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SUPPLEMENT ARTICLE
Antimicrobial Drug Use and Resistance among
Respiratory Pathogens in the Community
Donald E. Low
Department of Microbiology, Mount Sinai Hospital, and the University Health Network, University of Toronto, Toronto
There is substantial evidence that the overuse of antibiotics is a major cause for the emergence of resistance
in respiratory pathogens in the community. However, it is also recognized that the mechanisms of resistance,
the cost of resistance to the fitness of the organism, and the ability of the resistant strain to disseminate are
all important contributors to this problem. Therefore, when developing strategies to control and/or prevent
the emergence of resistance, health care professionals must take each of these factors into consideration. As
we enter a new era in the use of fluoroquinolones for the treatment of respiratory tract infections, we have
an opportunity to apply such lessons learned in the past to minimize or prevent the development of resistance
to this class of antimicrobial drugs in the future.
Numerous reviews in the medical literature, reports by
national and international organizations, conferences,
and papers commissioned by governments have addressed the crisis of antimicrobial drug resistance [1–3].
Most agree that this is a direct result of inappropriate
antimicrobial drug use, including overuse and misuse
[4–8]. However, the magnitude of this effect and the
time frame in which it occurs also depend on the mechanism of resistance, the cost of resistance to the fitness
of the organism, and the ability of the resistant organism to disseminate.
EMERGENCE OF RESISTANCE
Resistance can be either inherent or acquired. Inherent
resistance is resistance that results from the normal
genetic, structural, or physiological state of the microorganism. Acquired resistance develops when the organism has been able to either (1) undergo spontaneous
Financial support: Canadian Bacterial Diseases Network, University of Calgary,
Calgary, Alberta, Canada.
Reprints or correspondence: Dr. Donald E. Low, Dept. of Microbiology, Mount
Sinai Hospital, 600 University Ave., Rm. 1487, Toronto, Ontario, Canada M5G 1X5
([email protected]).
Clinical Infectious Diseases 2001; 33(Suppl 3):S206–13
2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3306S3-0017$03.00
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mutation that has resulted in a resistant phenotype or
(2) acquire resistance genes by horizontal transfer. The
frequency with which spontaneous mutations result in
a resistant phenotype depends on the spontaneous mutation rate, the number of mutations required in a gene
and the number of genes involved [9]. Among Mycobacterium tuberculosis, resistance to streptomycin results
from a change in 1 nucleotide of the gene that encodes
ribosomal protein S12 [10]. Horizontal gene transfer
allows organisms to share complex and elegant resistance mechanisms that may have evolved eons ago [11].
However, no matter how an organism becomes resistant, the use of antibiotics is what creates for these
bacteria a selective environment that allows them to
become the dominant flora.
COST OF RESISTANCE
If one of the solutions for the prevention and control
of resistance is to curtail the overuse of antimicrobial
drugs, then for such an approach to be successful, the
acquisition of a resistant trait by an organism must be
associated with a deleterious cost to the organism’s fitness. The effect of chromosomal mutations usually is
negative, occasionally is neutral, but rarely is positive
[12]. Schrag and Perrot [13] showed that spontaneous
chromosomal mutations that resulted in a streptomy-
cin-resistant rpsL mutant of Escherichia coli had a growth disadvantage relative to the parental stain. A number of investigators have presented evidence that, in the absence of selection
for the genes that they are carrying, plasmids impose a cost on
the fitness of their host bacteria [14, 15].
However, Chiew et al. [16] monitored streptomycin resistance in Enterobacteriaceae in their hospital in 1991, ∼20 years
after the cessation of the use of this agent. They found that up
to 20% of isolates were resistant to streptomycin. Four years
after the prohibition of the use of tetracycline as a food additive
to promote growth in pigs, there was no significant reduction
in the percentage of pigs that harbored tetracycline-resistant E.
coli [17]. These examples, in which antibiotic use has been
curtailed or discontinued yet resistance has not significantly
decreased, suggest that, at least for some antibiotics, the cost
of resistance is low and/or there is some other selective factor
associated with the resistant trait [14, 18–20].
