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Antimicrobial therapy is a key component of modern medical practice and a cornerstone for the development of
complex clinical interventions in critically ill patients. Unfortunately, the increasing problem of antimicrobial
resistance is now recognized as a major public health threat jeopardizing the care of thousands of patients
worldwide. Gram-positive pathogens exhibit an immense genetic repertoire to adapt and develop resistance
to virtually all antimicrobials clinically available. As more molecules become available to treat resistant
gram-positive infections, resistance emerges as an evolutionary response. Thus, antimicrobial resistance has
to be envisaged as an evolving phenomenon that demands constant surveillance and continuous efforts to iden-
tify emerging mechanisms of resistance to optimize the use of antibiotics and create strategies to circumvent this
problem. Here, we will provide a broad perspective on the clinical aspects of antibiotic resistance in relevant
gram-positive pathogens with emphasis on the mechanistic strategies used by these organisms to avoid being
killed by commonly used antimicrobial agents.
Keywords. antimicrobial resistance; multidrug-resistant; methicillin-resistant; vancomycin-resistant;
penicillin-resistant.
The discovery and commercialization of antimicrobials that failure to tackle it could jeopardize modern medical
revolutionized modern medicine and became a major achievements [2].
tool for the development of complex medical interven- MDR gram-positive organisms are major human
tions, such as cancer therapy, organ transplantation, pathogens, causing both healthcare- and community-
and management of the critically ill. Unfortunately, an- associated infections. Among them, methicillin-resistant
timicrobial resistance is now threatening the care of Staphylococcus aureus (MRSA), vancomycin-resistant
such patients. Indeed, infections caused by multidrug- Enterococcus faecium (VRE), and drug-resistant Strep-
resistant (MDR) organisms are associated with signi- tococcus pneumoniae have been designated as serious
ficant mortality and carry an important economic public threats by the US Centers for Disease Control
burden, estimated at >$20 billion per year, just in the and Prevention [1]. Indeed, MRSA and VRE are lead-
United States [1]. Furthermore, the World Health Orga- ing causes of healthcare-associated infections in the
nization has identified antimicrobial resistance as one of United States, with conservative estimates suggesting
the most serious health threats worldwide and suggested they cause >12 000 deaths per year. Similarly, infections
due to drug-resistant S. pneumoniae, the main cause of
bacterial pneumonia and meningitis in adults, are esti-
Correspondence: Cesar A. Arias, MD, PhD, University of Texas Medical School at mated to cause 19 000 excess admissions and 7000
Houston, 6431 Fannin St, MSB 2.112, Houston, TX 77030 (cesar.arias@uth.tmc. deaths per year in the United States alone [1].
edu).
Clinical Infectious Diseases® 2015;61(S2):S48–57 The genetic and biochemical bases of antimicrobial
© The Author 2015. Published by Oxford University Press on behalf of the Infectious resistance in gram-positive bacteria are diverse and
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
they frequently differ within genera and/or species.
DOI: 10.1093/cid/civ523 Further, evolution of bacterial resistance is tightly
Pathogen and
Resistance Strategy Antibiotic Gene(s) Involved Comments
Staphylococci
Drug inactivation β-lactams (penicillins with blaZ Plasmid-encoded β-lactamase that hydrolyzes penicillins;
or without cefazolina) isoxazolyl penicillins (eg, nafcillin), cephalosporins,a and
carbapenems are stable
Target replacement β-lactams mecA PBP2a has low affinity for β-lactams (except ceftaroline and
ceftobiprole)
Vancomycin (VRSA) vanA Gene cluster Acquired from enterococci; rare isolates described
Target modification Linezolid 23S rRNA genes, L3/L4 Mutations in 23S rRNA genes are main mediators of
ribosomal proteins resistance; cfr gene is the only transferable determinant
cfr of LNZ-R
Ceftaroline pbp2a Mutations in pbp2a associated with high-level ceftaroline
resistance (MIC >32 µg/mL)
Changes in cell Vancomycin (VISA) vraRS, yycFG, graRS, rpoB Many genes involved in the resistance phenotype, most
surface related to regulatory systems
adaptation Daptomycin mprF, dlt, Many genes involved in the resistant phenotype; main
vraRS, yycFG, pgsA, cls pathway seems to be repulsion of the antibiotic through
an increase in the net positive charge of the cell envelope
Enterococci
Drug inactivation β-lactams (penicillins) blaZ Rare, found mostly in E. faecalis
Target replacement Vancomycin van Gene clusters Several gene clusters described, most acquired on mobile
elements; intrinsic low-level resistance seen in
E. gallinarium and E. casseliflavus (VanC phenotype)
Target modification β-lactams (penicillin and pbp5 b PBP5-R differs from PBP5-S in only about 5% of amino acid
ampicillin) sequence; certain amino acid substitutions have been
directly implicated in ampicillin resistance (see text)
Linezolid 23S rRNA genes, L3/L4 Rare, mutations in 23S rRNA and L3/L4 are similar to those
ribosomal proteins, cfr found in staphylococci, as is the cfr gene
Changes in cell Daptomycin liaFSR, yycGF, gdpD, Most frequent mutations found in daptomycin-resistant
surface cls clinical isolates; many genes involved; resistance
adaptation pathways differ between E. faecalis and E. faecium
Streptococci
Target modification β-lactams (penicillin) PBPs (pbp2x, pbp2b in PBP changes are the most important determinant of
pneumococci), β-lactam resistance; mosaic PBPs are often found in
murM, cpoA, pdgA penicillin-resistant isolates
Linezolid 23S rRNA genes, L3/L4 Rare
ribosomal proteins, cfr
Unknown Daptomycin Unknown Rapid development of daptomycin resistance in certain
species of streptococci
Abbreviations: LNZ-R, linezolid resistance; MIC, minimum inhibitory concentration; PBP, penicillin-binding protein; rRNA, ribosomal RNA; VISA, vancomycin-
intermediate Staphylococcus aureus; VRSA, vancomycin-resistant S. aureus.
