Mechanisms of Antimicrobial Resistance in Bacteria

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The American Journal of Medicine (2006) Vol 119 (6A), S3S10




Mechanisms of Antimicrobial Resistance in Bacteria
Fred C. Tenover, PhD
Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

                   ABSTRACT

                  The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop
                  resistance to antimicrobial agents. Antimicrobial agents are often categorized according to their
                  principal mechanism of action. Mechanisms include interference with cell wall synthesis (e.g.,
                  -lactams and glycopeptide agents), inhibition of protein synthesis (macrolides and tetracyclines),
                  interference with nucleic acid synthesis (fluoroquinolones and rifampin), inhibition of a metabolic
                  pathway (trimethoprim-sulfamethoxazole), and disruption of bacterial membrane structure (polymyx-
                  ins and daptomycin). Bacteria may be intrinsically resistant to 1 class of antimicrobial agents, or
                  may acquire resistance by de novo mutation or via the acquisition of resistance genes from other
                  organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the
                  antibacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target,
                  to modify the drug's target site, or to produce an alternative metabolic pathway that bypasses the
                  action of the drug. Acquisition of new genetic material by antimicrobial-susceptible bacteria from
                  resistant strains of bacteria may occur through conjugation, transformation, or transduction, with
                  transposons often facilitating the incorporation of the multiple resistance genes into the host's genome
                  or plasmids. Use of antibacterial agents creates selective pressure for the emergence of resistant
                  strains. Herein 3 case histories-- one involving Escherichia coli resistance to third-generation ceph-
                  alosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a
                  third detailing multidrug resistance in Pseudomonas aeruginosa--are reviewed to illustrate the varied
                  ways in which resistant bacteria develop.  2006 by the Association for Professionals in Infection
                  Control and Epidemiology, Inc. and Elsevier Inc. All rights reserved.

                   KEYWORDS: Antimicrobial mechanisms of action; Bacterial infections; Microbial mechanisms of resistance;
                   Resistance genes



Throughout history, there has been a continual battle                            situation dramatically improved when penicillin became
between humans and the multitude of microorganisms                               available for use in the early 1940s. However, the eu-
that cause infection and disease. Bubonic plague, tuber-                         phoria over the potential conquest of infectious diseases
culosis, malaria, and more recently, the human immuno-                           was short lived. Almost as soon as antibacterial drugs
deficiency virus/acquired immunodeficiency syndrome                              were deployed, bacteria responded by manifesting vari-
pandemic, have affected substantial portions of the hu-                          ous forms of resistance. As antimicrobial usage in-
man population, causing significant morbidity and mor-                           creased, so did the level and complexity of the resistance
tality. Beginning around the middle of the 20th century,                         mechanisms exhibited by bacterial pathogens. The strug-
major advances in antibacterial drug development and                             gle to gain the upper hand against infections continues to
other means of infection control helped turn the tide in                         this day, although the number of scientists who are de-
favor of humans. With respect to bacterial infections, the                       veloping new antibacterial agents is beginning to dwin-
                                                                                 dle, even as bacteria evolve ever more clever mechanisms
                                                                                 of resistance.1
   Requests for reprints should be addressed to Fred C. Tenover, PhD,
Division of Healthcare Quality Promotion, Centers for Disease Control and
                                                                                    This article presents a brief overview of the problem of
Prevention, 1600 Clifton Road NE, Atlanta, Georgia 30333.                        bacterial resistance to antimicrobial agents and examines
   E-mail address: fnt1@cdc.gov.                                                 the mechanisms of action of commonly used antibacterial

0002-9343/$ -see front matter  2006 by the Association for Professionals in Infection Control and Epidemiology, Inc. and Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2006.03.011
S4                                                                The American Journal of Medicine, Vol 119 (6A), June 2006

