Figures
- FIGURE 1
Global deaths in 2019 directly attributable to Gram-negative antimicrobial resistance by pathogen–antimicrobial. Data from [11]. 3GCR: third-generation cephalosporin resistance; AGR: aminoglycoside resistance; CR: carbapenem resistance; FQR: fluoroquinolone resistance.
- FIGURE 2
Mechanisms of antibiotic resistance in Gram-negative bacteria. Shown are loss of porin channels which reduce antibiotic movement across the bacterial membrane; β-lactamases in the periplasmic space inactivating β-lactams; increased transmembrane efflux pump expression expelling antibiotics from within the bacteria; antibiotic-modifying enzymes altering antibiotics so they cannot interact with end targets; antibiotic target and ribosomal mutations interfering with antibiotic actions; metabolic bypass mechanisms allowing alternative enzyme pathways bypassing antibiotic inhibitory effects; and lipopolysaccharide mutations limiting specific antibiotics such as polymyxins from disrupting the cell membrane.
- FIGURE 3
Molecular, functional and phenotypic classification of β-lactamase enzymes. ESBL: extended-spectrum β-lactamase; KPC: Klebsiella pneumoniae carbapenemases; OXA: OXA-β-lactamases; NDM: New Delhi metallo-β-lactamase; VIM: Verona integron-encoded metallo-β-lactamase; IMP: imipenem's metallo-β-lactamase.
- FIGURE 4
Clinical approach to the treatment of microbiologically confirmed or suspected multidrug-resistant (MDR) Gram-negative bacterial infection. XDR: extremely drug-resistant; CTZ-TAZ: ceftolozane/tazobactam; CEF-AVI: centazidime-avibactam; CEFID: cefiderocol; IMI-REL: imipenem-cilastatin; AG: aminoglycoside; RIF: rifampicin; ESBL: extended-spectrum β-lactamase producing; MER: meropenem; FQ: fluoroquinolone; ERT: ertapenem; AMO-CLA: amoxicillin-clavulanate; FOS: fosfomycin; NTF: nitrofurantoin; TMP-SMX: trimethoprim-sulfamethoxazole; CRAB: carbapenem-resistant Acinetobacter baumannii; ERA: eravacycline; PLZ: plazomicin; COL-PMX: colistin-polymyxin B; TIG: tigecycline; CRE: carbapenem-resistant Enterobacterales; AZT: aztreonam; MER-VAB: meropenem-vaborbactam. #: high risk of mortality is considered >15%.
- FIGURE 5
The importance of appropriate timing, duration and spectrum of antimicrobial activity.
Tables
- TABLE 1
The “PES” score to assess the risk of pneumonia due to Pseudomonas aeruginosa, Enterobacteriaceae with extended-spectrum β-lactamases and methicillin-resistant Staphylococcus aureus pathogens
Age, years <40 0 40–65 1 >65 2 Male 1 Previous antibiotic use 2 Chronic respiratory disorder 2 Chronic renal disease 3 At emergency Consciousness impairment 2 Fever −1 Risk scores for infection are low: ≤1, moderate: 2–4, high: ≥5.
- TABLE 2
Antibiotic mechanisms of resistance of Gram-negative organisms
Resistance mechanism Pathogens commonly harbouring mechanism Antibiotic classes impacted by mechanism Therapeutic options to overcome mechanism Enzymatic inactivation ESBL Enterobacterales, P. aeruginosa, A. baumannii, S. maltophilia Penicillins, cephalosporins (all), aztreonam Carbapenems non-BL based on susceptibility testing Amp-C Inducible: E. cloacae, C. freundii, K. aerogenes
Stable derepressed: E. coli, A. baumannii, Shigella spp.