MINIMIZING THE COST OF RESISTANCE
Mechanisms by which the cost of resistance to the fitness of the
bacteria can be minimized or eliminated include gene variation,
which allows the bacteria to adapt and/or control expression of
the resistance trait in the absence of antibiotic selective pressure.
Because most newly arising mutations are neutral or deleterious,
it has been argued that the mutation rate has evolved to be as
low as possible. However, not all mutations are deleterious. Mutations may be beneficial for the microorganism that has found
itself in a new environment (e.g., exposure to antibiotics) or host.
Under such circumstances, mutations may play an important
role in adaptive evolution [21, 22].
Schrag and Perrot [13] created streptomycin-resistant E. coli
that were found to have a growth disadvantage of ⭓14% per
generation relative to the growth of the wild-type strain. However, after 180 generations of evolution occurred in the absence
of exposure to antibiotics, they found that the cost of resistance
was substantially reduced. Schrag et al. [23] were further able
to demonstrate that the second-site mutations that compensated for the streptomycin-resistant mutations in E. coli created
a genetic background in which streptomycin-susceptible alleles
had a selective disadvantage of 4%–30% per generation relative
to the adapted resistant strains. In addition, it appears that
these compensatory mutations have been fixed in long-term,
streptomycin-resistant laboratory strains of E. coli, which may
account for the persistence of streptomycin resistance in populations maintained in the absence of the antibiotic.
Sniegowski et al. [24] reported an increase in hypermutable
strains in populations of E. coli that were undergoing longterm adaptation to a new environment. LeClerc et al. [25]
reported that the incidence of mutators among isolates of pathogenic E. coli and Salmonella enteritidis was high (11%). They
found defects in the methyl-directed mismatch repair system
in all mutator phenotypes described. Of 9 independently derived hypermutable strains, 7 contained a defective mutS allele.
LeClerc and colleagues speculated that because these mutant
alleles increase the mutation rate and enhance recombination
among diverse species, this might help explain the rapid emergence of antibiotic resistance and of virulence genes. In addition
to mutator alleles, a variety of other mechanisms of genetic
variation have been identified, including recombination, gene
conversion, translocation, and inversion [26].
Down-regulation of the expression of a resistance function
can reduce the cost of resistance in an antibiotic-free environment. There are many resistance genes that are quiescent and
that are only induced in the presence of the antibiotic for which
they encode resistance. Many gram-negative species respond to
the presence of b-lactam antibiotics by inducing the synthesis
of a chromosomal AmpC b-lactamase [27]. The biosynthetic
machinery that is required to protect the cell wall target of
Enterococcus faecium and Enterococcus faecalis from vancomycin
is found on a transposable element that incorporates 5 genes
that are necessary to confer high-level, inducible glycopeptide
resistance. Two of these gene products, VanR and VanS, are
required for the vancomycin-induced resistance response.
Therefore, if a glycopeptide is not sensed in the environment,
transcription of these genes ceases, thereby minimizing the cost
to the fitness of the organism. If there is a minimal cost to the
fitness of the organism as a result of its being resistant, then
it may take considerable time until there is a reduction or
elimination of the resistant bacteria once the antibiotic selective
pressure is removed.
DISSEMINATION
For a resistant organism to emerge, it must possess characteristics that allow it to (1) effectively multiply within and disseminate from its hosts and (2) translocate to and colonize new
hosts. Many factors, or combinations of factors, contribute to
the transmissibility of resistant bacteria. Human demographics
and behavior play a critical role. For example, the increase in
the number of families in which both parents are working has
resulted in an increase in the number of children who attend
day care facilities and are exposed to other children who may
be carrying resistant organisms [28, 29]. International and national travel allows for rapid and widespread dissemination of
bacteria. Isolates of Streptococcus pneumoniae serotype 23F,
which has high levels of resistance to penicillin and which was
found initially in Spain, were isolated from children who attended a day care center in Cleveland [30]. In Iceland, almost
all of the multiresistant pneumococci that suddenly appeared
in clinical specimens from 1989 through 1992 belonged to serotype 6B, which was indistinguishable from a subgroup of
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Figure 1. Association between annual human consumption of macrolides (in tons) and frequency of macrolide resistance among group A streptococci
in Japan [39, 41, 42].
multiresistant pneumococci of serotype 6B that was present
with high incidence in Spain [31].