drugs and the mechanisms bacteria have developed to over-          cephalosporins, carbapenems, and monobactams, and the
come them.                                                         glycopeptides, including vancomycin and teicoplanin.17,18
                                                                   -Lactam agents inhibit synthesis of the bacterial cell wall
                                                                   by interfering with the enzymes required for the synthesis of
WHY IS RESISTANCE A CONCERN?                                       the peptidoglycan layer.18 Vancomycin and teicoplanin also
There are a number of reasons why bacterial resistance             interfere with cell wall synthesis, but do so by binding to the
should be a concern for physicians. First, resistant bacteria,     terminal D-alanine residues of the nascent peptidoglycan
particularly staphylococci, enterococci, Klebsiella pneu-          chain, thereby preventing the cross-linking steps required
moniae, and Pseudomonas spp,2-7 are becoming common-               for stable cell wall synthesis.18
place in healthcare institutions. Bacterial resistance often           Macrolides, aminoglycosides, tetracyclines, chloram-
results in treatment failure, which can have serious conse-        phenicol, streptogramins, and oxazolidinones produce their
quences, especially in critically ill patients. Inadequate em-     antibacterial effects by inhibiting protein synthesis.17,18
piric antibacterial therapy, defined as the initial use of an      Bacterial ribosomes differ in structure from their counter-
antibacterial agent to which the causative pathogen was not        parts in eukaryotic cells. Antibacterial agents take advan-
susceptible, has been associated with increased mortality          tage of these differences to selectively inhibit bacterial
rates in patients with bloodstream infections due to resistant     growth. Macrolides, aminoglycosides, and tetracyclines bind
Pseudomonas aeruginosa, Staphylococcus aureus, K pneu-             to the 30S subunit of the ribosome, whereas chloramphen-
moniae, Escherichia coli, Enterobacter spp, coagulase-neg-         icol binds to the 50S subunit.
ative staphylococci, and enterococci. 8,9 Prolonged therapy            Fluoroquinolones exert their antibacterial effects by disrupt-
with antimicrobial agents, such as vancomycin or linezolid,        ing DNA synthesis and causing lethal double-strand DNA
may also lead to the development of low-level resistance           breaks during DNA replication,19 whereas sulfonamides and
that compromises therapy, but that may not be detected by          trimethoprim (TMP) block the pathway for folic acid synthe-
routine susceptibility testing methods used in hospital lab-       sis, which ultimately inhibits DNA synthesis.20,21 The com-
oratories.10                                                       mon antibacterial drug combination of TMP, a folic acid ana-
    Resistant bacteria may also spread and become broader          logue, plus sulfamethoxazole (SMX) (a sulfonamide) inhibits 2
infection-control problems, not only within healthcare insti-      steps in the enzymatic pathway for bacterial folate synthesis.
tutions, but in communities as well. Clinically important              Disruption of bacterial membrane structure may be a
bacteria, such as methicillin-resistant S aureus (MRSA)3,11        fifth, although less well characterized, mechanism of action.
and extended-spectrum -lactamase (ESBL)producing E                It is postulated that polymyxins exert their inhibitory effects
coli,12,13 are increasingly observed in the community. In-         by increasing bacterial membrane permeability, causing
fected individuals, including children, often lack identifiable    leakage of bacterial contents.22 The cyclic lipopeptide dap-
risk factors for MRSA, and appear to have acquired their           tomycin apparently inserts its lipid tail into the bacterial cell
infections in a variety of community settings.14,15 Commu-         membrane,23 causing membrane depolarization and even-
nity-associated MRSA strains are typically less resistant to       tual death of the bacterium.
antimicrobial agents than healthcare-associated MRSA, but
are more likely to produce toxins, such as PantonValentine
leukocidin.14 The spread of resistant bacteria within the          MECHANISMS OF RESISTANCE TO
community poses obvious additional problems for infection          ANTIBACTERIAL AGENTS
control, not just in long-term care facilities but also among      Bacteria may manifest resistance to antibacterial drugs
sport teams, military recruits, and even children attending        through a variety of mechanisms. Some species of bacteria
day care centers--a task that is complicated by the in-            are innately resistant to 1 class of antimicrobial agents. In
creased mobility of our population. Finally, with respect to       such cases, all strains of that bacterial species are likewise
the cost-containment pressures of today's healthcare envi-         resistant to all the members of those antibacterial classes. Of
ronment, antibacterial drug resistance places an added bur-        greater concern are cases of acquired resistance, where
den on healthcare costs,16 although its full economic impact       initially susceptible populations of bacteria become resistant
remains to be determined.                                          to an antibacterial agent and proliferate and spread under the
                                                                   selective pressure of use of that agent. Several mechanisms
                                                                   of antimicrobial resistance are readily spread to a variety of
HOW DO ANTIBACTERIAL AGENTS WORK?                                  bacterial genera. First, the organism may acquire genes
Most antimicrobial agents used for the treatment of bacterial      encoding enzymes, such as -lactamases, that destroy the
infections may be categorized according to their principal         antibacterial agent before it can have an effect. Second,
mechanism of action. There are 4 major modes of action: (1)        bacteria may acquire efflux pumps that extrude the antibac-
interference with cell wall synthesis, (2) inhibition of pro-      terial agent from the cell before it can reach its target site
tein synthesis, (3) interference with nucleic acid synthesis,      and exert its effect. Third, bacteria may acquire several
and (4) inhibition of a metabolic pathway (Table 1).17             genes for a metabolic pathway which ultimately produces
   Antibacterial drugs that work by inhibiting bacterial cell      altered bacterial cell walls that no longer contain the binding
wall synthesis include the -lactams, such as the penicillins,      site of the antimicrobial agent, or bacteria may acquire
Tenover    Mechanisms of Antimicrobial Resistance in Bacteria                                                                   S5

