1. Antibiotic Review (80% of the knowledge, 80% of the time)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, Uottawa
Feb, 2015
print off mechanism of action wheel, flow chart beforehand
Avoid overtreating wound swab cultures and [+]ur C&S (catheterized or NH pts or recurrent UTIs being retested despite being asxs)
fosfomycin for recurrent UTI or other options used up or nosocomial UTIs

2. Objectives
Review clinically relevant pathogens in human disease in an ambulatory care setting
Review antibiotic classes and spectra of activity
Focus on bread and butter examples of each
Review treatment recommendations for common infections in primary care

3. Process Map the Bugs Map the Drugs Map the Battlefield
“Know your enemy”
Map the Drugs
“Save your ammo”
Map the Battlefield

4. Part 1 - Map the (Clinically Important) Bugs “Know your enemy”
Gram Negative
Aerobic
β-Lactamase Negative
Cocci (spheres)
Gram Positive
Bacilli (rods)
Anaerobic
β-Lactamase Positive

5. Map the Bugs Aerobes Anaerobes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Gram Positive Gram Negative Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

6. Anaerobes Above & below the diaphragm
Oral
Simple organisms
Easily handled by penicillins (beta-lactams)
Eg. Actinomyces Bifidobacterium Fusobacterium Lactobacillus Peptococcus Peptostreptococcus Propionibacterium
etc
Gut
Approx the same, except:
Human pathogens:
Bacteroides fragilis (B.frag)
Clostridium difficile (C.diff)
More virulent bugs requiring ‘bigger guns’…

7. Map the Bugs Aerobes Anaerobes Above & Below diaphragm 9
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]
Anaerobes
Above & Below
diaphragm
B.Frag
C.Diff 9 .

8. Map the Bugs Aerobes Anaerobes Below diaphragm 9 1 2 3 4 5 6 7 8
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 9 .

9. Gram[+] Bacilli Not usually pathogenic
Major Exception: Listeria monocytogenes
Listeriosis – enteritis, sepsis, meningitis +/- encephalitis

10. Map the Bugs Aerobes (Listeria) Anaerobes Below diaphragm 7
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
(Listeria)
β-L[+] β-L[-] b-L[+] b-L[-] β-L[+] β-L[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 7 .

11. Gm[-] Cocci Not usually pathogenic Major Exceptions:
Neisseria gonorrhea
Neisseria meningitidis
and
Moraxella catarrhalis
(formerly thought to be a type of Neisseria)

12. Map the Bugs Aerobes Anaerobes Below diaphragm 5 1 2 3 4
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
(Listeria) (Neisseria &
Moraxella)
β-L[+] β-L[-] β-L[+] β-L[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 5 .

13. β-Lactamase Enzymes
First penicillinase described in 1940’s even before penicillin was clinically available.
Most bugs produce some type of β-lactamase enzyme that destroys β-lactam antibiotics (pen’s, ceph’s, carbapenems)
Gm[+] cocci & β-lactamase [-]: Group A & B streps
give Penicillin
Beta hemolytic strep are all b-lactmase neg – all 100% pen sensitive – Group B, (obs) and now more prominent pathogens group C, group G, - oral and skin cellulitis pathogens

14. Map the Bugs Aerobes Anaerobes Below diaphragm 4 1 (G.A.S.) 2 3
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
(Listeria) (Neisseria &
Moraxella)
β-L[+] β-L[-] β-L[+] β-L[-]
1 (G.A.S.)
Anaerobes
Below
diaphragm
B.Frag
C.Diff 4 .

15. Gram Positive Gram Negative
Map the Bugs
Aerobes
Gram Positive Gram Negative
Cocci Bacilli
β-L[+] both β-L[+]&[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 3 .

16. Map the Clinically Important Bugs
Aerobes
Gram [+] Gram [-]
Cocci Bacilli
Atypicals
Legionella pneumonia
Chlamydia pneumonia
Mycoplasma pneumonia 3 .
Anaerobes
(esp. Gut organisms)
Eg. C-Diff
& B-frag 4 .

