(Chest. 1999;115:3S-8S.)
© 1999
American College of Chest Physicians
Overview of Resistance in the 1990s*
Thomas M. File, Jr., MD, MS, FCCP
* From Northeastern Ohio Universities, College of Medicine, Rootstown, OH,
and the Infectious Disease Service, Summa Health System, Akron, OH.
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Abstract
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The tremendous therapeutic advantage afforded by antibiotics is
being threatened by the emergence of increasingly resistant strains of
microbes. Selective pressure favoring resistant strains arises from
misuse and overuse of antimicrobials (notably extended-spectrum
cephalosporins), increased numbers of immunocompromised hosts, lapses
in infection control, increased use of invasive procedures and devices,
and the widespread use of antibiotics in agriculture and animal
husbandry. Outside the hospital, penicillin-resistant
Streptococcus pneumoniae is of greatest concern; recent
reports also indicate the appearance of outpatient
methicillin-resistant Staphylococcus aureus (MRSA)
infections. MRSA is a significant problem in the hospital, as are
vancomycin-resistant Enterococcus, oxacillin-resistant S
aureus, and multidrug-resistant Gram-negative bacilli. Owing to
the high rate of antibiotic use and other risk factors, a person is
more likely to acquire an antibiotic-resistant infection in the ICU
than anywhere else, either inside or outside the hospital. Responsible
antibiotic use and stringent infection-control policies are needed to
discourage the development of resistant strains.
Key Words: antimicrobials • cephalosporins • methicillin-resistant Staphylococcus aureus • nosocomial infections • resistance
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Introduction
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The
discovery of potent antimicrobial agents was one of the greatest
contributions to medicine in the 20th century. Unfortunately, the
emergence of antimicrobial-resistant pathogens now threatens these
advances. Antimicrobial resistance has resulted in increased morbidity
and mortality as well as higher health-care costs. Yearly expenditures
arising from drug resistance in the United States are estimated to
approach $4 billion and are rising.1
,2
The emergence of resistance is a result of factors such as increased
use and misuse of antimicrobial agents (notably the extended-spectrum
cephalosporins), increased use of invasive devices and procedures, a
greater number of susceptible hosts, and lapses in infection control
practices leading to increased transmission of resistant organisms. In
the hospital, widespread use of antimicrobials in the ICU and for
immunocompromised patients has resulted in the selection of
multidrug-resistant organisms.
|
Epidemiology and Transfer of Antimicrobial Resistance
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Microorganisms have a remarkable array of mechanisms with
which to overcome the effects of antimicrobial agents (Table 1
).
These include the production of structure-altering or inactivating
enzymes (eg, ß-lactamase- or aminoglycoside-modifying
enzymes), alteration of penicillin-binding proteins or other cell-wall
target sites, altered DNA gyrase targets, permeability mutations, and
ribosomal modification.3
,4
,5
,6
,7
Selective pressure resulting
from antimicrobial administration can lead to the growth of previously
susceptible strains that have acquired resistance or to the overgrowth
of strains that are intrinsically resistant. The emergence of
Stenotrophomonas maltophilia during imipenem therapy is an
example of selection of intrinsically antibiotic-resistant strains. In
general, resistance is acquired by mutational change or by the
acquisition of resistance-encoding genetic material. Increased use of
antimicrobial agents in clinical practice as well as the enormous
quantities of antibiotics employed in agriculture, fisheries, and
animal husbandry provide conditions favorable to the selection of
resistant microorganisms.8
Antibiotic use may exert
selective pressure both directly and indirectly—as occurs when
children in day-care centers who have not received antibiotics become
colonized with resistant organisms from their companions. In addition,
workers in the livestock industry may become colonized with resistant
strains through exposure to animal products from livestock that have
eaten antimicrobial-containing feed.9
In clinical
practice, the results of selective pressure are most evident in
extended-care facilities and in critical care areas of hospitals.
Antimicrobial resistance may be transferred between bacteria by
plasmids, transposons, or insertion-sequence mechanisms.4
Transferable plasmids may possess genes encoding resistance to a wide
range of antimicrobial agents. Thus, for Gram-positive and
Gram-negative organisms, a single transfer event can result in the
acquisition of several antimicrobial resistance determinants.
