Addressing Drug Resistance

in Gram-Negative Bacteria
Karl Evans R. Henson, MD, FPCP
Section of Infectious Diseases, UP-PGH
Financial disclosures

 Speakers bureau: MSD, BSV

 Consulting: MSD, Bayer
Acinetobacter
baumannii,
ARSP 2017
Respiratory 63%
Blood 13%
Mastering the Fight Against Drug Resistance
 Know your enemy: resistance enzymes
 Know your standard weapons
 Familiarize yourself with MICs
 Know your drug’s PK/PD
 Prolonged infusion of beta-lactams
 Know your weapons of last resort
 Polymyxins
 Combination antimicrobial therapy
 Inhalational antibiotics
 Drugs in the pipeline
Treatment Options
 Options for ESBL & AmpC Enterobacteriaceae
Drug Pros Cons
Meropenem/ Drugs of choice Covers P. aeruginosa & A. baumannii
imipinem
Ertapenem Drug of choice; NO P. aeruginosa & Less efficacious in early VAP and
A. baumannii coverage hypoalbuminemia??
Piperacillin- Shown to be effective in cUTI and Controversial! Not recommended for septic
tazobactam biliary tract infections shock or high-inoculum infections
(pneumonia, undrained abscess) - MERINO
Ceftolozane- FDA approved for cUTI and cIAI, Effective against XDR P. aeruginosa –
tazobactam pneumonia trial pending (use high reserve?
dose?
Tigecycline Approved for CAP, skin and soft tissue Bacteriostatic; higher mortality rates in
infection, and cIAI; no P. aeruginosa studies
coverage
Fluoroquinolones Oral anti-pseudomonal FQ resistance high in ESBL producers!
AVOID. Use only if MIC to FQ is very low.
Rodriguez-Baño, et al. Clin Micro Rev. 2018;31(2):e00079-17
Options for Carbapenem-Resistant Bugs

• Group 2
Polymyxins carbapenems
Colistin/CMS + •
•
Tigecycline
Rifampicin
Polymyxin B • Aminoglycosides
• Sulbactam
Polymyxins: Microbiology & Pharmacology
 Microbiology
 Active against: A. baumannii, P. aeruginosa, Klebsiella spp., Enterobacter
spp., E. coli, Salmonella spp., Shigella spp., Yersinia spp., Citrobacter spp.
 Intrinsically resistant: Gram-positives, anaerobes, Proteus spp., Providencia
spp., Morganella spp., Serratia spp., Burkholderia cepacia
 Pharmacodynamics
 Exhibits rapid and concentration-dependent killing against
susceptible P. aeruginosa, A. baumannii, and K. pneumoniae
 For susceptible A. baumannii and K. pneumoniae, PK/PD studies have
demonstrated regrowth of bacteria as early as 6 hours, attributed to
the presence of polymyxin heteroresistance
 Polymyxins are subjected to the inoculum effect – reduced antibiotic
efficacy in the face of high bacterial burdens
 Pharmacokinetic index: fAUC/MIC

Cai Y et al. Expert Rev Anti Infect Ther. 2015.

 JDelgado

Mechanism of Action
 Act as “cationic detergent”
 Binds to lipopolysaccharide 
alters cell membrane
permeability
 Damages cell membrane
permitting leakage of
intracellular contents  cell
death
 JDelgado

Spectrum of Activity
Polymixin

Gram-positive organisms 0
Enterobacteriaceae except Serratia spp., Proteus spp., +
Providencia spp., Morganella spp.
Extended-spectrum β-lactamases (ESBLs) +
Klebsiella pneumoniae Carbapenemases (KPCs) +
New Delhi metallo-β-lactamase (NDM-1) +
Acinetobacter baumannii including MDR +
Pseudomonas aeruginosa including MDR +
Stenotrophomonas maltophilia +
Burkholderia cepacia 0
Anaerobes 0
+ = susceptible; 0 = resistant
Dosing Polymyxin
COLISTIMETHATE NA (CMS)
• USE DOSE CALCULATOR!
• CONVERT: 1 mg = 30,000 IU
• LOAD: 4 x body wt (kg)
• MAINTAIN: varies between 130
mg/day to 360 mg/day, depending
on CrCl, and divided q8-12h
• DILUTE: Use 10 mL NSS to
reconstitute and 50 mL NSS to infuse
Nation RL et al. Clin Infect Dis. 2017;64(5)
(PK Study Group Dosing)
POLYMYXIN B (PMB)
• Use actual body weight
• CONVERT: 1 mg = 10,000 IU
• LOAD: 2.5 mg/kg, 2h infusion
• MAINTAIN: 1.5 mg/kg given q12h, 1h
infusion
• DILUTE: 300 to 500 mL D5 fluid for
every 500,000 (i.e.1 vial)
Sandri AM et al. Clin Infect Dis. 2013;57(4)
Prospective PK/PD study by Kaye et al ongoing
POLYMYXIN B (PMB)

