tested may rely on an oversimplified model of how it may
be manipulated. It is worth mentioning that antimicrobial agents of
similar spectrum may possess totally different mechanisms of action, and
thus may affect bacteria in different ways. In addition, infection
control is a hard to standardise parameter which could influence
relevant studies drastically.
At this point, it would be useful to discuss the third set of studies
included in our review. The latter evaluated resistance dynamics of each
of the on-cycle antibiotics during the application of antimicrobial
cycling protocols. They provide little information as to the overall
efficacy of cycling but could offer some ground for future research as
to which agents are actually less prone to the selection of resistant
strains. Ginn et al compared periods of predominant cefepime and
piperacillin-tazobactam use and found that cefepime, a fourth-generation
cephalosporin, was associated with higher overall resistance rates
(including co- and cross-resistance). There is plenty of observational
research which supports the notion that piperacillin-tazobactam is a
less important driver of antibiotic resistance than broad-spectrum
cephalosporins[9]. A rational explanation could lie on the fact that
broad-spectrum cephalosporins are less effective than inhibitor-based
beta-lactams in vitro against ESBLs, which are the among most widespread
multidrug-resistant strains within nosocomial environments and could be
theoretically preferentially selected under the pressure of
inappropriate antibiotic treatment.
On the other hand, Van Loon et al concluded that the homogeneous use of
cefpirome, another fourth-generation cephalosporin, was not associated
with an increase in the incidence of cefpirome-resistant strains, while
both piperacillin-tazobactam and levofloxacin use provoked resistance.
The results of those studies are seemingly contradictory and could be
confounded either by seasonality or breaks in infection control. Such
discrepancies underline the importance of the use of contemporaneous
controls as well as the need for bacterial typing data in future
research to facilitate a more meaningful interpretation of the data.
Bacterial typing becomes especially important in view of the fact that
most studies to date have used the unit-wide incidence of resistant
strains as the primary outcome indicator, but this is easily affected by
changes in colonization pressure and/or breaks in infection control. An
idea for future research would also be to differentiate colonization
rates in patient groups within the same ward who have and have not
participated in study protocols and use additional wards with similar
baseline characteristics as comparison units.
Lack of standardization of research protocols was once again a crucial
issue which limited our ability to evaluate with confidence the
replicability of findings and reach safer conclusions. Research
protocols differed in terms of the cycle length, the choice of empirical
agents, the opportunity to de-escalate, the acquisition of typing data
to assess cross-transmission dynamics, and the measurement of indicators
of potential collateral damage induced by the established policies.
Among the studies of our dataset it was only Van Duijn et al in 2018 who
utilised a cluster-randomised cross-over design to compare cycling with
mixing, which was a stronger study design than most. A more thorough
evaluation would be possible only if the study included control groups
and/or baseline data as well as bacterial typing to assess bacterial
clonality. It is true that the conduct of research well-designed and
rigorous to be of practical use to clinicians requires specialist
expertise of multiple kinds, and is logistically difficult.
Nevertheless, it is a worthwhile investment which should be co-ordinated
by national or international public health agencies with the ultimate
aim to safeguard the future value of antimicrobial agents.