NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Carbapenem Resistant Enterobacteriaceae

Authors

Hayden Z. Smith1; Brian Kendall2.

Affiliations
1 Creighton University
2 Providence

Last Update: January 16, 2023.

Continuing Education Activity

Gram-negative bacterial resistance to antibiotics has decreased the physician’s ability to combat infection.
Carbapenems are the most potent beta-lactam antibiotics for resistant bacteria, but carbapenem-resistant bacteria
inactivate this class of antibiotics. This activity outlines the evaluation and management of carbapenem-resistant
infections and reviews the role of the interprofessional healthcare team in evaluating, treating, and managing patients
with this condition.

Objectives:

Outline the treatment considerations for a patient with carbapenem-resistant Enterobacteriaceae infections.

Describe the reasons for a delayed diagnosis of carbapenem-resistant bacterial infections.

Review the etiology of carbapenem-resistance and its various mechanisms.

Identify the importance of collaboration and communications among the interprofessional team to improve
outcomes for patients affected by carbapenem-resistant bacterial infections.

Access free multiple choice questions on this topic.

Introduction
Antibiotic resistance is a growing problem. Resistance genes exist for all known antibiotics in use today, and
extremely resistant pathogens are becoming more common. Gram-negative bacteria have developed the broadest
spectrum of resistance due to multiple structural adaptations and antibiotic degradation enzymes, including expanded
spectrum beta-lactamases (ESBL), AmpC cephalosporinases, and carbapenemases. Carbapenemase-producing
Enterobacteriaceae (CRE) are of particular concern.

Carbapenem antibiotics are typically reserved for treating ESBL and AmpC producing bacteria.[1] Structurally,
carbapenems are similar to penicillins but have the addition of a carbapenem ring. Both antibiotics degrade the
bacterial cell wall at the penicillin-binding protein via a beta-lactam ring. The carbapenem groups of these antibiotics
act to protect the beta-lactam ring from some degratory enzymes produced by the bacterium.

Care is necessary when diagnosing, treating, and preventing CRE infections. Bacteria may have multiple resistance
mechanisms to carbapenems, but the most common is carbapenemase enzyme production.[2][3][4] These
carbapenemase-producing carbapenem-resistant Enterobacteriaceae (cpCRE) use diverse moieties to degrade
antibiotics. Other resistance mechanisms include increased efflux pump-action and specific porin blocking at the
bacterial cell membrane to limit permeability of the antibiotics, rendering them ineffective.

Etiology
Carbapenemase enzymes categorize into three groups: Ambler Class A, B, and D.

The most common Class A carbapenemases include KPC (Klebsiella pneumoniae carbapenemase) and IMI
(Imipenem-hydrolysing beta-lactamase). KPC is the most prevalent carbapenemase gene amongst all cpCRE.[5]
Class B is defined by a metallo-beta-lactamases (MBL) structures. These enzymes include NDM (New Delhi metallo-
lactamase), IMP (Imipenem-resistant Pseudomonas), and VIM (Verona integron-encoded metallo-lactamase). These
carbapenemases are usually found on plasmid vectors and other transposable elements, allowing them to spread
between bacteria. Due to a high sequence variability of 15% to 70%, these enzymes are difficult to detect with
molecular testing, slowing investigations to more fully understand their prevalence.[5]

OXA (Oxacillin-hydrolysing carbapenemase) enzymes make up class D carbapenemases. These genes are genetically
similar to ESBL genes, thus making them difficult to differentiate on molecular testing from other ESBL producers.
[4] OXA-48 is the most common isolate in this class and is typically found in Klebsiella pneumoniae.

Epidemiology
Class A KPC is the most common cpCRE. It is endemic to regions in China, India, Saudi Arabia, Greece, Columbia,
and Brazil, but rare in the United States, Australia, and France.[6] Little is known about cpCRE prevalence in
Africa. Current epidemiology suggests NDM-1 as the most common cause of carbapenem resistance.[7] Due to
international travel, researchers have identified all carbapenemase genes throughout the world.