mutations that limit access of antimicrobial agents to the        Table 1   Mechanisms of action of antibacterial agents
intracellular target site via downregulation of porin genes.
    Thus, normally susceptible populations of bacteria may         Interference with cell wall synthesis
become resistant to antimicrobial agents through mutation          ---Lactams: penicillins, cephalosporins, carbapenems,
                                                                     monobactams
and selection, or by acquiring from other bacteria the ge-
                                                                   --Glycopeptides: vancomycin, teicoplanin
netic information that encodes resistance. The last event          Protein synthesis inhibition
may occur through 1 of several genetic mechanisms, includ-         --Bind to 50S ribosomal subunit: macrolides,
ing transformation, conjugation, or transduction. Through            chloramphenicol, clindamycin, quinupristin-dalfopristin,
genetic exchange mechanisms, many bacteria have become               linezolid
resistant to multiple classes of antibacterial agents, and         --Bind to 30S ribosomal subunit: aminoglycosides,
                                                                     tetracyclines
these bacteria with multidrug resistance (defined as resis-        --Bind to bacterial isoleucyl-tRNA synthetase: mupirocin
tance to 3 antibacterial drug classes) have become a cause         Interference with nucleic acid synthesis
for serious concern, particularly in hospitals and other           --Inhibit DNA synthesis: fluoroquinolones
healthcare institutions where they tend to occur most com-         --Inhibit RNA synthesis: rifampin
monly.                                                             Inhibition of metabolic pathway: sulfonamides, folic acid
                                                                     analogues
    As noted above, susceptible bacteria can acquire resis-        Disruption of bacterial membrane structure: polymyxins,
tance to an antimicrobial agent via new mutations.18 Such            daptomycin
spontaneous mutations may cause resistance by (1) altering
                                                                     tRNA  transfer RNA.
the target protein to which the antibacterial agent binds by
modifying or eliminating the binding site (e.g., change in
penicillin-binding protein 2b in pneumococci, which results
in penicillin resistance), (2) upregulating the production of    cell lysis, can move resistance genes into previously sus-
enzymes that inactivate the antimicrobial agent (e.g., eryth-    ceptible strains.
romycin ribosomal methylase in staphylococci), (3) down-            Mutation and selection, together with the mechanisms of
regulating or altering an outer membrane protein channel         genetic exchange, enable many bacterial species to adapt
that the drug requires for cell entry (e.g., OmpF in E coli),    quickly to the introduction of antibacterial agents into their
or (4) upregulating pumps that expel the drug from the cell      environment. Although a single mutation in a key bacterial
(efflux of fluoroquinolones in S aureus).18 In all of these      gene may only slightly reduce the susceptibility of the host
cases, strains of bacteria carrying resistance-conferring mu-    bacteria to that antibacterial agent, it may be just enough to
tations are selected by antimicrobial use, which kills the       allow its initial survival until it acquires additional muta-
susceptible strains but allows the newly resistant strains to    tions or additional genetic information resulting in full-
survive and grow. Acquired resistance that develops due to       fledged resistance to the antibacterial agent.18 However, in
chromosomal mutation and selection is termed vertical evo-       rare cases, a single mutation may be sufficient to confer
lution.                                                          high-level, clinically significant resistance upon an organ-
    Bacteria also develop resistance through the acquisition     ism (e.g., high-level rifampin resistance in S aureus or
of new genetic material from other resistant organisms. This     high-level fluoroquinolone resistance in Campylobacter je-
is termed horizontal evolution, and may occur between            juni). The following case studies, which involve 3 different
strains of the same species or between different bacterial       bacterial species, serve to illustrate several of the ways in
species or genera. Mechanisms of genetic exchange include        which bacteria develop resistance to antibacterial drugs and
conjugation, transduction, and transformation.18 For each of     how different resistance mechanisms may interact to in-
these processes, transposons may facilitate the transfer and     crease the level or spectrum of resistance of an organism.
incorporation of the acquired resistance genes into the          Resistance patterns associated with these bacterial patho-
host's genome or into plasmids. During conjugation, a            gens are discussed in greater detail in other articles in this
gram-negative bacterium transfers plasmid-containing resis-      supplement.
tance genes to an adjacent bacterium, often via an elongated
proteinaceous structure termed a pilus, which joins the 2        CASE STUDIES
organisms. Conjugation among gram-positive bacteria is
usually initiated by production of sex pheromones by the         E coli: Development of Resistance to Third-
mating pair, which facilitate the clumping of donor and          Generation Cephalosporins
recipient organisms, allowing the exchange of DNA. During        E coli is a common cause of urinary tract infections and
transduction, resistance genes are transferred from 1 bacte-     bacteremia in humans, and is frequently resistant to amin-
rium to another via bacteriophage (bacterial viruses). This is   openicillins, such as amoxicillin or ampicillin, and narrow-
now thought to be a relatively rare event. Finally, transfor-    spectrum cephalosporins.24-26 Resistance is typically medi-
mation, i.e., the process whereby bacteria acquire and in-       ated by the acquisition of plasmid-encoded -lactamases,
corporate DNA segments from other bacteria that have             such as TEM-1, TEM-2, or SHV-1, which hydrolyze and
released their DNA complement into the environment after         inactivate these drugs.27 Some E coli strains develop resis-
S6                                                                The American Journal of Medicine, Vol 119 (6A), June 2006