a
The ability of certain types of staphylococcal β-lactamase to hydrolyze cefazolin may cause therapeutic failures.
b
PBP5 (encoded by pbp5) is part of the core genome of enterococci. Because of its decreased affinity for penicillin, it is responsible for the natural tolerance of these
organisms to β-lactams.
sequence variation of the pbp5 allele identified specific differ- low over the years and has been described in only a few E. fae-
ences between ampicillin-susceptible and ampicillin-resistant cium isolates [18].
isolates (harboring pbp5-S and pbp5-R alleles, respectively),
suggesting evolutionary adaptation [17]. Indeed, PBP5-R and β-Lactam Resistance in Pneumococci
PBP5-S sequences differ in approximately 5%, at the amino Streptococcus pneumoniae is naturally susceptible to most anti-
acid level, although no particular change has been consistently microbials, including penicillins, long considered the first-line
correlated with specific increases in the ampicillin MIC. Finally, therapy for pneumococcal infections. Current Clinical and Lab-
β-lactamase–mediated ampicillin resistance has also been de- oratory Standards Institute break points for parenteral penicil-
scribed in enterococcal isolates. Initially found in E. faecalis in lin establish that isolates not causing meningitis are categorized
the early 1980s, the frequency of this mechanism has remained as susceptible, intermediate, or resistant, with MICs of ≤2, 4,
addition, several outbreaks of cfr-positive S. aureus and S. epi- Although cfr has been reported in clinical enterococcal isolates
dermidis have been reported, and a 2013 report implicated cfr in [54], its overall frequency continues to be low.
local endemicity of LNZ-R in a hospital in Madrid [51]. Tedi-
zolid resistance has been described in vitro, and the main mech- LNZ-R Streptococci
anism relates to changes in the 23S rRNA (including the Very few cases of LNZ-R streptococci have been described, in-
presence of a dual-mutation T2571C plus G2576T) [52]. cluding sporadic reports of LNZ-R S. pneumoniae, Streptococ-
cus sanguinis, and S. oralis. In addition, the cfr gene was
LNZ-R Enterococci reported from a Streptococcus suis isolate of porcine origin
The first described LNZ-R clinical isolates were E. faecium re- [55]. In a 2014 report, no resistance was found in 6691 pneumo-
covered from patients receiving linezolid as part of a compas- cocci, 2463 viridans streptococci, or 4153 β-hemolytic strepto-
sionate program. As seen in other bacteria, the prevalence of cocci [53].
LNZ-R enterococci has remained low. Data from 6718 entero-
coccal isolates tested from 2004 to 2012 showed that the preva- DAPTOMYCIN RESISTANCE
lence of LNZ-R consistently remained <0.9% [53]. Mutations in
the 23S rRNA genes are the most frequently identified changes. Daptomycin (DAP) is a bactericidal lipopeptide antibiotic ac-
In fact, of 48 LNZ-R E. faecalis and 121 E. faecium, these tive against a wide range of gram-positive clinical pathogens.
mutations were the only identified resistance trait in 73% and It damages the cell membrane (CM) in a calcium-dependent
88% of isolates, respectively [45]. Furthermore, only 3 E. faeci- manner, interacting with its target mostly at the bacterial
um isolates harbored changes in the L3/L4 ribosomal proteins. division septum. Importantly, the presence of specific CM
Figure 2. Proposed mechanisms of action and resistance to daptomycin in Gram-positive organisms. A, The daptomycin-calcium complex interacts with
the cell membrane mainly at septal areas. B, In Enterococcus faecalis, the antibiotic is diverted from the septum (black arrow) in a process associated with
redistribution of anionic phospholipid microdomains (eg, cardiolipin) away from the septal plane. C, In Staphylococcus aureus and Enterococcus faecium, the
positively charged daptomycin-calcium complex is “repelled” from the cell surface in a process associated with increase in the net positive charge of the
cell envelope (not all strains). Abbreviations: DAP-R, daptomycin-resistant; DAP-S, daptomycin-susceptible.