Molecular testing has been the most effective way of understanding the epidemiology and spread of cpCRE. It can
identify specific strains of CRE and map their range within a hospital or across the world. Though uncommon,
regional genetic drift in carbapenemase genes may hinder the molecular identification of CRE strains, which could
cause phenotypic resistance that is missed by assays that detect specific gene sequences.

Patients usually acquire cpCRE infections in the hospital and long term care facilities.[8] The majority of these
patients have a long history of health-care facility exposure due to unrelated diagnoses. If a patient is found to have a
CRE infection, healthcare personnel need to utilize proper infection control protocols for the prevention of localized
outbreaks.

Pathophysiology
The prototypical beta-lactam antibiotic, penicillin G, is a simple beta-lactam ring with few R groups. It impairs the
function of the bacterial cell wall at the penicillin-binding protein (PBP), leading to the destruction of the organism.
The synthesis of beta-lactamases can induce bacterial resistance to this antibiotic. These enzymes hydrolyze penicillin
at its beta-lactam ring. Variations of penicillins like cephalosporins or carbapenems have a similar mechanism of
action at the PBP but can shield their beta-lactam ring from beta-lactamases with R groups on the adjacent
thiazolidine ring without hindering the beta-lactam function. Bacterial beta-lactamases have evolved to circumvent
the carbapenem R group shield rendering the antibiotic susceptible to degradation. Carbapenemases are beta-
lactamases active against carbapenem antibiotics.

Pathogenic bacteria have gained the ability to circumvent carbapenem hydrolysis through intrinsic and acquired
mechanisms. These mechanisms include enzymatic inactivation, porin selectivity, and efflux pumps. The earliest
instances of carbapenem resistance appeared in bacteria with intrinsic resistance. These bacteria are typically
opportunistic pathogens or environmental organisms that rarely cause infection. Aeromonas hydrophilia, Serratia
marcescens, and Enterobacter cloacae were some of the first environmental organisms discovered to cause
carbapenem resistance infections[9]. Researchers found extrinsic resistance on plasmids, which spread via bacterial
conjugation and which they discovered a few years after first describing intrinsic carbapenem resistance.[10]

Because Gram-negative bacteria have a cell wall and cell membrane, they are better able to control what molecules
pass through their outer membrane. This wall/membrane means bulky carbapenem molecules require transport into
the bacterial intermembrane space via porin channels to break down the PBP. Thus, porin channels may act as a filter
preventing carbapenems from reaching their site of action. Efflux pumps work at this space to remove the irregular or
hostile molecules and antibiotics, further regulating the intramembrane environment. The majority of non-cpCRE
resistance mechanisms act at this space to prevent degradation of the cell’s defenses without the production of a
carbapenem specific beta-lactamase.[4] Researchers well understand that Pseudomonas has intrinsic resistance to
ertapenem, and the likely reason is due to the lack of a porin that will let the large ertapenem molecule into the
intermembrane space. In some strains, Pseudomonas aeruginosa uses a combination of increased efflux pump
expression with down-regulation of OprD porin, leading to increased imipenem resistance. OprD porin resistance to
imipenem has also appeared in Enterobacter aerogenes and Klebsiella spp.[11]

History and Physical

Many sites can be the source of CRE, including the urinary tract, lungs, abdomen, surgical site, and bloodstream.
Typically patients with CRE infections have a history of long term exposure to health care facilities usually due to
unrelated comorbidity. This exposure usually coincides with long term and varied antibiotic use leading to the gradual
development of more and more resistant bacterial infections. Other risk factors include travel to an endemic area of
CRE, immunocompromised state, mechanical ventilation, and advanced age. All these factors combine to make
healthcare-associated CRE the most important factor in the spread of carbapenem resistance and are key points in a
patient’s history.