tance to third-generation cephalosporins and monobactams           the gene encoding the TEM-1 -lactamase was present in
(i.e., aztreonam) through the acquisition of ESBLs,27,28           all of the isolates, including those that were initially sus-
commonly arising through mutation of TEM-, SHV-, or                ceptible to third-generation cephalosporins, and indicated
CTX-Mtype enzymes. The ESBLs are not active against               the presence of a second -lactamase gene (the SHV type)
cephamycins, such as cefoxitin and cefotetan27-30; however,        in isolates that were resistant to third-generation cephalo-
resistance to cephamycins and other -lactams may arise as          sporins (data not shown).
a result of changes in the porins in the outer membrane               An additional surprise that merited further investigation
(proteins that form the water-filled channels through which        was the fact that several of the E coli isolates also exhibited
drugs and other molecules enter the bacterial cell). Such          resistance to cephamycins (i.e., cefoxitin and cefotetan) in
changes decrease or eliminate the flow of small hydrophilic        addition to the third-generation cephalosporins. Because
molecules like -lactam drugs across the membrane.31-35             ESBLs, like SHV-8, do not mediate resistance to cephamy-
The following case illustrates the interaction of these mech-      cins, this suggested that the E coli isolates had acquired an
anisms of resistance. A 4-year-old girl was admitted to an         additional resistance mechanism, beyond the -lactamases,
urban hospital in Atlanta with aplastic anemia and bactere-        that was responsible for the cephamycin resistance. Analy-
mia. Blood cultures collected during her first week in the         ses of the outer membrane protein profiles of the cefoxitin-
hospital were positive with E coli isolates that were resistant    resistant E coli isolates indicated loss of the major porin
to ampicillin and narrow-spectrum cephalosporins but re-           channel (OmpF) in the E coli outer membrane through
mained susceptible to third-generation cephalosporins. Over        which cephamycins enter the cell (Figure 2). Thus, during
the next 3 weeks, the child received a variety of antimicro-       a period of 2 months in the bloodstream of the 4-year old
bial agents directed against E coli and other suspected            patient, an E coli strain acquired a new -lactamase gene
bacterial pathogens in an attempt to treat her persistent          that mediated resistance to third-generation cephalosporins
fevers and bacteremia. The antibacterial agents included           (SHV-1), mutated the gene to increase the level of cepha-
penicillins (ticarcillin, oxacillin, and mezlocillin), amino-      losporin resistance (SHV-8), and downregulated its cell
glycosides (gentamicin), third-generation cephalosporins           wall porins (OmpF) to increase resistance not only to ceph-
(cefotaxime and ceftazidime), vancomycin, and clindamy-            alosporins but cephamycins as well.
cin. During the fourth week of hospitalization, several E coli
isolates showing increasing resistance to third-generation
cephalosporins were recovered from blood cultures. De-             S Aureus: Development of High-Level
creased susceptibility to aztreonam was also observed. The         Vancomycin Resistance
first resistant isolate showed only a modest increase in the       MRSA is a common cause of infection among hospitalized
minimum inhibitory concentration (MIC) of ceftazidime              patients. Vancomycin is the typical treatment for these in-
and other cephalosporins, but subsequent E coli isolates           fections, but over the last decade there has been increasing
showed much higher cephalosporin MICs, particularly to             concern about the development of MRSA strains with re-
ceftazidime.                                                       duced susceptibility to vancomycin. The first report of an
    Although it is possible that multiple strains of E coli        MRSA strain with reduced susceptibility to vancomycin
were present in this patient's bloodstream, thus accounting        (MIC  8 g/mL, reported as a vancomycin-intermediate S
for the change in antimicrobial susceptibility patterns, bac-      aureus [VISA]) appeared in Japan in 199736; this was fol-
terial strain typing studies indicated that there was only a       lowed by 13 confirmed VISA cases in the United States37
single strain of E coli present. This suggested that the E coli    (Centers for Disease Control and Prevention [CDC], unpub-
isolates had acquired a new resistance mechanism during            lished observations, 2005). The exact mechanism by which
the course of the infection. The -lactamases present in the        VISA isolates become resistant to vancomycin remains un-
bacterial isolates (which were identified using a protein          clear, but it probably involves thickening of the organism's
separation technique known as isoelectric focusing) indi-          cell wall due to the accumulation of cell wall fragments
cated that all the E coli isolates contained a TEM-1 -lac-         capable of binding vancomycin extracellularly, and changes
tamase (isoelectric point 5.4) (Figure 1), whereas the first       in several metabolic pathways that slow cell growth.38,39
isolate with low-level ceftazidime resistance contained, in        This was not the mechanism of vancomycin resistance
addition, a new -lactamase, SHV-1, which was produced              many researchers had predicted, which was the acquisition
in large quantities. The -lactamase studies also indicated         of the vanA vancomycin resistance gene from enterococci.
that high-level ceftazidime resistance was associated with a       Noble and coworkers40 demonstrated that transfer of the
mutated form of SHV-1 (which was designated SHV-8),                vanA resistance gene from Enterococcus faecalis to S au-
with a broader spectrum of resistance. (The change in a            reus was feasible in an in vitro model and on the skin of a
single amino acid, from aspartate to asparagine, at position       mouse. Indeed, it was this transfer of vanA in nature, leading
178, as documented by DNA sequence analysis of the re-             to emergence of a highly vancomycin resistant S aureus
sistance gene, was responsible for the increased resistance        (VRSA) strain (with MICs likely to be 256 g/mL), that
level).30 Polymerase chain reaction assays, designed to de-        caused concern among clinicians, microbiologists, and pub-
tect various -lactamase resistance genes, confirmed that           lic health officials. Those fears became a reality with the
Tenover    Mechanisms of Antimicrobial Resistance in Bacteria                                                                       S7




