1. Management of Multi-Drug Resistant Bacterial Infections
Ana alvarez, MD, FPIDS
Associate Professor
Pediatric Infectious Diseases
University of Florida College of Medicine- Jacksonville

2. Goals and Objectives
At the end of this talk, listeners should better understand
The epidemiology & evolution of antibacterial resistance and possible solutions
Management of resistant Gram positive organisms: the current options
Management of resistant Gram negative organisms: the current options

3. Bugs & Drugs: the saga Pre-antibiotic era (before 1941)
S. aureus bacteremia mortality ~98%
Antibiotic era
Many predicted demise of bacterial infections
Within 5yrs, 50% of S. aureus became resistant
60s: methicillin resistance among staphylococci
70s: Gram-negative infections were on the rise
Multi-drug resistant organisms emergence
ha-MRSA, VRE, ESBL, KPC, ca-MRSA, C. diff, VISA (96), VRSA (02), CRE

5. Impact of Antimicrobial Resistance
Estimates in the U.S.
At least 2,000,000 illnesses/year
23,000 deaths/year
~ $20 billion annual direct healthcare cost
Another ~ $35 billion in indirect costs to society

6. Nosocomial and Community-acquired Infections
Risk factors for MDRO
Nosocomial and Community-acquired Infections
Risk Factors
Antimicrobial therapy in preceding 90 days
Current hospitalization of 5 days or more
High frequency of resistance in the community or hospital unit
Presence of risk factors for health care-associated pneumonia
Hospitalization for 2 days or more in the preceding 90 days
Residence in a nursing home
Home infusion therapy
Chronic dialysis within 30 days
Home wound care
Family member with MDR pathogen
Immunosuppresive disease and/or therapy
Many of the advances in medical treatment— ICU interventions, joint replacements, organ transplants, cancer therapy, and treatment of chronic diseases such as diabetes, asthma, rheumatoid arthritis—are dependent on the ability to fight infections with antibiotics

7. Gram Positive Problem Streptococcus pneumoniae DRSP
Staphylococcus aureus
MRSA
VISA / VRSA
Enterococcus sp.
VRE

8. Penicillin-Resistant Streptococcus pneumoniae PRSP
1940s: all S. pneumoniae susceptible to penicillin
1960s: intermediately resistant S. pneumoniae
1970s: resistant S. pneumoniae
Multi-drug resistance
Erythromycin, TMP/SXL, Tetracycline, Chloramphenicol
Geographic variation
PRSP is rising steadily especially the highly resistant strains

9. Drug-Resistant Streptococcus pneumoniae Treatment options for Non-CNS infections
Penicillins
High dose may be effective
Extended-spectrum cephalosporins
Effective even for highly resistant strains
Clindamycin
For Pen/Cephalosporin-allergic patients for infections caused by susceptible strains
Vancomycin
For Pen/Cephalosporin-allergic patients
Carbapenems
Effective against PRSP

10. Drug-Resistant Streptococcus pneumoniae Treatment options for CNS Infections
Extended-spectrum cephalosporins
Do not use alone for meningitis caused by highly resistant strains
Vancomycin
For meningitis caused by highly resistant strains
Carbapenems
Very effective against PRSP
Rifampin
Used as adjunctive therapy for PRSP meningitis

11. Drug-Resistant Streptococcus pneumoniae Treatment options
Newer agents for DRSP in pediatrics
Oxazolidinone: linezolid
Fluoroquinolones: levofloxacin, moxifloxacin
Prevention
13-valent conjugate pneumococcal vaccine (universal)
Polysaccharide pneumococcal vaccine (for high risk patients)
Zyvox®
Levaquin®
Avelox®

12. Community-associated MRSA CA-MRSA
Clinical Presentation
Skin and skin structure infections (SSSI)
Necrotizing pneumonia
Failure to respond to usual 1st line drugs
Virulence: Panton-Valentine Leukocidin (PVL) gene
Risk for outbreaks (4 Cs):
Contact, crowding, contaminated surfaces, cleanliness

13. CA-MRSA Treatment Options for SSSI
Mild to moderate
Incision and drainage as indicated
Most important intervention
Antibiotic choices
Clindamycin (PO or IV)
TMP/SMX (if GAS nor suspected)
Doxycycline (if >7 y/o)

