1. Infectious Disease: Drug Resistance Pattern in New Mexico
Obi C. Okoli, MD.,MPH.
Clinic for Infectious Diseases
Las Cruces, NM.

2. Are these the world's sexiest accents?

3. Are these the world's sexiest accents?
13. Argentine
12. Thai
11. Trinidadian
10. Brazilian Portuguese
9. U.S. Southern
8. Scottish
7. Irish
5. Queen's English
4. Czech
3. Spanish
2. French
1. Italian
6. Nigerian - Dignified, with just a hint of willful naivete, the deep, rich "oh's" and "eh's" of Naija bend the English language without breaking it, arousing tremors in places other languages can't reach.

4. Penicillin became commercially available in 1941, when was the first case of penicillin resistant Staphylococcus species reported?
A. 1941
B. 1942
C. 1947
D. 1952
E. 1957

5. Methicillin was introduced in 1961, when was the first case of methicillin resistant Staphylococcus aureus (MRSA) in the U.S reported?
A. 1962
B. 1964
C. 1968
D. 1968
E. 1970

6. Vancomycin became commerically available in 1954, when was the first case of vancomycin resistant Staphylococcus aureus (VRSA) reported?
A. 1972
B. 1982
C. 1992
D. 2002
E. 2012

9. Reasons for Increasing Antibiotic Resistance
Total antibiotic consumption growing worldwide.
2000 – 2010 about 30% increase
USA consumes 10% of world output
Increased use of antibiotics in livestock
Inappropriate use
We know everything about antibiotics except how much to give – Maxwell Finland.

10. Largest five consumers of antimicrobials in livestock in 2010
Van Boeckel TP, et al. PNAS (18)
(A) Largest five consumers of antimicrobials in livestock in (B) Largest five consumers of antimicrobials in livestock in 2030 (projected). (C) Largest Increase in antimicrobial consumption between 2010 and (D) Largest relative increase in antimicrobial consumption between 2010 and CHN, China; USA, United States; BRA, Brazil; DEU, Germany; IND, India; MEX, Mexico; IDN, Indonesia; MMR, Myanmar; NGA, Nigeria; PER, Peru; PHL, Philippines.

11. Estimates of antimicrobial consumption in cattle, chickens, and pigs in OECD countries
Van Boeckel TP, et al. PNAS (18)

12. Antibiotics and Obesity

13. Timing of Low-Dose Penicillin Treatment and Risk of Obesity.
Figure 1. Timing of Low-Dose Penicillin Treatment and Risk of Obesity. Cox and colleagues1 transferred cecal microbiota from 18-week-old controls and penicillin-treated mice to 3-week-old germ-free mice to investigate the effects on body composition and metabolism. Mice that received penicillin-altered microbiota gained total mass and fat mass at a significantly faster rate than did mice that received microbiota from controls. Mice whose mothers were treated with penicillin before the birth of the pups and throughout the weaning process had a markedly altered body composition in adulthood, with increased total and fat mass, increased ectopic fat deposition, increased hepatic expression of genes involved in adipogenesis, decreased bone mineral content, and increased bone area. The body composition of adult male mice who had received penicillin after weaning was similar to that of controls.
Jess T. N Engl J Med 2014;371:

14. Principles of Anti-infective Therapy
Identification of the infecting organism and source of infection
Determination of antimicrobial susceptibility of infecting organism
Host factors
Previous adverse reactions
Age
Genetic or metabolic abnormalities
Pregnancy
Renal and hepatic function
Site of infection

15. Antibacterial Drug Classes
β-lactams
Aminoglycosides
Tetracyclines and chloramphenicol
Macrolides, clindamycin and ketolides
Glycopeptides
Polymyxins
Oxazolidiones
Quinolones
Metronidazole
Sulfonamides and Trimethoprim
Rifamycins

16. Which of the following antibiotic class has the most drug-drug interactions?
A. Penicillins
B. Fluoroquinolones
C. Macrolides
D. Aminoglycosides
E. Rifampin

17. β-lactams

18. β-lactams

19. How bacteria acquire genes that control resistance mechanisms
Transduction via bacteriophages (bacterial viruses) – specie specific
Transformation: scavenge and incorporate DNA from dead bacteria
Conjugation: cytoplasmic bridges between species with transfer of plasmids
Spontaneous mutations
David Gilbert MD

20. What is a plasmid? Extra chromosomal circular DNA
Can replicate independent of chromosomal DNA
Exchanged between species by conjugation
Can carry multiple antibacterial resistance determinants
David Gilbert MD

21. What is a transposon? Mobile short stretch of DNA
Can move between different point within a genome by a process termed transposition
Not capable of self-replication
David Gilbert MD

22. What is an integron?
Collects genes from transposons and forms chunks of DNA called cassettes
Integrons allow transposons/cassettes to move from chromosome to plasmid DNA
Then the plasmid DNA can spread via conjugation from one genus to another
David Gilbert MD

24. Challenges Determining Resistance Mechanisms
Bacterial have complex genetics including chromosomal and plasmid methods
Phenotypic determination requires interpretation and can be subjective
Molecular detection works well if the target of interest is known.