The use of antimicrobial drugs to which an organism is
resistant facilitates an increase in both the number and the
transmission of that organism. Brook and Gober [32] studied
the effect of prophylaxis with amoxicillin or sulfisoxazole in
children and found that the rate of recovery of oropharyngeal
b-lactamase–producing bacteria increased only after administration of amoxicillin, increasing from 20% to 100%. Three to
5 months after amoxicillin prophylaxis was discontinued, the
rate of carriage returned to baseline levels. Numerous studies
have identified prior antibiotic use to be the most significant
risk factor for carriage and transmission of penicillin-resistant
S. pneumoniae [33–36].
INAPPROPRIATE USE OF ANTIBIOTICS AND
RESISTANCE
Overuse. Overuse of antibiotics includes unnecessary antibiotic prescribing practices in clinical medicine and the use of
antibiotics to prevent disease and to promote animal growth
in agriculture. Much of the efforts to control resistance, some
of which have been successful, have been aimed at reducing
the overuse of antibiotics. However, establishing a precise quantitative relationship between the frequency of resistance to a
defined antibiotic and the volume of drug use has proved to
be difficult because of the paucity of longitudinal studies that
have recorded resistance and drug use patterns [37]. Despite
this lack of data, it seems reasonable to assume that such a
relationship exists because it is biologically plausible, because
there has been consistent evidence of the association in several
studies, and because the sequence of events over time supports
such a notion [38].
In Japan, the use of macrolides increased sharply after 1970,
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and ∼165–170 tons of macrolides were used annually in 1974,
1976, and 1977 [39]. Associated with this increase in use was
a rapid increase in macrolide resistance among group A streptococci (figure 1) [40, 41]. In 1972, 12% of group A streptococci
were resistant to macrolides. By 1974, this percentage had increased to 60%. During the late 1970s and 1980s, the use of
macrolides gradually decreased to 65–85 tons annually. Associated with this decrease in use was a marked reduction in
macrolide resistance (to !1%) [39, 40]. Although the great
majority of resistant isolates in the 1970s were M type 12 strains,
macrolide resistance among these strains had decreased from
86% to 13% by the 1980s [42].
In Finland, the use of erythromycin increased from 1.1 defined daily doses per 1000 inhabitants per day in 1979 to 3.2
defined daily doses per 1000 inhabitants per day in 1988 [43].
The frequency of erythromycin resistance among group A
streptococci was 4% in 1988, 7% in 1989, and 24% in 1990.
Resistance was represented by several different serotypes. As a
result of this frequency of resistance, there were nationwide
recommendations for the reduction in erythromycin use for
respiratory and skin infections in outpatients. These recommendations resulted in a 50% reduction in the number of
macrolide prescriptions, followed by an ∼50% decrease in resistance to macrolides among group A streptococci (figure 2)
[44]. Toward the end of the study period, there was a gradual
increase in the use of the newer macrolides, such as azithromycin and roxithromycin. However, there have been no further
data presented as to the impact of these agents on macrolide
resistance.
In Canada, there has been a significant reduction in the use
of outpatient antibiotics (from 25.4 million prescriptions in
1995 to 22.6 million prescriptions in 1999; IMS HEALTH).
Amoxicillin was the antimicrobial drug for which the reduction
in use was greatest. Associated with that reduction was a re-
Figure 2. Association between macrolide consumption and frequency of macrolide resistance among group A streptococci in Finland. Consumption
is expressed in terms of defined daily doses per 1000 inhabitants per day. Adapted from Seppala et al. [44].
duction in the prevalence of b-lactamase–producing Haemophilus influenzae, whereas the prevalence of b-lactamase–producing Moraxella catarrhalis remained at 190% (figure 3) [45].
A possible explanation may be related to the cost of resistance.
H. influenzae is unusually permeable to the aminopenicillins;
therefore, for a b-lactamase–producing isolate to be protected
against the action of an amoxicillin, it must produce large
amounts of b-lactamase to inactivate all the antibiotic [53].