• Use actual body weight

• CONVERT: 1 mg = 10,000 IU
• LOAD: 2.5 mg/kg, 2h infusion
• MAINTAIN: 1.5 mg/kg given q12h,
1h infusion
• DILUTE: 300 to 500 mL D5 fluid for
every 500,000 (i.e.1 vial)

Sandri AM et al. Clin Infect Dis. 2013;57(4)

Prospective PK/PD study by Kaye et al ongoing
 JDelgado

Polymixin B … is renal dose

adjustment necessary? Polymixin B total body clearance
did not show any relationship
with creatinine clearance.

Sandri AM. Clin Infect Dis 2013.

 JDelgado

Polymixin B exposures in patients with normal and impaired renal function

after receiving standard dosing of polymixin B were comparable.
Thamlikitkul, et al. Antimicrob Agent Chemother 2016.
 JDelgado

Polymixin B dose <1.3mg/kg/d was significantly associated with

30-day mortality (46.5% vs 26.3%; p = 0.008)
Nelson, et al. Antimicrob Agent Chemother 2015.
Polymyxin B Dosing: Conclusion
NO NEED TO ADJUST POLYMYXIN B
DOSE TO RENAL FUNCTION
COL vs COL + MERO
Paul et al. Lancet Infect Dis 2018

 Superiority RCT, 6 hospitals in Israel, Greece, and Italy

 Patients: Adults with bacteremia, HAP, VAP, urosepsis caused by
carbapenem-nonsusceptible GNB
 Intervention: COL 9M units loading then 4.5 M units q12h PLUS
MEROPENEM 2g prolonged infusion 3x a day
 Comparator: COL 9M units loading then 4.5 M units q12h alone
 Primary outcome: clinical failure (i.e. not meeting all success criteria
by ITT at 14 days post-randomization)
 “Treatment Success” – survival, hemodynamic stability, improved or
stable SOFA score, stable or improved ratio of P/F ratio in pneumonia,
microbiologic cure for bacteremia
 COL vs COL + MERO
Paul et al. Lancet Infect Dis 2018

 Pneumonia or bacteremia – 87%

 Acinetobacter baumannii infections – 77%
COL + MERO vs COL/Placebo
Kaye et al (US)

 RCT, double blind, multi-center, international (US, Israel, Taiwan,

Thailand)
 Patients: Adults with bacteremia or pneumonia due to XDR A.
baumannii, Klebsiella spp., E. coli, Enterobacter spp., P. aeruginosa
 Intervention: COL + MERO
 Comparator: COL + PLACEBO (mimic MERO)
 Primary outcome: mortality, followed for 4 weeks
 Secondary outcome: resistance – to determine COL monotherapy vs
COL combo reduces frequency of emergence of COL resistance
 Results pending, completion estimated in 2021
Summary: Polymyxin mono vs
combination therapy
 Based on retrospective data, combination therapy favored for CRE
infections, especially in septic shock
 For Acinetobacter and Pseudomonas, no clear advantage to combination
vs monotherapy, except maybe in A. baumannii infections in
 Immunosuppressed patients
 Patients with septic shock
 Organisms with borderline MICs
 Data is extremely limited. Prospective study pending

Karaiskos I, et al. Expert Rev Anti Infect Ther. 2017;15(12):1123-40

Combination Therapy: Conclusion

THE JURY IS STILL OUT. DATA STILL NEEDED.