Environmental pressure from the overuse of antimicrobial agents clearly
contributes to the spread of resistance determinants. Penicillin
resistance spread in the 1950s; cephalosporin resistance, during the
1970s; and resistance to third-generation cephalosporins, in the past
decade (Table 2
).
10
Virtually all major bacterial pathogens have acquired
antimicrobial resistance genes. At present, judicious use of
antibiotics and proper attention to infection control techniques are
our best weapons to combat the further spread of resistance.
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Resistance Associated With Community-Acquired Infections
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Outside the hospital, resistance to previously standard therapy is
emerging in several common pathogens. These include Salmonella,
Shigella, Neisseria gonorrhoeae, Streptococcus pneumoniae,
Haemophilus influenzae, and most recently Staphylococcus
aureus.11
Pathogens associated with respiratory tract
infections have significant impact because approximately 75% of oral
antimicrobial use is for respiratory tract infection. Greater than 35%
of Haemophilus species and 90% of Moraxella catarrhalis are
now resistant to the early ß-lactam (BL) agents by virtue of the
ß-lactamase enzymes they produce.12
,13
ß-Lactamase
inhibitors (BLI) combined with a penicillin can restore activity toward
such strains. Rare strains of H influenzae that are
ampicillin resistant but ß-lactamase negative have recently been
identified.12
Of greatest concern, however, is the recent
emergence of resistance in S pneumoniae. Recent multicenter
studies indicate that penicillin resistance rates in the United States
are now approximately 24 to 34%, with high-level resistance rates of 9
to 14%.14
,15
Resistance to other commonly used agents
(cephalosporins, macrolides, tetracyclines,
trimethoprim/sulfamethoxazole) is also increasing. The clinical
relevance of drug-resistant strains of S pneumoniae in lower
respiratory tract infections has been debated, but recent studies
suggest a correlation between the presence of high-level penicillin
resistance and increased mortality in invasive S pneumoniae
pneumonia.16
Risk factors associated with
penicillin-resistant pneumococci include past and current antimicrobial
use and the presence of a family member in a day-care center. The
Working Group for Drug-Resistant S pneumoniae recently
convened by the Centers for Disease Control and Prevention (CDC) made
several recommendations to help reduce the incidence of resistant
S pneumoniae (Table 3
).
Recent studies indicate that isolation of methicillin-resistant S
aureus (MRSA) is no longer limited to nosocomial infections or
special-risk groups17
; reports of outpatient MRSA
infections in both children and adults are
increasing.17
,18
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Resistance Associated With Nosocomial Infections
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Most studies show a higher rate of resistance associated with
nosocomial pathogens, particularly from ICUs, than with
community-acquired organisms.19
Although Gram-negative
bacteria remain a major cause of nosocomial infection, Gram-positive
bacteria and fungi have become increasingly important. Data from the
National Nosocomial Infection Surveillance (NNIS) reporting system and
many institutional studies indicate a changing distribution of
nosocomial pathogens over the past two decades.20
Currently, coagulase-negative Staphylococcus, S aureus, and
Enterococcus species account for well over half of the nosocomial
bloodstream infections.21
Specific bacterial pathogens
that are significant problems in hospitals today include MRSA,
multidrug-resistant Gram-negative bacilli, vancomycin-resistant
enterococci (VRE), and oxacillin-resistant S aureus (Table 2
).22
,23
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ICU-Related Infections
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Project ICARE (Intensive Care Antimicrobial Resistance
Epidemiology), a multicenter study implemented in 1994 by the hospital
infections program of the CDC in cooperation with Emory University,
collected information from the microbiology laboratories of eight US
hospitals.2
The initial evaluation indicates that the
percentage of resistant isolates from inpatients was significantly
higher than that from outpatients for the following
antimicrobial/organism combinations: methicillin/S aureus,
ceftazidime/Enterobacter cloacae, imipenem/Pseudomonas