25. Major Mechanisms of Antibiotic Resistance
Enzymatic inactivation – β-lactams
Target site absent – intrinsic resistance
Target site modification – MRSA PBP2 to PBP2a
Excessive binding sites – hVISA and VISA
Altered cell wall permeability - porin channel shrink up
Drug efflux - tetracyclines

26. Common Resistant Organisms in New Mexico
Methicillin-resistant Staphylococcus aureus (MRSA)
Escherichia coli (ESBL)
Pseudomonas aeruginosa
Vancomycin resistant Enterococcus faecium (VRE)
Klebsiella pneumonia (ESBL and KPC)
Acinetobater sp
Stenotrophomonas maltophilia
Clostridium difficile

27. β-lactams Resistance β-lactams inhibit bacterial cell wall synthesis
Peptidoglycan in cell wall protects bacterial against osmotic rupture
β-lactams inactivate penicillin-binding proteins (PBPs)

28. β-lactams Resistance Destruction of antibiotic by β-lactamase
Failure of of antibiotic to penetrate the outer membrane of gram-negative bacteria to reach PBP targets
Efflux of drug across outer membrane of gram-negative bacteria
Low-affinity binding of antibiotic to target PBPs
NDM-1

29. Staphylococcal Resistance
Penicillin became commercially available in 1941
Staphylococcal resistance reported soon after
Staphylococcal cassette chromosome (SCCmec) carries mecA gene that encodes an altered PBP2 -- MRSA
mecC is a novel gene that confers resistance, often cefoxitin resistant and oxacillin susceptible

30. Arias CA, Murray BE. N Engl J Med 2009;360:439-443.
Common Mechanisms of Resistance in Methicillin-Resistant Staphylococccus aureus.
Common Mechanisms of Resistance in Methicillin-Resistant Staphylococccus aureus. The top three panels depict a schematic magnification of the bacterial cell wall. In Panel A, resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus is caused by the production of a β-lactamase enzyme (penicillinase) and a low-affinity penicillin-binding protein (PBP) 2a. In Panel B, high-level resistance to glycopeptides is caused by the replacement of the last amino acid of peptidoglycan precursors (D-alanine [D-Ala] to D-lactate [D-Lac]). In Panel C, low-level resistance to glycopeptides is associated with increased synthesis of peptidoglycan, “trapping” the antibiotic in outer layers and preventing its interaction with precursors exiting the cytoplasm through the cell membrane. In Panel D, mechanisms of resistance involve mutations or modifications in either the DNA or ribosomal RNA (rRNA). D-Glu denotes D-glutamate, L-Lys L-lysine, and UDP-GluNAc uridine diphosphate N-acetylglucosamine.
Arias CA, Murray BE. N Engl J Med 2009;360:

31. S. aureus Infections in Intensive Care Units in the National Nosocomial Infections Surveillance System, 1987 through 1997.
Figure 3. S. aureus Infections in Intensive Care Units in the National Nosocomial Infections Surveillance System, 1987 through 1997. Data include total infections, infections with methicillin-resistant strains, and infections with methicillin-resistant strains sensitive only to vancomycin. Isolates were tested for sensitivity to the following antimicrobial agents: gentamicin, tobramycin, amikacin, ciprofloxacin, clindamycin, erythromycin, chloramphenicol, trimethoprim–sulfamethoxazole, and vancomycin. Some hospitals did not test for susceptibility to all these antibiotics. Data were kindly provided by Dr. Robert Gaynes, Hospital Infection Program, National Center for Infectious Diseases.
Lowy FD. N Engl J Med 1998;339:

32. Vancomycin Resistance
hVISA: Heteroresistant VISA
Presence of subpopulations of VISA at a rate of 1 organism per 105 to 106 organisms
VISA: Vancomycin intermediate S. aureus
MIC for vancomycin is 4-8µg/ml
VRSA: Vancomycin resistant S. aureus
VRSA if the vancomycin MIC is ≥16µg/ml.

33. Mechanisms of S. aureus resistance to vancomycin
J. Clin. Invest. 111:1265–1273 (2003).

34. Carbapenem Resistant Organisms – CRE & KPC
Production of β-lactamase that hydrolyzes carbapenems
Diminished permeability
Efflux of drug across outer membrane of gram-negative bacteria
Production of altered PBP target
Intrinsic resistance – Proteus, Providencia, Morganella

35. Treatment of Resistant Organims
Consult local antibiogram
Consult Infectious Disease
Appropriate antibiotic therapy
Antibiotic stewardship