CONTINUE COMBINATION THERAPY FOR NOW.
COLISTIMETHATE NA/COLISTIN (COL) POLYMYXIN B (PMB)
Amphipathic, detergent-like  pore formation in bacterial cell wall  cell death
Administered as a prodrug, CMS, then Administered as the active drug
converted in vivo to active agent COL
Time to peak COL concentration delayed: Peak plasma PMB concentration occurs at
slow conversion of CMS  COL (highly the end of the infusion
variable but may be 7h)
Renally cleared, dose adjustment needed Non-renally cleared, i.e. no renal dose
in renal failure adjustment necessary
CMS rapidly cleared in urine, only 30%
converted to COL; COL cleared by non-
renal routes
On NEPHROTOXICITY: both are potentially nephrotoxic, but CMS>PMB.
Polymyxin-associated AKI is usually mild to moderate and reversible.

Cai et al. Expert Rev Anti Infect Ther. 2015.

Zavascki and Nation. Antimicrob Agents Chemother. 2017.
Zavascki and Nation. Antimicrob Agents Chemother. 2017.
Nephrotoxicity and Polymyxins

COL – black
PMB - gray

Rigatto MH et al.
Antimicrob Agents
Chemother.
2016;60(4):2443-9.
Zavascki and Nation. Antimicrob Agents Chemother. 2017.
Nephrotoxicity: Conclusion
COLISTIN IS MORE NEPHROTOXIC THAN
POLYMYXIN B
 JDelgado

Neurotoxicity

 Due to interaction of polymixins with the high lipid content of

nerve cells
 Facial and peripheral paresthesia – most common
presentation
 Neuromuscular blockade (leading respiratory failure) – most
severe presentation
 Weaknesss, vertigo, visual disturbance, ptosis, diplopia,
confusion, irritability, ataxia, areflexia, dysphagia, dysphonia,
psychosis
 Risk factors: hypoxia, concomitant medications (e.g. muscle
relaxants, sedatives, corticosteroids), impaired renal function

Spapen, et al. Ann Intensive Care 2011.

 JDelgado

Other Adverse Effects

 Hypersensitivity reactions
 Only reported in 2 patients
 Can occur with either agent
 Hyperpigmentation
 Appears to be unique with polymixin B
Associated with melanocyte activation

Koch-Weser, et al. Ann Intern Med 1970.

Mattos, et al. J Clin Phar Ther 2017.
 JDelgado

Polymixins for UTI

 CMS - Elimination in the urine; clearance of bacteriuria

 CMS excreted in high concentration in the urine
Converted to active drug, colistin
 Polymyxin B should NEVER be used for UTI
 JDelgado

Polymyxins for Pneumonia

 Distribution of polymyxins to the lung parenchyma is relatively poor
 Mouse infection model: “substantially less effective in
decreasing bacterial burden in the lungs compared with
antibacterial effect observed in thigh muscles”
 Inhaled administration achieves higher colistin concentrations
in lung tissue, epithelial lining fluid and sputum than parenteral
administration
 Recent HAP/VAP guidelines recommend inhaled polymyxins (weak
recommendation; very low-quality evidence)

Cheah, et al. J Antimicrob Chemother 2015.

Inhaled antibiotics: Why do it?

 Inadequate local concentrations compared to targeted pathogens’ MICs

 Increased systemic toxicity when administered in boosted doses to
supervene low lung perfusion
 Bad perfusion in consolidated areas of the lung
Inhaled Polymyxin: How to do it

 Must be given with systemic therapy

 No data/experience with polymyxin B.
 Inhaled colistin dose: 50-75 mg CBA in 3-4 mL saline 2-3x a day
 Ideally, use vibrating mesh nebulizer
 JDelgado

Intrathecal/ Intraventricular Polymxins

 CSF penetration of polymixins is low (CSF-to-serum ratio only 5%)
 Increased CSF-to-serum ratio if given via intrathecal or
intraventricular route
 Most published literature report use of colistin
 Major toxicities: chemical meningitis, ventriculitis, seizures
 Colistin: 10 mg/day CBA (~300,000 IU)
 Polymyxin B: 5-10 mg/day (50,000-100,000 IU)

Markantonis, et al. Antimicrob Agent Chemother 2009.

Points to Ponder On
 The enemy: resistance enzymes. Not all enzymes are
created equal.
 The weapons: review your PK/PDs
 There are very limited options for carbapenem-resistant
MDROs. You will frequently need to use polymyxins
 PMB does not need renal dose adjustment
 COL is more nephrotoxic than PMB
 You will not be faulted for using combination therapy in most
cases
 Polymyxins likely do not have high enough lung concentration
to be very effective in pneumonias. Consider inhaled
polymyxins in severe infections.
Questions?