CRE genes do not confer increased pathogenicity, making initial presentation similar to other infections caused by a
less resistant strain of the same organism. The key indicator of CRE infections may be the uncontrolled progression of
the illness, leading to a more advanced disease state despite empiric antibiotic intervention. Therapeutic failure of
empiric therapy may indicate a resistant organism, possibly CRE; a definitive diagnosis of CRE takes place in the lab
via phenotypic or molecular techniques.

Evaluation
Phenotypic diagnosis requires bacterial culture and identification. Disk diffusion or automated susceptibility testing is
done to identify the carbapenem resistance phenotype. By referencing MIC breakpoints, the final diagnosis of
carbapenem resistance is possible. The drawbacks of this process include delayed diagnosis and limited information
on specific resistance mechanisms.

Molecular identification is much faster (hours instead of days) and can quickly determine the type of resistance
mechanism involved. However, this method simply indicates the presence of a resistance gene and may not determine
the efficacy of specific antibiotics. Early detection of CRE infections helps improve treatments and decrease the
likelihood of spreading the infection. The most common modality of detection is multiplex PCR and microarray
technologies. The development of new molecular assays continues.

Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) is the newest technology applied to the
identification of CRE. This technique uses laser ionization of bacterial proteins to create a proteomic profile. Beta-
lactamase and metallo-beta-lactamase specific information are then extrapolated from the profile to determine CRE
status.[12] This method is demonstrated to have 98.9% and 97.1% sensitivity and specificity, respectively. Cost, lack
of access to MALDI-TOF units, and relative newness of this method are the most significant barriers to further
utilization of this diagnostic modality.

Treatment / Management
Treatment of CRE depends on the site of infection, pathogen isolated, resistance profile, and species-specific native
resistances (see Table 1). Since CRE have developed resistance to preferred antibiotics, second-line therapies are
necessary. Due to the complexity and variability of possible treatments, plans should be driven by in vitro
susceptibility testing.[13] An infectious disease specialist and microbiologist should be consulted. Antibiotics that
may have activity against CRE include carbapenems, polymyxins, aminoglycosides, tigecycline, fosfomycin, and
beta-lactam/beta-lactamase inhibitors (BLBLI).

Combination therapy with multiple unrelated antimicrobial agents has been shown to decrease mortality in the setting
of high-risk infections where death is a likely outcome. These data are best described in bloodstream infections (BSI)
and septic shock with Class A carbapenemase-producing organisms. Typically treatment is centered on a polymyxin
backbone coupled with other targeted antibiotics (see Table 2). This data has its basis from meta-analyses of different
CRE therapies, which demonstrated lower mortalities when using polymyxin based treatment, and researchers found
synergy between the triple combination of polymyxin, carbapenem, and rifampin or tigecycline.[14][15][16]
[17] Where available, fosfomycin has also shown increased effectivity in CRE infections and may be considered in
triple therapy.[18] In theory, carbapenems (ideally with MIC <16), may have some activity when used in combination
with antibiotics of different mechanisms.[15][17] It bears mention these conclusions are extrapolated from a handful
of mainly retrospective studies, and further research is needed. Less evidence exists for the role of carbapenem/beta-
lactamase inhibitors (CBLI) for treating high-risk infections, but may be considered as a carbapenem alternative in
triple therapy.[19]

Relative contraindications for specific dual therapy include polymyxin with an aminoglycoside due to increased
kidney injury. Antibiotics from the same class may be contraindicated due to an increase in toxic side effects without
added therapeutic benefit. Less data is available for the treatment of infections due to Class B and D carbapenemases.
Limited data suggest targeted dual and triple therapy with a similar polymyxin backbone for the treatment of OXA
and MBL producing CRE[20].

Polymyxin-resistance CRE (see Table 1) should have treatment with a tigecycline backbone and either an
aminoglycoside, fosfomycin, or polymyxin and rifampin depending on susceptibilities.[2][3][21] If facing a pan-
resistant infection, a cocktail of meropenem, plus ertapenem (double carbapenem regimen) or ceftazidime-avibactam,
plus aztreonam has been a suggestion despite in vitro resistance to individual antibiotics due to presumed synergistic
activity, though data in this subgroup is poor.[20] If available, investigational drugs and therapies could merit
consideration in the setting of pan-resistance.

