ANTIBIOTICS CHOICE RESISTANCE GRAM NEGATIVE BACTERIAL INFECTION

1. GNB Resistance and choice
of Antibiotics

2. Gram Negative Organism

3. Definition of
MDR/XDR/PDR
Infections ?

4. Fig. 1
Clinical Microbiology and Infection 2019 25943-950DOI: (10.1016/j.cmi.2019.04.013)
Major mechanisms of antimicrobial resistance, including carbapenem resistance, in
Enterobacteriaceae.

5. Mechanisms of antibiotic resistance of Gram-negative and Gram-positive bacteria.
In GNB, outer lipid membrane layer has the role of obstructing the entry of drugs into the bacterial cell.

7. Intrinsic and acquired
beta-lactamases in
Enterobacteriaceae.

8. β-Lactamases (Ambler Classification)

10. Mechanisms of
Resistance of
MDR/XDR GNBs

16. Use with a carbapenem or colistin to treat infections with KPC-3 producers

20. AZTREONAM

28. Polymixins
• Reserve IV colistin for infections due to polymyxin-susceptible but multiresistant bacteria and use in combination.
(Conditional for)
• Higher dosage regimens in critically ill patients. (Conditional for)
• Use colistin with meropenem for susceptible KPC-producing Klebsiella spp. if the meropenem MIC is <8 mg/L and higher
meropenem dose by continuous infusion if the MIC is >8 and <32 mg/L. (Conditional for)
• Consider colistin with aminoglycosides or tigecycline strains producing KPC or other carbapenemases, which are
susceptible but resistant to meropenem with MIC >32 mg/L. (Conditional for)
• Monitor renal function especially in the elderly, those receiving high intravenous doses for prolonged periods and those on
concomitant nephrotoxic agents, e.g. aminoglycosides. (Strong for)
• Reconsider use of polymyxins in selective digestive decontamination regimens as these agents are now important last
therapeutic options against CPE

29. Pharmacotherapy Volume 39, Number 1, 2019

30. TIGECYCLINE

31. FOSFOMYCIN

33. Third-generation cephalosporin-resistant Enterobacterales (3GCephRE) (ESBLs)
Question 1.1: What is the antibiotic of choice for 3GCephRE
• In Blood Stream Infection (BSI) and severe infection, consider a carbapenem (imipenem or meropenem) as targeted
therapy (strong recommendation for use, moderate certainty of evidence).
• BSI without septic shock, ertapenem instead of imipenem or meropenem may be used (conditional recommendation for
use, moderate certainty of evidence).
• In low-risk, non-severe infections, (consideration of antibiotic stewardship) consider piperacillin-tazobactam,
amoxicillin/clavulanic acid or quinolones (conditional recommendation for use, moderate certainty of evidence/good
practice statement).
• Cotrimoxazole for non-severe complicated UTI (cUTI) (good practice statement).
• Stepdown targeted therapy with carbapenems in stabilized patient, use old b-lactam/b-lactamase inhibitors (BLBLI),
quinolones, cotrimoxazole or other antibiotics based on the susceptibility pattern of the isolate (good practice statement).

34. • No recommendation for tigecycline (strong recommendation against use, very low certainty of evidence).
• New BLBLI are reserved for extensively resistant bacteria and avoid use due to antibiotic stewardship
considerations (good practice statement).
• Cephamycins (e.g. cefoxitin, cefmetazole, flomoxef) and cefepime not be used (conditional recommendation
against use, very low certainty of evidence).
• Cefoperazone-sulbactam, ampicillin-sulbactam, ticarcillin clavulanic acid usage- insufficient evidence, no
recommendation can be issued.

35. 2. Carbapenem-resistant Enterobacterales
What is the antibiotic of choice for CRE
• Severe CRE infections, Use meropenem-vaborbactam or ceftazidime-avibactam if active in vitro (conditional
recommendation for use, moderate and low certainty of evidence).
• Severe infections due to CRE-carrying metallo b- lactamases (MBL) and/or resistant to all other antibiotics, including
ceftazidime-avibactam and meropenem-vaborbactam, recommend treatment with cefiderocol (conditional
recommendation for use, low certainty of evidence).
• Non-severe CRE infections, consider Ciprofloxacin, levofloxacin, trimethoprim-sulfamethoxazole, nitrofurantoin, or a
single-dose of an aminoglycoside options for uncomplicated cystitis
• cUTI and pyelonephritis or infections outside of the urinary tract, Extended-infusion meropenem if susceptible (i.e.,
meropenem MICs ≤1 mcg/mL)
• No tigecycline for BSI and HAP/VAP; if necessary, in pneumonia, may use high dose tigecycline (conditional
recommendation against use, low certainty of evidence).