14. CA-MRSA Treatment Options for SSSI
Severe to critical
Incision and drainage as indicated
Antibiotic choices
Vancomycin
Clindamycin (PO or IV)
Consider Vanco + nafcillin/oxacillin

15. MRSA Treatment Options for Bacteremia and other serious infections
Community-associated
Vancomycin +/- gentamicin (sepsis)
Clindamycin (pneumonia, osteomyelitis, etc)
TMP/SMX (SSSI)
Health care-associated (multidrug resistant)
Vancomycin +/- gentamicin
TMP/SMX
Newer agents

16. Vancomycin Failure Slower bactericidal activity than β-lactams
Delay in achieving therapeutic levels
Emergence of resistant strains
MIC “creep” among susceptible strains
hVISA, VISA, VRSA
Clearly inferior to β-lactams for MSSA bacteremia and endocarditis
Highly variable tissue penetration
Limited penetration into bone, lung, and CSF
Inactive against MRSA in biofilm

17. MRSA Other Treatment Options
Linezolid
Daptomycin (not for pneumonia)
Tigecycline
Ceftaroline
Telavancin
Quinupristin-dalfopristin

18. Risk Factors for VISA or VRSA VISA - MIC 4-8 VRSA - MIC ≥ 16
Prior MRSA infection or colonization
Exposure to vancomycin
Malignancy, diabetes, renal failure, and recent major surgery
“high bacterial load” infection
Endocarditis, deep abscess, prosthetic joint infection
Penetration of antibiotics is limited
Low serum levels of vancomycin early in the treatment of MRSA infections

19. VISA/VRSA Treatment Options
Linezolid
Daptomycin (not for pneumonia)
Tigecycline
Ceftaroline
Quinupristin-dalfopristin
Combination (controversial):
vancomycin + linezolid +/- gentamicin
vancomycin + TMP/SMX

20. Enterococci Intrinsic Resistance
cephalosporins, antistaphylococcal penicillins, clindamycin, aminoglycosides and TMP
Transferable Resistance… VRE
Vancomycin MIC ≥ 32mcg/mL
Encoded by genetic material on plasmids / transposons
VanA, vanB, vanC, vanD & vanE genes
E. faecium (85-90%) > E. faecalis (10-15%)
DANGER: reservoir for resistance in GPC

21. VRE Control Infection control measures
Restriction of inappropriate vancomycin use
Empiric therapy without cultures
Routine prophylaxis in LBW infants
Treatment for MRSA colonization
Primary therapy for antibiotic-associated colitis
Treatment for contaminants (e.g. CoNS single cultures)
Surgical prophylaxis
Topical use or use for irrigation
Restriction of extended-spectrum cephalosporin use
Remove temporary medical devices such as catheters and ventilators as soon as no longer needed

22. Treatment options for VRE
Quinupristin-dalfopristin
Effective against E. faecium not E. faecalis
Linezolid (R 20%)
Daptomycin
Tigecycline (for polymicrobial infections)
Synercid®
Zyvox®
Cubicin®
Tygacil®

23. Linezolid (Zyvox®) Pfizer Pharmaceutical Class: Oxazolidinone
The first truly new antibiotic in 30 years
Inhibits protein synthesis at ribosomal level
Highly active against Gram positive agents
Staphylococci (including MRSA, MRSE)-static
S. pneumoniae (?PRSP); GAS; GBS -cidal
Enterococcus spp. (including VRE) -static

24. Linezolid (Zyvox®) Uses
VRE infections with bacteremia
Nosocomial and community-acquired pneumonia
MSSA, MRSA, S. pneumoniae
Complicated SSSI
Staphylococcus spp., Streptococcus spp. (GAS)

25. Linezolid (Zyvox®) Available for both oral and IV use
High bioavailability
High degree of safety; however:
Diarrhea, nausea, thrush, headache, tongue discoloration
prolonged treatment (>14 d): hematological adverse events (e.g. thrombocytopenia)
Peripheral and optic neuropathy, rare
irreversible