38. MRSA and VRE Prevalence and Incidence Rates from 2012 to 2014
Memorial Medical Center, Las Cruces NM

39. ESBL Rates from 2012 to 2014
Memorial Medical Center, Las Cruces NM

40. MRSA, VRE and E.coli Resistant to ciprofloxacin from 2002 to 2013
Memorial Medical Center, Las Cruces NM

41. Treatment of Resistant Bacteria – Staphylococcus sp
TMP-SMX
Doxycyline/Minocycline
Clindamycin
Linezolid
Vancomycin
Daptomycin
Telavancin
Tigecycline
Quinupristin-Dalfopristin
Oritavancin
Dalbavancin
Ceftaroline

42. Which of this drugs should not be used to treat MRSA that is resistance to erythromycin?
A. TMP-SMX
B. Doxycyline
C. Clindamycin
D. Linezolid
E. Vancomycin

43. D-test for Macrolide-Inducible Resistance to Clindamycin

44. Treatment of Resistant Bacteria – Enterococcus sp
Ampicillin
Vancomycin
Linezolid
Daptomycin
Quinupristin-Dalfopristin
Combination treatment
Penicillin G + gentamicin
Ampicillin + ceftriaxone
Ampicillin + gentamicin
Daptomycin + Ampicillin or ceftaroline

45. What is the drug of choice for treatment of pan-sensitive Enterococcus faecalis?
A. Ampicillin
B. Vancomycin
C. Linezolid
D. Gentamicin
E. Streptomycin

46. Treatment of MDR Gram-negative bacteria
Carbapenems
Colistin
Polymyxin
Tigecycline
Sulbactam
Doxycycline/Minocycline
Ceftazidime/Avibactam
Ceftolazone/tazobactam

47. Treatment of Resistant Bacteria – ESBL
Carbapenems
Cephalosporin-β-lactamase agents
Ceftazidime-avibactam
Ceftolazone-tazobactam
Aminoglycosides

48. Treatment of Resistant Bacteria – ESBL
Clinical Infectious Diseases 2015;60(9):

49. Treatment of Resistant Bacteria – MDR Pseudomonas
Carbapenems
Cephalosporin-β-lactamase agents
Ceftazidime-avibactam
Ceftolazone-tazobactam
Polymyxins
Aminoglycosides

50. What is the preferred dose of Piperacillin/tazobactam for treatment of Pseudomonas aeruginosa infections?
A g IV q6h
B g IV over 4 hours three times daily
C. 4.5 g IV over 4 hours three times daily
D. Continuous infusion of 13.5 g over 24 hours
E. Continuous infusion of 16 g over 24 hours

51. Carbpenems
Imipenem, meropenem and doripenem (but not Ertapenem) are active against P.aeruginosa and Acinetobacter
Used for ESBL producers and all are susceptible to Acinetobacter carbapenemases
Acinetobacter activity of Doripenem ≥ Imipenem > Meropenem, but differences are small
Doripenem may be more effective for P. aeruginosa than other carbapenems.
Use in combination therapy for MDR bacteria.
Larry Danziiger, PharmD, FIDSA

52. Polymyxins Active against most Gram-negative pathogens
>90% of Acinetobacter, P.aeruginosa, E.coli, Klebsiella and Citrobacter
>80% of Enterobacter are susceptible
Resistance increasing, particularly in P.aeruginosa, Acinetobacter, and KPC producers
Susceptibility issues/Formulation issues.
Clinical indications
Bacteremia
VAP
Meningitis
Now mainstay treatment for MDR
Larry Danziiger, PharmD, FIDSA

53. Tigecycline Broad spectrum Clinical indications Aerobes and anaerobes
Lacks activity for P. aeruginosa
Activity against MDR isolates
Clinical indications
VAP
Clinical resolution reported
Non-bacteremia
Low serum concentrations
Larry Danziiger, PharmD, FIDSA

54. Sulbactam Place in therapy VAP Bacteremia Meningitis
Aerosolized administration is experimental
Bacteremia
Meningitis
Limited data, non conclusive
Not available in the US
Larry Danziiger, PharmD, FIDSA

55. Doxycycline/Minocycline
Clinical indications
Minocycline has essentially the same spectrum of activity against mico-organisms as doxycycline
Stenotrophomonas maltophilia
MDR Acinetobacter baumannii
VAP?
Bactermia?
Larry Danziiger, PharmD, FIDSA

56. Combination Therapy
Targets multiple mechanisms of action thereby preventing resistance
Synergy among antibiotics resulting in broad spectrum
To reduce severity or incidence of adverse effects
No combination exhibits synergy consistently
Combination therapy remains controversial
Larry Danziiger, PharmD, FIDSA

57. Potential Combinations
Polymyxin B + carbapenems
Polymyxin B + rifampin
Polymyxin B + carbapenems + rifampin
Polymyxin B + Doxycycline
Polymyxin B + ceftriaxone
Carbapenems + rifampin
Tigecycline + aminoglycosides
Larry Danziiger, PharmD, FIDSA

58. Treatment of Resistant Bacteria – Clostridium difficile
Metronidazole
Oral vancomycin
Fidaxomicin
FMT

59. Questions?