Plasmid-mediated: K. pneumoniae, E. coli, Salmonella spp.Strong inducers: cephamycins, aminopenicillins, first-generation cephalosporins
Weak inducers: piperacillin-tazobactam, third-generation cephalosporins, aztreonamCefepime
Carbapenem non-BL based on susceptibility testingCarbapenemases KPC Enterobacterales Penicillins, cephalosporins (all), carbapenems, aztreonam Newer-generation BL/BLI Cefiderocol non-BL based on susceptibility testing MBL (NDM, VIM, IMP) P. aeruginosa, S. maltophilia, Enterobacterales Penicillins, cephalosporins (all), carbapenems Ceftazidime/avibactam PLUS aztreonam cefiderocol non-BL based on susceptibility testing OXA-48 Acinetobacter, Enterobacterales Penicillins, cephalosporins (narrow), carbapenems Ceftazidime/avibactam Cefiderocol non-BL based on susceptibility testing Other inactivating enzymes AME Enterobacterales, Acinetobacter, Pseudomonas, S. maltophilia Aminoglycosides Based on susceptibility testing Porin mutations OprD protein Pseudomonas, Acinetobacter Aminoglycosides, carbapenems Based on susceptibility testing Omp proteins Enterobacterales, Acinetobacter Aminoglycosides, carbapenems, tigecycline Efflux pumps MexAB-OprM Pseudomonas β-lactams including carbapenems, macrolides, fluoroquinolones, tetracyclines, TMP/SMX Based on susceptibility testing MexXY-OprM Pseudomonas Aminoglycosides MexCD-OprJ Pseudomonas β-lactams including carbapenems Target site modification 16s rRNA mutation or methylation 30S ribosomal mutation Pseudomonas, Enterobacterales Aminoglycosides Based on susceptibility testing Topoisomerase IV or DNA gyrase mutation Pseudomonas, Enterobacterales, Acinetobacter, S. maltophilia Fluoroquinolones 23S rRNA mutation or methylation 50S ribosomal mutation Enterobacterales Macrolides RNA polymerase mutation Enterobacterales Rifampin DHFR overproduction or DHPS mutation Enterobacterales TMP/SMX Lipid A neutralisation Enterobacterales, Pseudomonas, Acinetobacter Colistin PBP mutation Pseudomonas β-lactams including carbapenems ESBL: extended-spectrum β-lactamases; KPC: Klebsiella pneumoniae carbapenemases; MBL: metallo-β-lactamases; NDM: New Delhi MBL; VIM: Verona integron-encoded MBL; IMP: imipenem's MBL; OXA: OXA-β-lactamases; AME: aminoglycoside-modifying enzymes; DHFR: dihydrofolate reductase; DHPS: dihydropteroate synthase; PBP: penicillin-binding protein; P. aeruginosa: Pseudomonas aeruginosa; A. baumannii: Acinetobacter baumannii; S. maltophilia: Stenotrophomonas maltophilia; BL: β-lactam; E. cloacae: Enterobacter cloacae; C. freundii: Citrobacter freundii; K. aerogenes: Klebsiella aerogenes; E. coli: Escherichia coli; K. pneumoniae: Klebsiella pneumoniae; BLI: β-lactam inhibitor; TMP: trimethoprim; SMX: sulfamethoxazole.
- TABLE 3
Novel and pipeline antibiotic treatment options for Gram-negative respiratory infections
Drug class and indication(s)# Notable activity¶ Development phase Comments Novel antibiotics Ceftolozane/ tazobactam BL/BLI HABP/VABP ESBL-E, MDR P. aeruginosa FDA/EMA approved Verify ESBL-E
No CRE activityCeftazidime/ avibactam BL/BLI HABP/VABP MDR P. aeruginosa, CRE (class A, KPC), AmpC and ESBL-E FDA/EMA approved No MBL activity
Not reliable against A. baumannii
Limited anaerobic activityImipenem/ cilastatin/ relebactam BL/BLI HABP/VABP CRE (KPC), ESBL-E, MDR P. aeruginosa FDA/EMA approved No additional activity against A. baumannii, compared to imipenem
No MBL activity
Anaerobe and MSSA activityMeropenem/ vaborbactam BL/BLI HABP/VABP CRE (KPC), ESBL-E, non-MDR P. aeruginosa and non-MDR A. baumannii FDA/EMA approved No additional activity against MDR P. aeruginosa or MDR A. baumannii compared to meropenem
No MBL activity