17. 1 - Gram [+] Cocci Staphylococcus S. aureus S. epidermidis
Methicillin resistant (MRSA)
Methicillin sensitive (MSSA)
S. epidermidis
Methicillin resistant (MRSE)
Methicillin sensitive (MSSE)
Skin commensal
Rarely pathogenic
Streptococcus
Group A (pyogenes) (β-Lact[-])
Group B (agalactiae) (β-Lact[-])
Neonates, v. elderly, obstetrics
S. pneumonia
etc. etc.
Enterococcus
(Formerly thought to be ‘Strep D’)
E. faecalis
E. faecium
A “mean” hospital organism 

18. 2 - Gram [-] Bacilli “Easy” to Kill Proteus mirabilis Escherichia coli
Klebsiella pneumonia
Salmonella
Shigella
Haemophilus influenza
(Moraxella catarrhalis) (actually a Gm[-] coccus)
PEcKSS-HiM
“Hard” to Kill
Serratia
Pseudomonas
Acinetobacter
Citrobacter
Enterobacter
SPACE bugs

19. 2.5 - Gram [-] Bacilli “Easy” to Kill Proteus mirabilis
Escherichia coli
Klebsiella pneumonia
Salmonella
Shigella
PEcKSS bugs
“Hard” to Kill
Serratia
Pseudomonas
Acinetobacter
Citrobacter
Enterobacter
SPACE bugs
?“Moderate” To Kill
Haemophilus influenza
(Moraxella catarrhalis) (actually a Gm[-] coccus)
HiM bugs

20. Gram Negative vs Gram Positive
Gm[-]: red on stain. (ie. Don’t retain stain) Gm[+]: blue-purple on stain;
Gm[-]: must pass through pores Gm[+]: molecules < 100kDa pass easily.
Gm[-]: b-lactamases concentrated in periplasmic space Gm[+]: b-lactamases diffuse outside cell;

21. Map the Bugs Summary Atypicals: Anaerobes: Gram positive aerobes:
Mycoplasma pneumo
Chlamydia pneumo
Legionella pneumo
Map the Bugs Summary
Anaerobes:
Oral
Gut – Bfrag & Cdiff
Gram positive aerobes:
Cocci
Staph
Aureus
MRSA (~8-10%)
MSSA
Epiderimidis
MRSE (~65%)
MSSE
Strep
Group A strep (pyogenes)
Group B strep (agalactiae)
Strep Viridans
Strep pneumo etc.
Enterococcus
Faecalis
Faecium
Bacilli
Listeria
Gram negative aerobes:
Bacilli
Easy to Kill
PEcKSS (Proteus, Ecoli, Klebsiella, Salmonella, Shigella)
HiM (H.flu and Moraxella (actually a Gm[-]coccus))
Hard to Kill
SPACE bugs (Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter)
Cocci
Neisseria
gonorrhaea
meningitidis
Moraxella catarhallis
Strep viridan – 10-20% resistant to clinda – fine with cefs

22. Map the Bugs - Summary Otitis media: S.pneumo, Hi,M
Conjunctivitis: viral
Sinusitis: viral
AECOPD: S.pneumo, Hi,M
Oral abscess: oral anaerobes
C.A.P: S.pneumo, atypicals –CAP+comorb./risk factors, or NHAP: also HiM bugs
Pharyngitis: viral
(Group A Strep)
Bronchitis: viral
Skin abscess: anaerobes, staph, strep
N.B. Boils = Staph
Cellulitis: MSSA, GAS, GBS
Pyelonephritis: PEcK
H.pylori:
Cdiff / Bfrag:
UTI (Cystitis): PEcK
Traveller’s Diarrhea: (80% bacterial): EcSS, (camphlyobacter)

23. Part 2 - Map the Drugs (Save your Ammo)

24. Map the Drugs Arms race! Older drugs tend to be simpler drugs
Remember: “Bigger guns breed higher walls”
Older drugs tend to be simpler drugs
More narrow spectrum
Broad spectrum drugs breed resistance
Superbugs develop
MRSA, VRE, ESBL, etc
Older drugs have more safety data
Tend to be less toxic
Learn their history
Learn their pharmacology

25. Part 2 - Map the Drugs “Save your Ammo”
Fluoroquinolones
Penicillins
Tetracyclines
Aminoglycosides
Macrolides
Vancomycin
Carbapenems
Cephalosporins
Clindamycin
Metronidazole

26. Antibiotics – Mechanisms of Action
From: Accessed Dec 28/12

27. Beta-Lactams - Penicillins
Amoxicillin / Ampicillin Cloxacillin / Methicillin
(po) (iv) (clinic) (lab)
Amox + Clavulanic acid
Anti-Staph
Anti-Strep

28. Beta-Lactams - Cephalosporins
1st Generation
Cephalexin (Keflex™)(or Cefadroxil) (po)
Cefazolin (Ancef™) (iv)
2nd Generation
Cefuroxime (po & iv)
3rd Generation
Ceftriaxone, Cefotaxime, Ceftazidime (iv)
Cefixime (Suprax™) (po)
4th Generation
Cefepime (iv)
Increasing Gram[-] coverage
Cefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID
- Same spectrum of activity, better serum and tissue levels, only QD-BID, cheap and covered by ODB too.
- Ceftaz, cefixime weak on MSSA – others are ok in general

29. Beta-Lactams – Other (FYI) (IV only, inpatient use only)
Piperacillin (plus tazobactam)
big gun, tazo = suicide substrate, like clavulanic acid
Carbapenems
Meropenem
Imipenem
Ertapenem
Monobactams
Aztreonam
Broad spectrum, big gun antibiotics that cover Gm[+], both easy and hard to kill Gm[-] bugs, even some anaerobes.