This is accomplished by the presence of 2 strong, overlapping
b-lactamase promoters and, in some cases, by having multiple
copies of the b-lactamase plasmid [54, 55]. In M. catarrhalis,
the b-lactamase genes are present as single copies on the chromosome and sometimes have deletions in their promoters [56,
57]. This is reflected by the increased susceptibility of b-lactamase–producing M. catarrhalis to aminopenicillins, compared with the susceptibility of b-lactamase–producing H. influenzae to aminopenicillins [46, 47, 56]. Therefore, as a result
of the smaller amounts of enzyme produced, b-lactamase–
producing M. catarrhalis may be more fit then its H. influenzae
counterpart in the absence of the selective pressure of aminopenicillins.
Misuse. Misuse of antibiotics includes inappropriate dose,
duration, and/or frequency of administration. Bacterial exposure to low and/or prolonged concentrations of an antibiotic
may have a role in the selection of resistance [6, 58, 59]. This
may occur by killing the susceptible normal flora and allowing
preexisting resistant organisms to survive or by increasing the
likelihood for subsequent colonization of the host with resistant
bacteria. Another mechanism involves selecting for isolates that
have developed antibiotic resistance de novo by spontaneous
chromosomal mutations [9]. For example, drug-resistant tuberculosis is produced by the selection of resistant strains in
patients who have failure to complete chemotherapy with the
correct combination of drugs. M. tuberculosis becomes drug
resistant through random, spontaneous genetic mutations. The
proportion of naturally occurring resistance has been established for several of the primary antituberculosis drugs: for
rifampin, 1/108; for ioniazid and streptomycin, 1/10 6 ; and for
ethambutol, 1/10 4. The probability of ioniazid and rifampin
resistance occurring in the same organism is 1/10 8 ⫻ 1/10 6 (or
1/1014). Because the total number of bacilli in an infected person, even in a person with advanced cavitary disease, does not
approach this value (1014), spontaneous evolution of drug-resistant tuberculosis occurs infrequently. Therefore, to prevent
the emergence of resistance, physicians must ensure that effective
regimens for the treatment of tuberculosis contain multiple drugs
to which the organisms are susceptible. When ⭓2 drugs are used
simultaneously, each drug helps prevent the emergence of tubercle bacilli that are resistant to the other drugs.
This approach to the prevention of the emergence of M.
tuberculosis resistance could be applied to strategies for the
prevention of resistance to fluoroquinolones. However, 1 drug
(the fluoroquinolone) that is able to bind to and inhibit each
of its 2 targets is used, rather than 2 drugs, each of which has
a different target. The fluoroquinolones are potent antibacterial
agents that have DNA gyrase and DNA topoisomerase IV as
their intracellular targets. The key step in quinolone action is
trapping of gyrase or topoisomerase IV on DNA as ternary
drug-enzyme-DNA complexes [60]. The complexes block replication fork movement, inhibiting DNA synthesis. Inhibition
of DNA synthesis correlates well with inhibition of growth as
measured by MIC. Depending on the fluoroquinolone and the
organism, 1 of these will be the primary target—that is, the
target for which the fluoroquinolone has greater affinity—and
the other will be the secondary target. For example, in Neisseria
gonorrhoeae, the primary target for ciprofloxacin is DNA gyrase
and the secondary target is topoisomerase IV. If an inadequate
dose of ciprofloxacin is used, then concentrations of ciprofloxacin that only allow inhibition of the primary target may
be achieved (figure 4, solid line). The likelihood of a preexisting
Antimicrobial Drug Use and Resistance • CID 2001:33 (Suppl 3) • S209
Figure 3. Frequency of b-lactamase–positive Haemophilus influenzae
and Moraxella catarrhalis in Canada. Dark bars denote H. influenzae, and
light bars denote M. catarrhalis. Data were adapted both from previous
publications [46, 47, 48–52] and from the Canadian Bacterial Surveillance
Network (Mount Sinai Hospital, Toronto).
spontaneous mutation in the quinolone-resistance–determining region (QRDR) of the GyrA subunit of the DNA gyrase
that results in resistance is in the order of 1/10 8 . However, if a
dose of ciprofloxacin is used that provides concentrations that
allow for binding to both DNA gyrase and topoisomerase IV
(figure 4, broken line), then the likelihood of preexisting spontaneous mutations occurring in both targets is in the order of
1/10 8 ⫻ 1/10 8 (or 1016). The Centers for Disease Control and
Prevention in Atlanta have recommended the use of singledose, oral therapy with 500 mg of ciprofloxacin for the treatment of uncomplicated gonorrhea due to N. gonorrhoeae [61].