Figure 1 Isoelectric focusing for -lactamases. The -lactamases present in the bacterial isolates indicate that all the Escherichia coli
isolates contain a TEM-1 -lactamase (isoelectric point 5.4) (lanes AC and GI), whereas the first isolate with low-level ceftazidime
resistance also contains SHV-1, a new -lactamase that was produced in large quantities (lane G). High-level ceftazidime resistance is
associated with a mutated form of SHV-1, with a broader spectrum of resistance (designated SHV-8) (lanes AC).




Figure 2 Porin profiles of Escherichia coli isolates. Cefoxitin-resistant strains are missing OmpF porin; OmpF is the channel through
which cephamycins and other cephalosporins enter the cell.


first reported case of VRSA in the United States in July              total of 6.5 weeks of vancomycin therapy over a 6-month
2002.41,42                                                            period. In mid June 2002, cultures of exudates from the
    The first case of VRSA involved a 40-year-old woman               catheter exit site and the catheter tip specimen grew both
from Michigan who was undergoing dialysis. The patient                VRSA and vancomycin-resistant E faecalis (VRE). Heel
had diabetes mellitus, hypertension, peripheral vascular dis-         cultures also became positive with VRSA. Table 2 shows
ease, and chronic renal failure.42 She developed chronic foot         the susceptibility pattern for the VRSA isolated from the
ulcers that eventually became infected with MRSA. Recur-              exit-site wound.42 The VRSA exhibited high-level resis-
rent infections of the foot ulcers led to amputation of the           tance to vancomycin (MIC  1,024 g/mL) and various
right first metatarsal in February 2002 and the fourth meta-          other antibacterial agents, but remained susceptible to
tarsal in April 2002. During the last hospitalization, the            quinupristin-dalfopristin, TMP-SMX, and linezolid.
patient developed MRSA bacteremia and an abscess asso-                   The recovery of MRSA and VRE at the infection site
ciated with a graft for dialysis access. The patient underwent        suggested that transfer of a vanA vancomycin resistance
a number of catheterizations during this time and received a          gene from VRE to MRSA had occurred, most likely by
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