26. Daptomycin (Cubicin®Cubist Pharmaceutical)
New class: Cyclic Lipopeptides
Parenteral IV formulation only
Very limited experience in children
Active against Gram+ bacteria resistant to methicillin, vancomycin or linezolid
Synergy with ß-lactams & aminoglycosides
Shares mechanism with no other antibiotic
No cross resistance demonstrated to date
Not indicated for treatment of pneumonia
Low levels in bronchoalveolar lining fluid and lung parenchyma in clinical studies
Inactivated by surfactant

27. Telavancin (Vibativ) Analogue of vancomycin Dual mechanism of action
Inhibition of peptidoglycan synthesis AND disruption of cell membrane potential
Rapid bactericidal activity against most gram-positive pathogens (not VRE)
Better penetration into the lungs vs. vancomycin
Side effects
Renal events (higher incidence than vancomycin), N/V, foamy urine, coagulation test interference, boxed warning to avoid in pregnancy
Not active against VRE, decreased response vs vancomycin in patients with renal impairment

28. Ceftaroline (Teflaro)
Broad-spectrum cephalosporin (5th generation)
Pediatric studies are ongoing
Activity against
Most gram-positive organisms including MRSA (FDA- approved only in cSSSIs)
Enterobacteriaceae, except ESBL producers
Lack useful activity against Pseudomonas, A. baumannii, Enterococcus spp., ESBLs and anaerobes
Adverse Events (<10%)
Diarrhea, nausea, headache, and insomnia, urine discoloration and odor

29. Other recently approved antibiotics for Gram-positives
Approved in 2014 for skin & skin structure infections (SSSIs) including MRSA
Tedizolid (Sivextro) – Oxazolodinone
PO or IV, once daily, adults only
Other potential use: pneumonia (CAP & Vent-associated)
Dalbavancin (Dalvance) - Lipoglycopeptide
IV, 2 dose regimen one week apart, adults only
Other potential use: CAP
Oritavancin (Orbactiv) – Glycopeptide
Single IV dose, adults only
CXA 201- being develoved by Cubist

30. Gram Negative Problem
Gram-negative sepsis is still very common in Pediatrics
Neonatal sepsis
Infections in the neutropenic patients
Urosepsis
Intraabdominal infections
Hospital-associated infections (central lines, mechanical ventilation, urinary catheters, etc)
Gram-negative sepsis is often fatal
There is increasing anti-microbial resistance among GNB

31. Resistance in GNB
Examples of Gram-negative bacteria which are becoming increasingly resistant:
Enterobacter spp.
Serratia spp. Morganella spp.
Klebsiella spp. Providentia spp.
Acinetobacter baumannii Citrobacter spp.
Pseudomonas aeruginosa
Burkholderia spp. & Stenotrophomonas spp.

32. Evolution of β-Lactamases
Wild-Type
β-lactamase (TEM-1, TEM-2, SHV-1)
AmpC; ESBL (TEM, SHV, CTX-M)
Carbapenemase (KPC, MBL,NDM-1)
Penicillins
β-lactam/β-lactamase inhibitors; Cephalosporins
Carbapenems
ESBL=extended-spectrum β-lactamase; KPC=Klebsiella pneumonia carbapenemase; MBL=metallo-β-lactamase; TEM-1,TEM-2, SHV-1, TEM, SHV, CTX-M=types of β-lactamases.

33. ESBL-producing GNR ESBL= extended spectrum ß-lactamase
Produced mainly by Klebsiella spp. and E. coli against extended-spectrum cephalosporins
Inducible enzyme mutations
Carried on plasmids; transferable among GNB
Organisms are resistant to all betalactams, only susceptible to cephamycins (cefotetan, cefoxitin) & carbapenems
Treatment options:
Carbapenems: imipenem, meropenem, ertapenem

34. Carbapenem-Resistant Enterobacteriaceae (CRE)
Different mechanisms of resistance
Production of carbapenemases: carbapenem-hydrolyzing beta-lactamases
KPC (K. pneumoniae carbapenemase)
MBL (metallo-beta lactamases) e.g. NDM-1 (New Delhi metallo- beta-lactamase)
OXA-carbapenemase
Resistant to ALL penicillins, cephalosporins, and carbapenem
Activity may be encoded on chromosomes or plasmids.
Concurrent resistance genes (e.g. fluoroquinolones and AG) are common.
CRE can spread from person to person