36. Question 2.2: Should combination therapy be used for the treatment of CRE?
• CRE infection susceptible to and treated with ceftazidime-avibactam, meropenem-vaborbactam or cefiderocol, do not
recommend combination therapy (strong recommendation against use, low certainty of evidence)
• Aztreonam and ceftazidime-avibactam combination therapy for severe CRE infections carrying MBL and/or resistant to
new antibiotic monotherapies (conditional recommendation for use, moderate certainty of evidence).
• Severe CRE infections susceptible in vitro only to polymyxins, aminoglycosides, tigecycline or fosfomycin, or in the case
of non-availability of new BLBLI -- combination therapy of drug active in vitro (conditional recommendation for use,
moderate certainty of evidence).
• No recommendation for or against specific combinations.
• If meropenem MIC is ≤ 8 mg/L, high-dose extended-infusion meropenem as part of combination therapy if the new
BLBLI are not used (conditional recommendation for use, low certainty of evidence).

37. 3. Carbapenem-resistant Pseudomonas aeruginosa
What is the antibiotic of choice for CRPA
• Severe infections (complicated cystitis, pyelonephritis, non urinary site), options ceftolozane-tazobactam if active in vitro
(conditional recommendation for use, very low certainty of evidence).
• Non-severe or low-risk infections (uncomplicated cystitis ), (antibiotic stewardship, individual basis and the source of
infection) – options Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, cefiderocol, or a
single-dose of an aminoglycoside (good practice statement)
Should combination therapy be used for the treatment of CRPA?
• Cannot recommend for or against the use of combination therapy with the new BLBLI (ceftazidime-avibactam and
ceftolozane-tazobactam) or cefiderocol.
• Severe CRPA infections susceptible to polymyxins, aminoglycosides, or fosfomycin, combination therapy for vitro
active drugs (conditional recommendation for use, very low certainty of evidence).
• No recommendation for or against specific combinations can be provided.

38. 4. Carbapenem-resistant Acinetobacter baumannii
- Question 4.1: What is the antibiotic of choice for CRAB?
• If CRAB susceptible to sulbactam and ampicillin-sulbactam for HAP/VAP (conditional recommendation, low certainty of
evidence).
• CRAB resistant to sulbactam, use polymyxin with minocycline or high-dose tigecycline if active in vitro. Lacking
evidence, we cannot recommend on the preferred antibiotic.
• Recommend against cefiderocol for the treatment of infections caused by CRAB (conditional recommendations against
use, low certainty of evidence).
• For mild CRAB, single agent- ampicillin-sulbactum, polymyxin B, minocycline can be used.

39. Question 4.2: Should combination therapy be used for the treatment of CRAB?
• Do not recommend polymyxin-meropenem combination therapy (strong recommendation against use; high certainty of
evidence) or polymyxin- rifampin combination therapy (strong recommendation against use, moderate certainty of
evidence).
• Severe and high-risk CRAB infections, combination therapy including two in vitro active antibiotics among the available
antibiotics (polymyxin, aminoglycoside, tigecycline, minocycline, sulbactam combinations) (conditional
recommendation for use, very low certainty of evidence).
• Infections with a meropenem MIC <8 mg/L, carbapenem combination therapy, using high-dose extended-infusion
carbapenem dosing. (good practice statement).
All carbapenem-resistant Gram-negative bacteria
• For pan-resistant CR-GNB (resistant also to polymyxins), treatment with the least resistant antibiotic/s based on MICs
relative to the breakpoints is considered. (Good practice statement Expert opinion)

40. Stenotrophomonas maltophilia
• For mild infections, TMP-SMX, minocycline, tigecycline, levofloxacin, or cefiderocol monotherapy
• For moderate to severe infections (1) TMP-SMX and minocycline- preferred , (2) ceftazidime-avibactam and aztreonam,
when intolerance or inactivity of other agents.
Extended-spectrum β-lactamase-Producing Enterobacterales
• Nitrofurantoin and trimethoprim-sulfamethoxazole - for uncomplicated cystitis.
• Ertapenem, meropenem, imipenem-cilastatin, ciprofloxacin, levofloxacin, or trimethoprim-sulfamethoxazole - options for
pyelonephritis and cUTIs.
• Carbapenem is preferred for infections outside of the urinary tract.
• Piperacillin-tazobactam and cefepime not recommended for infections outside of the urinary tract, even if susceptible.

52. Structure of
Gram-negative
bacteria and
their
mechanisms of
resistance.

56. An overview of
carbapenem resistance
detection and
characterization in
gram negative
organisms.

58. Characteristics of commercial carbapenemases detection assays that have been approved for detection
of carbapenemases in CRE isolates