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Conference Summary
Consequences of Bacterial
Resistance to Antimicrobial Agents
Jean Claude Desenclos* and Didier Guillemot† ,
on behalf of the conference speakers
*Institut National de Veille Sanitaire, Saint Maurice, France; and †Institut
Pasteur, Paris, France
In December 2002, a colloquium was organized by the Institut Pasteur
and the Institut de Veille Sanitaire, Paris, France, to review what current
knowledge exists on the impact of antimicrobial bacterial resistance and
address the methodologic obstacles to its assessment.
Simply to state that a patient died of an infection caused by a resistant
organism does not prove that the death was due to the resistance. To prove
the statement as to cause of death, two approaches—"imputable death"
and "attributable death"—are complementary and have been shown
to provide comparable results. The estimation of "imputable death"
requires analyzing the clinical history of a series of deaths that were
caused by resistant strains of infection and to count by clinical judgment
those related to the resistance. To estimate the "attributable"
fraction of death or illness, the excessive risk for death or illness
must be documented for patients who are infected with the resistant strains,
in comparison with those who are infected with sensitive strains. The
study design must control for confounders by matching the groups at inclusion
or by adjustment. Among these confounders the most important are the severity
of the underlying illness before onset of infection, which may be associated
with both the risk for death and the risk of antibiotic resistance of
the bacterium. The time at which death is evaluated is another key issue
of the study design. An excessive rate of mortality may be observed during
the first months of follow-up and not during a longer follow-up.
Multidrug- (isoniazid and rifampicin) resistant tuberculosis (MDRTB)
is associated with a more than threefold increased death if an appropriate
anti-TB regimen is not used early in the course of the infection. In western
countries where the prevalence of MDRTB is low and second-line drugs are
available, MDRTB only requires prompt detection and adequate management
to limit the consequence of resistance. However, in developing countries
where second-line treatments are not readily available, and where 95%
of worldwide tuberculosis cases occur which are responsible for 26% of
the potentially avoidable death, one can predict an increasing impact
of MDRTB on death in the years to come. Several studies suggest that in
acute otitis media caused by Streptococcus pneumoniae, the bacteriologic
failure rate increases with penicillin G minimal inhibitory concentration.
Although bacteriologic failure does not mean clinical failure, the risk
for acute otitis media relapses and complications linked to resistance
is poorly documented. Higher penicillin G MICs of S. pneumoniae
strains observed in mastoitidis than those in otitis and sinusitis does
not prove that the severe acute otitis media complications increase with
S. pneumoniae resistance. Whether invasive infections with resistant
S. pneumoniae strains are linked to excessive death rates remains
controversial. Two studies suggest that death may be greater with higher
levels of resistance to penicillin G, and several failures have been reported
with macrolide or fluoroquinolone therapy. In countries with high levels
of drug resistance and where multidrug resistance is frequent, such as
southwestern Europe, the likelihood of treatment failure in meningitis
or mastoiditis might be greater. Because widespread use of pneumococcal
conjugate vaccine has been shown to reduce the risk for resistant infections,
epidemiologic studies to evaluate potential benefits of conjugate vaccine
introduction are needed in countries most affected by resistance.
The quinolone resistance in bacterial diarrhea due to Campylobacter
jejuni can lead to therapeutic failure associated with an increased
duration of symptoms and an increased rate of hospitalization. For non-typhi
Salmonella, resistance was associated with an increased rate and
duration of hospitalization, a twofold increased risk of death during
a 2-year period after the infection, and an increased rate of invasive
infection (1). Antimicrobial use may cause a transient
decrease in a person’s resistance to colonization by noncommensal bacteria
as well as infection upon exposure to a food-borne pathogen. The additional
selective effect of antimicrobial resistance results in a greater than
threefold increase in vulnerability to infection by an antimicrobial-resistant
pathogen among persons receiving antimicrobial therapy for unrelated reasons.
The net result, which has been demonstrated for salmonellae and campylobacters,
is an excessive rate of illness caused by the interaction between resistance
in these bacteria and unrelated use of antimicrobial agents in humans.
This relationship may also explain why outbreaks of resistant food-borne
agents which lead to an excess illness among imunocompromised persons
or persons at risk, may be more common in hospitals than in communities.
Studies of the clinical outcome of methicillin-resistant Staphylococcus
aureus (MRSA) infections in comparison to methicillin-sensitive S.
aureus (MSSA) infections have produced conflicting results. A dozen
studies compared MRSA and MSSA infections of the same infection site with
adjustment for at least one recognized criterion of illness severity and
included at least 30 patients. In studies of MRSA bacteremia in which
the analyses took into account the presence of shock, the source of the
infection, underlying disease(s), the medical setting in which the infection
occurred, the appropriateness of antibiotics prescribed, the age and sex
of the patients, no increased death was associated with MRSA, although
inappropriate therapy was associated with a poorer outcome. In contrast,
for bone infections and mediastinitis, MRSA may increase the risk of death.
The complete results of standard antimicrobial susceptibility tests are
not generally available to the prescriber before at least 48–72 hours.
The initial regimen prescribed may be not adequate during the first 2
to 3 days of treatment. This may impact death or illness attributable
to multi-resistant bacteria. Shortening this interval, rapid diagnosis
techniques based on molecular identification of resistance mechanisms
could improve outcome. For example, methicillin resistance in S. aureus
colony is detectable within 6 hours. Studies on clinical specimens showed
that resistance-detection techniques, coupled with DNA identification
of the bacterium, gave an excellent concordance to discriminate MRSA and
MSSA and for MDRTB. Advances in the field of DNA microchips might soon
improve the clinical impact of these techniques.
With more clinical failures, more expensive alternative regimens, the
cost-effectiveness ratio of the treatment of antimicrobial bacterial resistant
infections will inevitably rise. However, very few studies have addressed
this issue; it requires precise and documented scenarios based on close
collaboration between clinicians, microbiologists, epidemiologists and
economists. Proposing prospective scenarios and foreseeing all the public
health consequences of antimicrobial bacterial resistance is difficult.
Although the impact on life expectancy should remain relatively limited
in western nations, this will not be the case in developing countries
where alternative regimens are usually either not available or too costly.
Quantifying the consequences of antimicrobial bacterial resistance is
a key element for allocating resources for public health programs. Some
evidence exists of such consequences on illness and death, most of which
appear to be associated with inappropriate or delayed therapy. Nevertheless,
more studies which take into account the specific methodologic difficulties
mentioned above are needed to better convince policy makers.
Reference
- Helms M, Vastrup P, Gerner-Smidt P, Molbak K. Excess
mortality associated with antimicrobial drug-resistant Salmonella
typhimurium. Emerg Infect Dis 2002; 8:490-5
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