35. Treatment Options for CRE
Tx should be tailored to antimicrobial susceptibility testing for agents outside beta-lactams and carbapenem
Combination therapy with 2 or more agents is recommended, especially for severe infections
Improved mortality
Polymyxins: colistin and polymyxin B
Fosfomycin (for UTI)
Tigecycline
Aztreonam
Carbapenems in combination with other agents
Synergy and additive activity

36. Tigecycline (Tigacyl Wyeth Pharmaceuticals)
Glycylcycline (tetracycline derivative)
Broad-spectrum activity against many resistant GPC and GNB & anaerobes
S. pneumoniae, S. aureus/MRSA, E. faecium
H. influenzae, Enterobacter, E.coli, Klebsiella, Serratia, Citrobacter, Shigella, Salmonella
Pseudomonas, Providencia, Proteus & Morganella are RESISTANT!
Bacteroidis fragilis, Clostridium perfringens
Major side effects
N/V (~20% of patients)
Post-marketing reports of pancreatitis

37. Tigecycline Practical uses MDR gram negative organisms
Acinetobacter spp., ESBLs, KPCs
Limitations
Emergence of resistance among GNR during treatment
Nausea/Vomiting
Reduced if patients are eating or co-administered with ondansetron
Avoid use as monotherapy in severely ill patients
Increased risk of death (FDA warning)

38. Colistin …a polymyxin An old fellow! (… used in the 1960s)
Detergent effect disrupting the cell membrane
Rekindled interest nowadays:
pan-resistant P aeruginosa and Acinetobacter
Adverse effects
Nephrotoxicity: up to 20-30%, reverses
Neurotoxicity: seizures, ataxia, weakness

39. Fosfomycin Unique mechanism of action
Inhibits enzyme involved in peptidoglycan synthesis
Bactericidal
Retains high and prolonged urinary concentrations
No cross-resistance
Retains activity against many MDR organisms
Rapid resistance when used as monotherapy
May have synergy with other antimicrobials
aminoglycosides
Cai Y et al. J Antimicrob Chemother. 2009;64:

40. Fosfomycin PK
Only approved as an oral formulation in US for uncomplicated UTI
3g x 1 dose
Low systemic absorption
Well-tolerated
Decreased side effects (GI disturbances)
Remains therapeutic for days
Unlabeled q48-72hr dosing for complicated UTI x21 days
Data lacking for upper UTI
IV option available in Europe for cSSSIs
Compared to linezolid

41. Possible Combinations for CRE
Colistin PLUS tigecycline
Colistin PLUS aminoglycoside IV (if susceptible)
May consider tobramycin (inhaled) for pneumonia for less systemic absorption
Colistin PLUS rifampin IV/PO
Rifampin has synergistic activity for MDR gram-negatives
Colistin PLUS a carbapenem
Strain does not have to be susceptible to carbapenem
Ampicillin-sulbactam ± Colistin
Sulbactam alone is effective against A. baumannii
Pachon-Ibanez ME et al. J Antimicrob Chemother. 2010;54(3):

42. Recently approved antibiotics for Gram-negatives
Ceftolozane/tazobactam (Zerbaxa) – FDA approved December 2014
Active against GNB, including Pseudomonas
Cefatzidime/Avibactam (Avycaz) – FDA approved February 2015
Combination with a novel β-lactamase inhibitor
Active against multi-drug resistant GNB, including Pseudomonas
Avibactam inhibits KPC, AmpC and some Class D beta lactamases, but is is NOT active against NDM-1
CXA 201- being develoved by Cubist

43. What can healthcare providers do?
Know if patients with MDRO are hospitalized at your facility, and stay aware of MDRO infection risks
ask if your patients have received medical care somewhere else, including another country
Follow infection control recommendations with every patient, using contact precautions for patients with MDRO
whenever possible, dedicate rooms, equipment, and staff
Remove temporary medical devices as soon as possible
Prescribe antibiotics wisely
use culture results to modify prescriptions if needed
implement antibiotic stewardship program

44. Thank you! Gracias! Shukran! شكرًا