Treatment of non-life threatening CRE infections continues to be driven by susceptibility testing. Although no
randomized control trials have been done in this population strictly comparing monotherapy to combination therapy,
there is little evidence demonstrating decreased mortality with polymyxin based combination therapy to targeted
monotherapy.[22][21] Careful monitoring of disease progression and emerging resistance is advisable if using
monotherapy in treating such infections.

Complicated urinary tract infections (cUTI) with CRE present in patients with recurrent UTI who have had repeated
exposure to multiple antibiotics. Susceptibility and urine drug concentrations should drive effective antibiotic therapy.
Aminoglycosides and fosfomycin are preferred therapies for cUTI if susceptible.[18] KPC is typically resistant to
aminoglycosides and fosfomycin, making tigecycline and colistin useful in these cases.  Meropenem-vaborbactam
monotherapy has been demonstrated effective against KPC-producing bacteria and now has FDA approval for cUTI;
however, OXA and MBL CRE can be resistant to this antibiotic.[19]

When treating complicated intra-abdominal infections (cIAI) and soft tissue infections, tissue perfusion, and
susceptibility testing help to guide therapy. Tigecycline is often useful as initial therapy for antibiotic-resistant cIAI,
but newer BLBLI are becoming increasingly popular.[20][23] Ceftazidime-avibactam and meropenem-vaborbactam
reach adequate tissue levels in the abdomen and are effective treatments.[20] The research on this is limited, but
ceftazidime-avibactam shows efficacy in vitro during animal studies against KPC and OXA-48 producing CRE.
[24] Also, some research suggests the addition of metronidazole improves outcomes of cIAI in CRE infections.[25]

When treating bloodstream infections (BSI), it is important to note that standard dose tigecycline does not usually
reach therapeutic blood levels. Doubling the dose to 200 mg for loading and continuing therapy with 100 mg twice
daily has been recommended.[26] Fosfomycin should not be used as monotherapy when treating BSI in countries
where intravenous formulations are available.

Polymyxin B or inhaled colistin are possible antibiotics for the treatment of localized pneumonia due to CRE, and
commonly used in cycstic fibrosis patients.[27] Tigecycline and aminoglycosides are effective treatments for
pneumonia when susceptible, but have poor lung penetration. Thus higher doses should be considered when using
these antibiotics to treat pulmonary infections.

Differential Diagnosis
Possible causes of carbapenem antibiotic resistance:

Carbapenemase production

Decreased porin expression

Increased efflux pump action

Complications
Complicating factors during diagnosis and treatment of CRE is identifying resistance to previously discussed drug
regimens. Commonly induced resistance mechanisms in CRE to other active antimicrobials include aminoglycosides,
fosfomycin, and BLBLI.

The acquisition of a single point mutation in the 16S rRNA methyltransferase leads to resistance of all
aminoglycosides.[28] This mutation can occur de novo or in combination with other resistance mechanisms. It is best
studied in NDM cpCRE but can also be present in many other carbapenem producers.[29] Fosfomycin resistance is
common in E.coli, but many other Enterobacteriaceae, including ESBL and CRE, do not demonstrate resistance.
Resistance to this drug is typically seen by selecting for resistant microbes through monotherapy of fosfomycin.
[30] Ceftazidime-avibactam generally is used for OXA-48 and KPC CRE, but when resistance appears among these
isolates, mutations in bla and bla induce resistance, respectively.[31]

Consultations
If a patient demonstrates infection with CRE, an infectious disease consult is necessary. Specialized tests may also
need to be run by a microbiologist and thus should be involved in definitive diagnosis and treatment planning.

Deterrence and Patient Education

Any CRE infection is considered complicated, and patients need to understand the risks of their disease. They must
understand the risks and benefits of specific therapies for CRE, as well. These risks include but not limited to,
nephrotoxicity, ototoxicity, GI effects, QTc prolongation, and paresthesia. In the event of recurrent or colonized CRE,
patients should be aware of the increased future risk of pathogenic CRE.