Anaerobe and MSSA activityCefiderocol BL HABP/VABP CRE (KPC and MBL), ESBL-E, MDR A. baumannii and P. aeruginosa FDA/EMA approved Inactive against Gram-positives and anaerobes Delafloxacin Fluoroquinolone
CABPESBL-E FDA/EMA approved Limited P. aeruginosa activity
Broad Gram-positive and atypical coverageEravacycline Fluorocycline
No indicationsCRE (KPC and MBL), EBSL-E, MDR A. baumannii FDA/EMA approved Limited clinical efficacy data against MDR infections
Often lower MICs than tigecycline
Low rates of and in vitro activity against C. difficileOmadacycline Tetracycline CABP ESBL-E, KPC, MBL, MDR A. baumannii FDA/EMA approved No Pseudomonas or Proteus spp. activity
Broad Gram-positive and atypical coveragePlazomicin Aminoglycoside
No indicationsCRE (KPC and MBL), ESBL-E FDA/EMA approved Variable P. aeruginosa activity
No A. baumannii activity
Limited safety and efficacy data
Consider in combination therapy regimensPipeline antibiotics Arbekacin Aminoglycoside Aminoglycoside-inactivating Gram-positive and Gram-negative pathogens Phase III Highly active against MRSA and shows activity against MDR-P. aeruginosa and -A. baumannii Aztreonam/ avibactam Monobactam/BLI ESBL, KPC, MBL, AmpC, OXA-48 Phase III No increased activity to P. aeruginosa compared to aztreonam monotherapy
No A. baumannii activityCefepime/ enmetazobactam BL/BLI ESBL, AmpC, limited evidence of KPC and OXA-48 Phase III No increased activity to P. aeruginosa compared to cefepime monotherapy
No class B β-lactamase activityCefepime/ taniborbactam BL/BLI ESBL, KPC, class B β-lactamases (VIM, NDM, SPM-1, GIM-1), AmpC, OXA-48 Phase III Adds activity to cefepime against CRE and carbapenem-resistant P. aeruginosa Cefepime/ zidebactam BL/BLI ESBL, KPC, MBLs, AmpC, OXA-48 Phase III Active against carbapenem-resistant P. aeruginosa
Limited Acinetobacter spp. activityMurepavadin OMPTA Highly active against MDR P. aeruginosa Phase III Showed activity against colistin, ceftolozane/tazobactam and tobramycin nonsusceptible P. aeruginosa Sulopenem Carbapenem ESBL, AmpC Phase III Does not provide additional activity to current carbapenems BL: β-lactam; BLI: β-lactamase inhibitor; HABP: hospital-acquired bacterial pneumonia; VABP: ventilator-associated bacterial pneumonia; ESBL-E: extended spectrum β-lactamase Enterobacterales; MDR: multidrug-resistant; P. aeruginosa: Pseudomonas aeruginosa; FDA: United States Food and Drug Administration; EMA: European Medicines Agency; CRE: carbapenem-resistant Enterobacteriaceae; KPC: Klebsiella pneumoniae carbapenemase; MBL: metallo-β-lactamase; A. baumannii: Acinetobacter baumannii; MSSA: methicillin-sensitive Staphylococcus aureus; CABP: community-acquired bacterial pneumonia; MIC: minimum inhibitory concentration; C difficile: Clostridium difficile; OXA: OXA-β-lactamases; VIM: Verona integron-encoded metallo-β-lactamases; NDM: New Delhi metallo-β-lactamases. #: EMA or FDA; ¶: inclusive of in vitro and in vivo data, which may not correlate with clinical efficacy.
- TABLE 4
Monoclonal antibody treatment options for Gram-negative respiratory infections
Target Gram-negative target(s) Development phase Studied place in therapy A1102 LPS-O-antigen D-galactan-III K. pneumoniae Pre-clinical Prevention A1124 LPS-O-antigen o25b E. coli Pre-clinical Prevention AR-101 LPS 011 exopolysaccharide P. aeruginosa Phase II Treatment AR-105 Alginate exopolysaccharide P. aeruginosa Phase II Prevention and treatment Anti-Hyr1 Hyr1 peptide 5 A. baumannii and K. pneumoniae Pre-clinical Prevention KB001-A Pcrv protein P. aeruginosa Phase II/III Prevention MEDI3902 Pcrv protein and Psl exopolysaccharide P. aeruginosa Phase II Prevention LPS: lipopolysaccharide; K. pneumoniae: Klebsiella pneumoniae; E. coli: Escherichia coli; P. aeruginosa: Pseudomonas aeruginosa; A. baumannii: Acinetobacter baumannii.