However, in some countries, gonococcal infections have been
treated with a single, orally administered dose of 250 mg of
ciprofloxacin. The failure of gonococcal infections to respond
to treatment with 250 mg of ciprofloxacin has been well documented [62]. The continued use of inadequate doses of fluoroquinolones for the treatment of N. gonorrhoeae may account
for the continuing de novo emergence of resistant strains [63].
The emergence of resistance of S. pneumoniae to antimicrobial drugs that are used to treat respiratory pathogens has led
to changes in recommended antimicrobial drug treatment regimens [64, 65]. Fluoroquinolones, such as levofloxacin, moxifloxacin, and gatifloxacin, are now recommended as therapeutic options when patients with pneumonia are at risk for
infection due to multidrug-resistant pneumococci. Of concern
is the potential for the emergence of S. pneumoniae that is
resistant to the fluoroquinolone class as a whole [66]. For example, the treatment of acute exacerbations of chronic bronchitis (AECB) with 500 mg of ciprofloxacin given twice daily
may not achieve adequate bactericidal concentrations at the site
of colonization or infection, thereby creating a selective environment that favors those strains of S. pneumoniae with preexisting mutations in the primary target and an elevated MIC
S210 • CID 2001:33 (Suppl 3) • Low
(figure 4, solid line). Specific rates of eradication of S. pneumoniae
in patients with AECB have been variable, ranging from 63% to
90% [67, 68]. Clinical trials of the treatment of patients with
AECB have reported strains of fluoroquinolone-resistant S. pneumoniae for which selection occurred during fluoroquinolone
therapy [68, 69].
Emergence of resistance of S. pneumoniae to fluoroquinolones has already been described in Canada, Spain, Hong Kong,
and Ireland. In Canada, Chen et al. [70] found that the prevalence of ciprofloxacin-resistant pneumococci (MIC, ⭓4 mg/
mL) increased from 0% in 1993 to 1.7% in 1997–1998 (P p
.01; figure 5). In adults, the prevalence increased from 0% in
1993 to 3.7% in 1998. This was associated with an increase in
the consumption of fluoroquinolones. Overall, the number of
fluoroquinolone prescriptions increased from 0.8 to 5.5 per 100
persons per year from 1988 through 1997 [70]. In addition to
the increase in the prevalence of pneumococci with reduced
susceptibility to fluoroquinolones, the degree of resistance has
also increased (figure 5). From 1994 through 1998, there was
a statistically significant increase in the proportion of isolates
with an MIC of ciprofloxacin of ⭓32 mg/mL (P p .04). Linares
et al. [71] found an increase in the proportion of ciprofloxacinresistant pneumococci in Spain (from 0.9% in 1991–1992 to
3% in 1997–1998). Both groups of investigators found that the
resistant strains were more likely to be isolated from the sputum
of older patients, which suggests a possible source and reservoir
for fluoroquinolone-resistant pneumococci. Ho et al. [72] examined the susceptibilities of 181 pneumococcal isolates from
4 regional laboratories in Hong Kong and found that 12% of
Figure 4. The consequence of DNA gyrase and DNA topoisomerase
IV mutations on fluoroquinolone activity. The dark bars and light bars
denote the 2 topoisomerase enzymes (topoisomerase IV or DNA gyrase,
respectively) that are the intracellular targets for the fluoroquinolones.
The height of the bars indicates the amount of fluoroquinolone required
to bind to and inhibit enzyme function and have an antibacterial effect.
The solid lines and broken lines denote the concentration that the fluoroquinolone is able to achieve as a result of either the dosage or activity
of the agent.