30. Antibiotics – Mechanisms of Action
From: Accessed Dec 28/12

31. Fluoroquinolones 2nd generation 3rd generation 4th generation
Ofloxacin
Ciprofloxacin
Norfloxacin
3rd generation
Levofloxacin
4th generation
Moxifloxacin
Covers: Gm[-]’s
PEcKSS-HiM & SPACE bugs
3rd and 4th gen. FQs cover strep pneumo. well too
Ofloxacin
Ciprofloxacin
Anti-pseudomonal – the only PO option!
Norfloxacin
Same spectrum as Cipro (even anti-Pseudomonal) – but only for cystitis UTI.
Concentrates in the G.U. system only
N.B. Not good enough for pyelonephritis or systemic infection

32. Fluoroquinolones The “Respiratory FQs” Levofloxacin Moxifloxacin
Concentrate in alveolar macrophages
Greater than serum concn
Levofloxacin
the more active L-enantiomer of Ofloxacin
Renal clearance
Moxifloxacin
Hepatic clearance
Enhanced coverage of:
Strep pneumo
Oral Anaerobes
Atypicals
N.B. only Moxi cover B.frag
Neither covers C.diff
(Both will cover Clostrium non-difficile strains)
Both have 100% oral bioavailability
Therefore PO = IV dose

33. Antibiotics – Mechanisms of Action
From: Accessed Dec 28/12

34. Macrolides Coverage of: Clarithromycin Azithromycin Erythromycin
Atypicals, Strep pneumo, & Hi.M. (Hflu & Mcat)
So, good for respiratory infections!
N.B. But doesn’t cover PEcKSS or SPACE bugs
Erythromycin
Efficacy: Poorer coverage of H.flu, MSSA
Toxicity:
Prokinetic = diarrhea!
Worse for QTc prolongation
Convenience: QID dosing
Clarithromycin
Better Hflu &MSSA coverage
Less QTc prolongation vs E
Shorter half-life vs Azithro
BID dosing x 7-10days
New daily ‘XL’ formulation
Azithromycin
An azalide, (not a macrolide)
Same spectrum of activity
Less QTc prolongation vs E & C!
Long t1/2 – QD dosing x 5d
BUT can breed resistant S.pneumo (since below [MIC] for long periods of time)

35. Antibiotics – Mechanisms of Action
From: Accessed Dec 28/12

36. Aminoglycosides Gentamicin Tobramycin Amikacin
Reserved for Pseudomonas aeruginosa
Amikacin
All excellent Gram[-] coverage:
PEcKSS-HiM and SPACE bugs
Efficacy: excellent Gm[-]
Toxicity:
Nephrotoxicity
Ototoxicity
Less now with daily dosing
Cost:
Cheap, old meds
Convenience
Now Once daily IV/IM

37. Pharmacodynamics Relationship between Abx Concentration & Effect
Concentration Dependent Killing
Higher the peak, better the kill
i.e. Ratio of peak drug concentration and M.I.C. determines rate of kill.
Eg. FQs, AGs
Time Dependent Killing
Time over MIC matters
i.e. Independent of peak concentration. Determined by length of time over MIC
Eg. B-lactams (Pen, Ceph etc)
Log [Conc]
Peak
Log [Conc]
MIC
MIC
Time (h)
Time (h)

38. Pharmacodynamics Relationship between Abx Concentration & Effect
Concentration Dependent Killing
Higher the peak, better the kill
i.e. Ratio of peak drug concentration and M.I.C. determines rate of kill.
Eg. FQs, AGs
With renal impairment:
Maintain the peak, lengthen the interval
This ensures good rate of killing while allowing enough time to eliminate the drug and avoid toxicities
For eg:
If CrCL = 90mL/min - Levofloxacin 750mg q24h po
If CrCL = 30mL/min – Levofloxacin 750mg q48h po
Peak
Peak
Log [Conc]
Log [Conc]
MIC
MIC
Time (h)
Time (h)

39. Pharmacodymamics Bactericidal vs Bacteriostatic
Bactericidal Abx
B-lactams (Pen, Ceph)
Aminoglycosides (AGs)
Fluoroquinolones (FQs)
Rifampin
Metronidazole
Vancomycin
Bacteriostatic Abx
Tetracyclines
Macrolides
Clindamycin
Chloramphenicol
Rarely a clinically important characteristic, unless the patient is immunocompromised or the risk of death with delayed/incorrect therapy is high.