- TABLE 5
Bacteriophage therapies for Gram-negative respiratory infections
Phage components Bacterial target Development phase Administration route AB-PA01 cocktail Pa193, Pa204, Pa222, Pa223 P. aeruginosa Pre-clinical Intravenous ± nebulised AB-PA01 m1 Pa193, Pa204, Pa222, Pa223, Pa176 P. aeruginosa Pre-clinical Intravenous ± nebulised Acinetobacter therapies 2ϕ ± ϕAb124 A. baumannii Pre-clinical Topical or nebulised Achromobacter cocktail Not specified A. xylosoxidans Pre-clinical Oral + nebulised Navy Phage cocktail 1 Paϕ1, PaSKWϕ17, PaSKWϕ22 P. aeruginosa Pre-clinical Intravenous ± nebulised Navy Phage cocktail 2 PaATFϕ1 and PaATFϕ3 P. aeruginosa Pre-clinical Intravenous Adaptive Therapeutics phage BdPF16phi4281 B. dolosa Pre-clinical Intravenous P. aeruginosa: Pseudomonas aeruginosa; A. baumannii: Acinetobacter baumannii; A. xylosoxidans: Achromobacter xylosoxidans; B. dolosa; Burkholderia dolosa.
- TABLE 6
Oligonucleotides for Gram-negative respiratory infections
Gene silenced and typical function Silencing clinical result Development phase Bacterial target CTX-M-15 ASO blaCTX−M-15
Encodes resistance to third-generation cephalosporinsReduced MIC to third-generation cephalosporins Pre-clinical E. coli; other Gram-negatives MexB siRNA mexB
Encodes efflux pump componentRestored activity of resistant antibiotics Pre-clinical E. coli; other Gram-negatives NDM-1 ASO blaNDM-1
Encodes carbapenemasesRestored activity of resistant antibiotics Pre-clinical P. aeruginosa; other Gram-negatives NDM: New Delhi metallo-β-lactamases; MIC: minimum inhibitory concentration; E. coli: Escherichia coli; P. aeruginosa: Pseudomonas aeruginosa.
- TABLE 7
Key components of an effective antimicrobial stewardship programme
Description Outcomes Pre-authorisation Prescribers are required to gain approval prior to use of certain antimicrobials Ensures appropriate antibiotic selection and dosing
Prevents unnecessary initiation of antibioticsProspective audit and feedback External review of antibiotics after initiation, with suggestions from experts on optimal use Reduction in unnecessary use of broad-spectrum antibiotics Facility-specific treatment guidelines Specific treatment guidelines for common conditions, such as community-acquired pneumonia, UTI and surgical prophylaxis, taking into account national guidelines and local susceptibilities and formulary options Simplifies antibiotic prescribing for common conditions
Allows for consensus between stewardship team and prescribersAntibiotic time-outs Provider-led reassessment of the continuing need for antibiotics after additional clinical information has returned Improves the appropriateness of antibiotic use
Encourages antibiotic de-escalation when appropriatePharmacy-based interventions Prescribing interventions by pharmacy to optimise antibiotic use
May be incorporated into electronic health recordDose optimisation, dose adjustments based on renal function, changing intravenous antibiotics to oral formulation Rapid diagnostics Early pathogen identification using technology such as PCR to identify bacterial infection prior to awaiting culture results Earlier identification of causative organism can lead to antibiotic de-escalation and optimisation of antibiotics Clinical decision support system Incorporation of clinical and patient-specific data into electronic health record to provide providers with relevant information prior to prescribing antibiotics Decreased overall antibiotic use and improved use of antibiotics in patients with sepsis UTI: urinary tract infection
Jump To
- Article
- Abstract
- Abstract
- Introduction
- Antibiotic resistant Gram-negative pulmonary infections: key organisms and their epidemiology
- Overview of main resistance mechanisms
- Impact of Gram-negative antibiotic-resistant pulmonary infection on outcomes
- Novel and pipeline antibiotics
- Monoclonal antibodies
- Bacteriophage therapy
- Oligonucleotides
- Role of stewardship in curbing MDR spread
- Conclusions
- Footnotes
- References
- Figures & Data
- Info & Metrics