Enhancing Healthcare Team Outcomes

CRE outbreaks are usually uncommon and isolated to institutional or geographic regions. The prevalence of
community-acquired CRE has been reported to be 0% to 29.5%, and early screening detection of CRE-colonization in
patients can help prevent or limit outbreaks via proper isolation methods.[4] Long term care facilities have been
shown to have lower rates of CRE than acute care hospitals, but this may be due to poor detection and surveillance
methods.[32] Any healthcare facility should be aware of the risk CRE poses to patients and should take part in regular
institutional, local, and national surveillance. An epidemiological assessment should accompany any case of CRE into
etiology to limit further spread.

Examples of how an interprofessional team approach applies in the case of CRE infections is bringing in an infectious
disease specialist, as well as an infectious disease board-certified pharmacist. They will be more familiar with the
latest antibiogram data and resistance patterns and help the team to focus therapy appropriately. Nurses need to be
familiar with the proper administration of these drugs, as well as their common adverse events so that they can report
any concerns to the team as they develop. These scenarios demonstrate how an interprofessional team can best
address the management of therapy for these infections. [Level 5]

Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

References
1. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment
of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and
meta-analysis. J Antimicrob Chemother. 2012 Dec;67(12):2793-803. [PubMed: 22915465]
2. Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella
pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev. 2012
Oct;25(4):682-707. [PMC free article: PMC3485753] [PubMed: 23034326]
3.
Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, Cornaglia G, Garau J, Gniadkowski
M, Hayden MK, Kumarasamy K, Livermore DM, Maya JJ, Nordmann P, Patel JB, Paterson DL, Pitout J, Villegas
MV, Wang H, Woodford N, Quinn JP. Clinical epidemiology of the global expansion of Klebsiella pneumoniae
carbapenemases. Lancet Infect Dis. 2013 Sep;13(9):785-96. [PMC free article: PMC4673667] [PubMed: 23969216]
4. Codjoe FS, Donkor ES. Carbapenem Resistance: A Review. Med Sci (Basel). 2017 Dec 21;6(1) [PMC free article:
PMC5872158] [PubMed: 29267233]
5. Marsik FJ, Nambiar S. Review of carbapenemases and AmpC-beta lactamases. Pediatr Infect Dis J. 2011
Dec;30(12):1094-5. [PubMed: 22105420]
6. Perez F, Van Duin D. Carbapenem-resistant Enterobacteriaceae: a menace to our most vulnerable patients. Cleve
Clin J Med. 2013 Apr;80(4):225-33. [PMC free article: PMC3960994] [PubMed: 23547093]
7. Poirel L, Benouda A, Hays C, Nordmann P. Emergence of NDM-1-producing Klebsiella pneumoniae in Morocco.
J Antimicrob Chemother. 2011 Dec;66(12):2781-3. [PubMed: 21930570]
8. Arnold RS, Thom KA, Sharma S, Phillips M, Kristie Johnson J, Morgan DJ. Emergence of Klebsiella pneumoniae
carbapenemase-producing bacteria. South Med J. 2011 Jan;104(1):40-5. [PMC free article: PMC3075864]
[PubMed: 21119555]
9. Franco MR, Caiaffa-Filho HH, Burattini MN, Rossi F. Metallo-beta-lactamases among imipenem-resistant
Pseudomonas aeruginosa in a Brazilian university hospital. Clinics (Sao Paulo). 2010;65(9):825-9. [PMC free
article: PMC2954731] [PubMed: 21049207]
10. Sotgiu G, Are BM, Pesapane L, Palmieri A, Muresu N, Cossu A, Dettori M, Azara A, Mura II, Cocuzza C,