aeruginosa, ceftazidime/P aeruginosa, and
vancomycin/Enterococcus species. The percentage of resistance decreased
in stepwise fashion for organisms isolated from ICU patients, non-ICU
inpatients, and outpatients.2
Recent studies of nosocomial infections in ICUs illustrate the
prevalence and risk factors for infections in this setting. In a 1-day
point prevalence study of ICUs in 17 countries in Western Europe, 21%
of patients had an ICU-acquired infection, with pneumonia being the
most common.24
Microorganisms most frequently reported
were Enterobacteriaceae (34.4%), S aureus (30.1%, 60%
methicillin resistant), P aeruginosa (28.7%), and
coagulase-negative staphylococci (19.1%). Risk factors for
ICU-acquired infection were as follows: longer ICU stay; mechanical
ventilation; diagnosis of trauma; central venous, pulmonary artery, and
urinary catheterization; and stress-ulcer prophylaxis. In a similar
study performed in 118 ICUs in the United States in 1994, 25% of all
patients had nosocomial infection, with pneumonia being the number 1
diagnosis (37%). In the two studies, 62% and 61% of ICU patients
were receiving antimicrobials at the time of the evaluation; almost one
quarter of antimicrobials were third-generation cephalosporins (Table 4
).
25
Perhaps no other factor is more responsible for the development of
antimicrobial resistance than antimicrobial use in hospitals, where
approximately 25 to 40% of all inpatients receive the drugs. A number
of studies in hospitals have found an association between antimicrobial
use and antimicrobial resistance.19
Table 5 shows the variety of antimicrobial agents used in 101 adult ICUs
defined from project ICARE.
With increasing resistance of nosocomial pathogens, surveillance
assumes a critical role in guiding physicians toward appropriate
parenteral antimicrobials and in tracking patterns of drug
susceptibility. A recent surveillance study in 43 medical centers in 23
states focused on broad-spectrum drugs, such as cephalosporins, BLI
combinations, and fluoroquinolones.23
The resistance
problems identified as being of greatest clinical concern were as
follows: VRE; penicillin-resistant S pneumoniae;
oxacillin-resistant S aureus; ciprofloxacin-resistant
Escherichia coli; third-generation cephalosporin-resistant
E coli, Klebsiella, and Citrobacter, and imipenem-resistant
P aeruginosa (Table 6
).
23
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Vancomycin-Resistant Enterococci
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VRE have become an enormous concern over the past
decade.5
Two major reasons these organisms have thrived in
the hospital environment are their intrinsic resistance to several
commonly used antibiotics and their ability to acquire resistance to
antibiotics, either by mutation or via receipt of foreign genetic
material from transfer of plasmids or transposons. Vancomycin had been
in clinical use for > 30 years before significant levels of VRE were
observed. However, vancomycin use increased tremendously from 1981 to
1989 to treat MRSA, drug-resistant pneumococci, and Clostridium
difficile colitis.5
,26
Acquisition of VRE by
hospitalized patients has been associated with length of stay,
underlying disease, intensity of antibiotic exposure, and exposure to
broad-spectrum cephalosporins and parenteral and oral vancomycin. VRE
colonization, however, is not easily differentiated from infection, and
rates of colonization with VRE far exceed the infection
rates.27
In some cases, treatment may not be indicated.
The treatment of VRE poses a challenge for clinicians.5
VRE is divided into resistance phenotypes primarily on the basis of
patterns of resistance to specific drugs. Van A and Van B phenotypes
occur primarily in Enterococcus faecalis and
Enterococcus faecium. Van A strains are highly resistant to
vancomycin and resistant to teicoplanin. Van B isolates were initially
believed to be resistant only to modest levels of vancomycin but remain
susceptible to teicoplanin. Class C resistance is described in
Enterococcus gallinarium and Enterococcus
casseliflavus, which demonstrate intrinsic low-level resistance to
vancomycin but are susceptible to teicoplanin.27
Laboratory detection of glycopeptide resistance in enterococci has
improved as a result of revised breakpoints for reading disk diffusion
susceptibility tests and updated techniques for automated testing
systems. Addition of a standardized screening method, with 6 µg/mL of
vancomycin in agar plates, provides a useful supplement to other
techniques.