Figure 5. The increasing prevalence and MICs of Streptococcus pneumoniae that is not susceptible to ciprofloxacin (MIC, ⭓4 mg/mL) in Canada. All MIC units are in micrograms per milliliter. Adapted from Chen
et al. [70].
stains had MICs of ciprofloxacin of ⭓4 mg/mL. In Northern
Ireland ciprofloxacin resistance was linked to penicillin resistance. Eighteen (42.9%) of 42 penicillin-resistant pneumococci
were resistant to ciprofloxacin [73].
The prevalence of fluoroquinolone-resistant pneumococci
may increase dramatically as they are increasingly used for lower
respiratory tract infections. In pneumococcal pneumonia, the
total number of bacteria may be as high as 1010 to 1012 [74].
Therefore, if an agent is used that only achieves levels that
result in binding to 1 of the 2 targets, then the likelihood of
selecting for an isolate with a preexisting mutation in the QRDR
of the primary target is 1/10 8 [75]. Weiss et al. [76] described
an outbreak of S. pneumoniae serotype 23F that caused lower
respiratory infection among patients in a chronic respiratory
disease ward. The isolate in the first cluster of infections had
an elevated MIC of ciprofloxacin of 4 mg/mL as the result of
a parC mutation in topoisomerase IV. In the second cluster of
cases, the MIC had increased to 16 mg/mL as the result of an
additional mutation in gryA. Two patients in the first cluster
(both with AECB) and 3 patients in the second cluster (1 with
hospital-acquired pneumonia and 2 with AECB) had treatment
failure with 500 mg of ciprofloxacin given twice daily. Davidson
et al. [77] described 2 patients with community-acquired pneumonia due to S. pneumoniae that were treated as outpatients
with levofloxacin. Both patients had treatment failure in association with the selection of resistance to levofloxacin as the
result of parC and gyrA mutations during therapy.
A possible strategy to curtail or prevent the emergence of
fluoroquinolone resistance in S. pneumoniae is the use of fluoroquinolones with the lowest MICs and, therefore, with the
greatest affinity for the topoisomerase target enzymes (figure
4, broken line) [78]. By the use of such agents that bind to both
targets at therapeutic drug levels, the likelihood of selecting a
strain with a mutation in both target sites while therapy is
administered would be 1/10 8 ⫻ 1/10 8 (or 1016) [79]. Evidence
that such a strategy may be effective is provided by the experience with the fluoroquinolones and the treatment of infections due to H. influenzae and M. catarrhalis. Despite the widespread use of ciprofloxacin for the treatment of lower
respiratory tract infections, including AECB, during the past
10 years, reports of resistant isolates are rare [80–83]. For both
organisms, the MIC90 of ciprofloxacin is !0.06 mg/mL [84]. The
area under the curve (AUC) for ciprofloxacin is ∼20–30
(mg 7 mg 7 mL⫺1) when an oral dose of 500 mg is used [85].
Therefore, the AUC/MIC ratio when treating infections due to
H. influenzae and M. catarrhalis would be 1300, a value well
above the ratio of 125 that is predictive of clinical cures and
microbiological eradication when treating infections due to
gram-negative pathogens [86, 87]. Similarly with the new fluoroquinolones, such as moxifloxacin, the AUC/MIC ratio for
susceptible S. pneumoniae is ∼180 and the peak/MIC ratio is
20, ratios that are well above the peak/MIC ratio that is predictive of microbiological eradication and favorable clinical
outcomes [88–90].
CONCLUSION
Although the data are compelling for the association between
resistance and the volume of antimicrobials consumed, there
are numerous other factors that must be taken into account if
we are to devise appropriate strategies to control or prevent
the emergence of antimicrobial resistance in the outpatient setting. We are entering a new era with the recent approval of
several new fluoroquinolones for the treatment of respiratory
pathogens, including S. pneumoniae, and the prospect of several
additional candidates in the near future. If we are to preserve
this class of antimicrobial drugs, it is incumbent upon us to
not only avoid overusing these agents by prescribing them for
trivial infections, but also to learn how to use them appropriately so as to minimize the emergence of resistance [91].
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