Aliberti S, Piana A. Nosocomial transmission of carbapenem-resistant Klebsiella pneumoniae in an Italian
university hospital: a molecular epidemiological study. J Hosp Infect. 2018 Aug;99(4):413-418. [PubMed:
29621600]
11. Doumith M, Ellington MJ, Livermore DM, Woodford N. Molecular mechanisms disrupting porin expression in
ertapenem-resistant Klebsiella and Enterobacter spp. clinical isolates from the UK. J Antimicrob Chemother.
2009 Apr;63(4):659-67. [PubMed: 19233898]
12. Sparbier K, Schubert S, Weller U, Boogen C, Kostrzewa M. Matrix-assisted laser desorption ionization-time of
flight mass spectrometry-based functional assay for rapid detection of resistance against β-lactam antibiotics. J
Clin Microbiol. 2012 Mar;50(3):927-37. [PMC free article: PMC3295133] [PubMed: 22205812]
13. Rodríguez-Baño J, Cisneros JM, Gudiol C, Martínez JA. Treatment of infections caused by carbapenemase-
producing Enterobacteriaceae. Enferm Infecc Microbiol Clin. 2014 Dec;32 Suppl 4:49-55. [PubMed: 25542052]
14. Lee J, Patel G, Huprikar S, Calfee DP, Jenkins SG. Decreased susceptibility to polymyxin B during treatment for
carbapenem-resistant Klebsiella pneumoniae infection. J Clin Microbiol. 2009 May;47(5):1611-2. [PMC free
article: PMC2681849] [PubMed: 19261795]
15. Gomez-Simmonds A, Nelson B, Eiras DP, Loo A, Jenkins SG, Whittier S, Calfee DP, Satlin MJ, Kubin CJ,
Furuya EY. Combination Regimens for Treatment of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream
Infections. Antimicrob Agents Chemother. 2016 Jun;60(6):3601-7. [PMC free article: PMC4879408] [PubMed:
27044555]
16. Lee GC, Burgess DS. Treatment of Klebsiella pneumoniae carbapenemase (KPC) infections: a review of
published case series and case reports. Ann Clin Microbiol Antimicrob. 2012 Dec 13;11:32. [PMC free article:
PMC3552987] [PubMed: 23234297]
17. Giannella M, Trecarichi EM, Giacobbe DR, De Rosa FG, Bassetti M, Bartoloni A, Bartoletti M, Losito AR, Del
Bono V, Corcione S, Tedeschi S, Raffaelli F, Saffioti C, Spanu T, Rossolini GM, Marchese A, Ambretti S, Cauda
R, Viscoli C, Lewis RE, Viale P, Tumbarello M., Italian Study Group on Resistant Infections of the Società
Italiana Terapia Antinfettiva (ISGRI-SITA). Effect of combination therapy containing a high-dose carbapenem
on mortality in patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection. Int J
Antimicrob Agents. 2018 Feb;51(2):244-248. [PubMed: 28842283]
18. Livermore DM, Warner M, Mushtaq S, Doumith M, Zhang J, Woodford N. What remains against carbapenem-
resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline,
nitrofurantoin, temocillin and tigecycline. Int J Antimicrob Agents. 2011 May;37(5):415-9. [PubMed: 21429716]
19. Lee Y, Kim J, Trinh S. Meropenem-Vaborbactam (Vabomere™): Another Option for Carbapenem-Resistant
Enterobacteriaceae. P T. 2019 Mar;44(3):110-113. [PMC free article: PMC6385729] [PubMed: 30828230]
20.
Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Machuca I, Pascual A. Treatment of Infections Caused by Extended-
Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae. Clin Microbiol Rev. 2018
Apr;31(2) [PMC free article: PMC5967687] [PubMed: 29444952]
21. Shiber S, Yahav D, Avni T, Leibovici L, Paul M. β-Lactam/β-lactamase inhibitors versus carbapenems for the
treatment of sepsis: systematic review and meta-analysis of randomized controlled trials. J Antimicrob
Chemother. 2015 Jan;70(1):41-7. [PubMed: 25261419]
22. Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Paño-Pardo JR, Venditti M, Tumbarello M,