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Extended-Spectrum ß-Lactamases
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Concomitant with the widespread use of the third-generation
cephalosporins, strains of Klebsiella, E coli, and other
species have appeared that produce extended-spectrum ß-lactamases
(ESBLs) able to hydrolyze oxyimino-ß-lactams.4
,28
ESBLs
are most prevalent in Klebsiella pneumoniae; data from the
NNIS indicate a prevalence from 1.6 to 12.8%. Because of the greater
sensitivity of ceftazidime for detecting ESBLs and the inoculum effect
that confounds results with other extended-spectrum cephalosporins,
many consider ceftazidime-resistant K pneumoniae strains to
be resistant to all extended-spectrum cephalosporins regardless of the
minimum inhibitory concentration (MIC) obtained at standard inoculum.
Potential therapeutic options include cefoxitin and cefotetan; these
cephamycins are not susceptible to hydrolysis by ESBLs. Imipenem has
been effective in animal models and is a reliable alternative; however,
in one study, the use of imipenem was associated with the emergence of
resistance in other Gram-negative bacilli (eg, Acinetobacter
species).28
Most ESBLs are more susceptible to inhibition
by BLIs than cephalosporins. Piperacillin/tazobactam has been shown to
inhibit ceftazidime-resistant K pneumoniae.29
Outbreaks have been controlled by limiting use of oxyimino-ß-lactams
and using BL/BLI as broad-spectrum alternatives.
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Conclusions
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The variety of mechanisms by which bacteria develop resistance is
startling. Reducing resistance depends on the clinician, the patients
who demand antibiotics for viral illness, and the pharmaceutical
industry, which should promote antibiotics
appropriately.7
,8
,30
,31
The threats associated with
antimicrobial resistance should serve as strong incentives for
responsible and judicious use of antimicrobial agents. There is a need
for both prudent use of antibiotics and stringent appropriate infection
control policies to reduce the emergence of resistance.
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Appendix 1
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Dr. Segreti: We have found that about 20% of our
Klebsiella and about 10% of our E coli are ESBL producers,
and about half of them have cross-resistance to quinolones.
Dr. File: We’re not surprised to see MRSA resistance, but I
was a little bit surprised to see the amount of resistance of
methicillin-susceptible S aureus to fluoroquinolones in the
study by Jones et al.23
We are beginning to see increasing
resistance of E coli and Enterobacter, and resistance of
Pseudomonas, to the fluoroquinolones. At some hospitals, 90% of their
Pseudomonas are resistant to ciprofloxacin. To me, that is pretty
significant.
Dr. Bernstein: There are certain new fluoroquinolones that
are being advertised as active against MRSA. Have you found any
significant differences among different fluoroquinolones?
Dr. File: Generally there is a class difference. In other
words, the MIC for an MRSA will be higher across the board for all the
newer quinolones. But you are starting with a different baseline for
each quinolone. For example, trovafloxacin may have a little lower MIC
for MRSA than older quinolones, but it still is going to be higher than
for the average methicillin-susceptible strain. In general, I would not
consider any of these newer third-generation fluoroquinolones to be
good empiric drugs for MRSA.
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Footnotes
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Correspondence to: Thomas M. File, Jr., MD, MS, FCCP, Chief,
Infectious Disease Service, Summa Health System, 75 Arch St, Suite 105,
Akron, OH 44304; e-mail: tfile@neoucom.edu
Abbreviations: BL = ß-lactam;
BLI = ß-lactamase inhibitor; CDC = Centers for Disease Control
and Prevention; ESBL = extended-spectrum ß-lactamase;
ICARE = Intensive Care Antimicrobial Resistance Epidemiology;
MIC = minimum inhibitory concentration;
MRSA = methicillin-resistant Staphylococcus aureus;
NNIS = National Nosocomial Infection Surveillance;
VRE = vancomycin-resistant enterococci
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TOP
Abstract
Introduction