40. Combination Therapy Why? Broaden spectrum
(eg. Mixed infection)
Synergistic activity for hard to kill bugs
(eg. Enterococcus or pseudomonas)
Prevent resistance
(eg. TB)
Reduce dose and side effects

41. Map the Drugs Pharmacology Summary
Many antibiotic classes
Beta-lactams generally safest agents.
Even at high doses
Some have overlapping mechanisms of action
Avoid combining similar mechanisms of action
Competing effects may reduce effectiveness of one agent
Eg. Penicillins + vancomycin – cell wall synthesis inhibitors
Eg. Tetracyclines + aminoglycosides –protein synthesis inhibitors via 30-S subunit of the ribosome

42. For: skin, dental infx (staph, strep, & anaerobes)
Map the Drugs – Summary
For: TB, MRSA
For: skin, dental infx (staph, strep, & anaerobes)
Clinda resistance higher in all groups of staph and strep all >10%, some >20-25%
(MSSA 25% MRSA 50% resistance)
plus some oral anaerobes
From: Accessed Dec 28/12

43. Part 3 – Map the Battlefield

44. Map the Battlefield Rational Prescribing
Individual
Efficacy
Could be reduced, BUT:
Empiric tx still effective if it is well chosen
(Lower risk infections, properly dosed, clinically stable, true indication etc.)
Toxicity
Reduced with narrow spectrum tx
Cost
Reduced with older tx
Convenience
Usually less convenient
Population
Efficacy
Maintained long term with lower resistance rates
Toxicity
Reduced since lifespan of older drugs is maintained
Cost
Reduced insurance costs, economic losses, hospital costs dealing with superbugs
Convenience
VS.

45. Map the Battlefield

46. Map the Bugs - Summary Otitis media: S.pneumo, Hi,M
Conjunctivitis: viral
Sinusitis: viral
AECOPD: S.pneumo, Hi,M
Oral abscess: oral anaerobes
C.A.P: S.pneumo, atypicals –CAP+comorb./risk factors, or NHAP: also HiM bugs
Pharyngitis: viral
(Group A Strep)
Bronchitis: viral
Skin abscess: anaerobes, staph, strep (GAS, GBS)
N.B. boils = staph
Cellulitis: MSSA, GAS, GBS
Pyelonephritis: PEcK
H.pylori:
Cdiff / Bfrag:
UTI (Cystitis): PEcK
Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter)

47. Map the Battlefield
Otitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)
Conjunctivitis: viral – no tx
Sinusitis: viral – no tx
AECOPD: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)
Oral anaerobes: abscess drainage +/- tx
(Amox 2g – pre dental sx?)
C.A.P: S.pneumo, atypicals – (Amox, Macrolides (Clarithro/Azithro))
CAP+comorb./risk factors, or NHAP: also HiM bugs (Combine AmoxClav or Cef2 + Macrolide (or use FQ))
Pharyngitis: viral – no tx
(Group A Strep – Pen VK)
Bronchitis: viral – no tx
Skin abscess: drainage +/- tx
Cellulitis: MSSA, GAS, GBS - (Clox, Cef1, & Clinda (more resistant)
H.pylori: triple po tx PPI + (Clarithro +/- Amox +/- Metro)
Pyelonephritis: PEcK – (Septra, Amox-Clav, FQ (not Norflox)
Cdiff / Bfrag: Metro / po Vanco
UTI (Cystitis): PEcK – (Septra, Macrobid, Amox+/-Clav, Norflox)
Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter) - Septra, FQ, (Azithro)

48. (Group A Strep, oral anaerobes, Neisseria)
Map the Battlefield
Penicillin
(Group A Strep, oral anaerobes, Neisseria)
Amoxicillin / Ampicillin Cloxacillin
(Strep & Enterococcus plus (Staph aureus, Staph epi)
Easy-to-Kill Gm[-](ie. PEcKSS))
Amox/Clav (Vancomycin)
(for Strep & Entero & PEcKSS-HiM) (for MRSA / MRSE)
(H.flu & Moraxella can be ~35% amox resistant) (~8-10% / ~ 65% resistant)