Daikos G, Cantón R, Doi Y, Tuon FF, Karaiskos I, Pérez-Nadales E, Schwaber MJ, Azap ÖK, Souli M, Roilides
E, Pournaras S, Akova M, Pérez F, Bermejo J, Oliver A, Almela M, Lowman W, Almirante B, Bonomo RA,
Carmeli Y, Paterson DL, Pascual A, Rodríguez-Baño J., REIPI/ESGBIS/INCREMENT Investigators. Effect of
appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-
producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis. 2017
Jul;17(7):726-734. [PubMed: 28442293]
23. Kelesidis T, Karageorgopoulos DE, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant
Enterobacteriaceae: a systematic review of the evidence from microbiological and clinical studies. J Antimicrob
Chemother. 2008 Nov;62(5):895-904. [PMC free article: PMC8445635] [PubMed: 18676620]
24. van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-
Lactamase Inhibitor Combinations. Clin Infect Dis. 2016 Jul 15;63(2):234-41. [PMC free article: PMC4928383]
[PubMed: 27098166]
25. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, Llorens L, Newell P, Pachl J. Efficacy
and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated
Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect
Dis. 2016 Jun 01;62(11):1380-1389. [PMC free article: PMC4872289] [PubMed: 26962078]
26. Huang D, Yu B, Diep JK, Sharma R, Dudley M, Monteiro J, Kaye KS, Pogue JM, Abboud CS, Rao GG. In Vitro
Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae
Carbapenemase (KPC)-Producing K. pneumoniae. Antimicrob Agents Chemother. 2017 Jul;61(7) [PMC free
article: PMC5487624] [PubMed: 28438930]
27. Gurjar M. Colistin for lung infection: an update. J Intensive Care. 2015;3(1):3. [PMC free article: PMC4336271]
[PubMed: 25705428]
28. Doi Y, Wachino JI, Arakawa Y. Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA
Methyltransferases. Infect Dis Clin North Am. 2016 Jun;30(2):523-537. [PMC free article: PMC4878400]
[PubMed: 27208771]
29. Li JJ, Sheng ZK, Deng M, Bi S, Hu FS, Miao HF, Ji ZK, Sheng JF, Li LJ. Epidemic of Klebsiella pneumoniae
ST11 clone coproducing KPC-2 and 16S rRNA methylase RmtB in a Chinese University Hospital. BMC Infect
Dis. 2012 Dec 23;12:373. [PMC free article: PMC3543704] [PubMed: 23259910]
30. Karageorgopoulos DE, Miriagou V, Tzouvelekis LS, Spyridopoulou K, Daikos GL. Emergence of resistance to
fosfomycin used as adjunct therapy in KPC Klebsiella pneumoniae bacteraemia: report of three cases. J
Antimicrob Chemother. 2012 Nov;67(11):2777-9. [PubMed: 22782489]
31. Both A, Büttner H, Huang J, Perbandt M, Belmar Campos C, Christner M, Maurer FP, Kluge S, König C,
Aepfelbacher M, Wichmann D, Rohde H. Emergence of ceftazidime/avibactam non-susceptibility in an MDR
Klebsiella pneumoniae isolate. J Antimicrob Chemother. 2017 Sep 01;72(9):2483-2488. [PubMed: 28637339]
32. Gniadek TJ, Carroll KC, Simner PJ. Carbapenem-Resistant Non-Glucose-Fermenting Gram-Negative Bacilli:
the Missing Piece to the Puzzle. J Clin Microbiol. 2016 Jul;54(7):1700-1710. [PMC free article: PMC4922101]
[PubMed: 26912753]
Disclosure: Hayden Smith declares no relevant financial relationships with ineligible companies.

Disclosure: Brian Kendall declares no relevant financial relationships with ineligible companies.
Figures

Notable Intrinsic Drug Resistance. Hayden Smith, MD

 Possible Treatment Regimens for High-Risk Infections. Hayden Smith, MD

Copyright © 2023, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (
http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used
commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK551704 PMID: 31869168