49. Beta-Lactams - Cephalosporins
MSSA and Strep & PEcKSS
(same as Amox)
N.B. never Enterococcus!
1st Generation
Cephalexin (Keflex™) or Cefadroxil (po)
Cefazolin (Ancef™) (iv)
2nd Generation
Cefuroxime (po & iv)
3rd Generation
Ceftriaxone, Cefotaxime, Ceftazidime (iv)
Cefixime (Suprax™) (po)
4th Generation
Cefipime (iv)
To boost: for PEcKSS-HiM
(same as Amox/Clav)
Increasing Gram[-] coverage
SPACE bugs: The Big Guns
Cefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID
- Same spectrum of activity, only BID, cheap and covered by ODB too.
serratia, enterobacter and citrobacter – have inducible beta-lactamase genes – avoid Cephalosporins in general

50. SPACE bugs The Big Guns: 3rd and 4th generation Cephalosporins
Carbapenems (Meropenem)
Piperacillin/Tazobactam
Aminoglycosides (Gentamicin, Tobramicin)
Fluoroquinolones (Levofloxacin, Moxi, Cipro)

51. Reserved for Pseudomonas
Ciprofloxacin (FQ)
The only PO agent!
(Use Norfloxacin for UTI if a FQ is needed)
Ceftazidime (Cef3)
Cefipime (Cef4)
Tobramycin (AG)
Piperacillin/Tazobactam
Meropenem

52. Need for Bigger guns
There is a higher risk of Gram negative SPACE bugs with:
More risk factors / comorbidities
COPD, HIV, Diabetes, CKD etc
More institutionalized settings
Community  Retirement Home  Nursing Home  Hospital ward  ICU  ventilated pt in ICU.

53. Map the Battlefield
PEN – for b-lact[-] Gm[+] cocci (GAS, GBS), oral anaerobes, Neisseria (meningitidis)
?What to do for Strep pneumo /Enterococcus?
Amox po / Amp iv (also good for PEcKSS)
How to boost? Amox/Clav (for HiM-PEcKSS)
?What to do for Staph?
Clox (MSSA, MSSE); Else Vanco (MRSA, MRSE)
What about Cef1? (cephalexin / cefadroxil po or cefazolin iv)
Maps to Amox/Amp for PEcKSS and strep
N.B. NOT Enterococcus (Cef’s never cover enterococcus!)
How to boost? Cef2 (cefuroxime) for HiM-PEcKSS
What about SPACE bugs?
FQs, AGs, Cef3, Cef4, Pip/Tazo, Meropenem)
Reserved for Ps aureginosa:(cipro, tobra, ceftazidime, cefipime, pip/tazo, meropenem)
What about gut anaerobes? (Metro/PO Vanco)
What about atypicals? (Macrolides, Tetracyclines (doxy))
Where does Septra fit? (analogous with Amox/Clav and Cef2)

54. Summary This is far from an exhaustive review
Some parts have been highly simplified for use in clinical practice
Some memorization is needed with regular review of the material to retain this knowledge
Doing so will allow you to choose empiric antibiotics with greater comfort in difficult situations and unfamiliar settings.

55. Case 1 Mr. PT 68 y.o. smoker with AE-COPD
Vitals stable; ambulatory; fever, productive cough, phlegm is green
PMHx: HTN, COPD
Allergies: penicillin
Meds: Tiotropium 18mcg qd, Ramipril 10mg qd
Expected pathogens?
Rx options?
Management of allergy status?
Rx: ________ ?
Explore allergy type – sensitivity vs allergy
Type 3 delayed hypersensitivity reactions – up to 21 days after exposure
Options: Amox +/- Clav, Cefuroxime, Septra to cover Strep pneumo, HiM bugs

56. Allergy status Severe diarrhea, pain Rash at age of 5 y.o.
Rash 2 weeks post Rx
involved hives (raised, intensely itchy spots that come and go over hours), with wheezing & swelling of the skin & throat
Major rash 3 yrs ago
flat, blotchy, spread over days but did not change by the hour
Anaphylaxis .
GI upset = side effect, not allergy
Rash - hypersensitivity not true allergy (IgE mediated)
“Only about 20 percent of people will be allergic to penicillin 10 years after their initial allergic reaction if they are not exposed to it again during this time period”
10% report allergy to penicillin (~90% not true allergy)
estimated frequency of anaphylaxis at 1-5 per cases of penicillin therapy.
the major determinant in the immunological reaction is the similarity between the side chain of first generation cephalosporins and penicillins, rather than the ß-lactam structure that they share. This means that the risk of an allergic reaction to cephalosporins in those with an established IgE-mediated allergy to penicillin may be low or non-existent,
- avoid Cef1; ok with Cef2, Cef3, Cef4