أستاذنا الدكتور سمير الأنصاري

1. ANTIBIOTICS
2015 IN ICU
SAMIR EL ANSARY

2. CriticalCare Antibiotics

3. Definitions
• Minimum Inhibitory Concentration
– Antimicrobial concentration that inhibits visible
microbial growth in artificial media
• Gram Stain
– Gram positive
– Gram negative
• Acid fast

4. • Problems with MIC:
•Fixed drug concentration
•All or none parameter. Growth vs. no growth
•Does not provide information on the time course of
antimicrobial activity
•Drug concentrations change throughout the dosing
interval
•Does not capture interpatient pharmacokinetic
variability
•Does not provide info on post-antibiotic effects

5. Gram staining
FOR differentiating bacterialspecies into (gram-
positive and gram-negative).
The name comes from its inventor, Hans Christian
Gram.
Gram staining differentiates bacteria by the chemical
and physical properties of their cell walls by
detecting peptidoglycan, which is present in a thick
layer in gram-positive bacteria.

6. Gram staining
In a Gram stain test, gram-positive bacteria retain
the crystal violet dye, while a counterstain
(commonly safranin or fuchsine) added after
the crystal violet gives all gram-negative
bacteria a red or pink coloring.

7. Acid-fastness
A physical property of certain bacteria (and, less
commonly, protozoa), specifically their resistance to
decolorization by acids during staining procedures.
The high mycolic acid content of certain Protozoa cell
walls, and those of Mycobacteria, is responsible for
the staining pattern of poor absorption followed by
high retention. Usually used to identify
mycobacteria.

8. Pharmacodynamics
Time Dependent Killing
• Beta-Lactams
– Penicillin
– Cephalosporins
– Piperacillin-Tazobactam
– Carbapenems
• Meropenem
• Ertapenem

9. • Pharmacokinetics versus
pharmacodynamics
•Pharmacokinetics mathematically describe the
relationship of antibiotic concentration to time.
• Aabsorption, distribution, metabolism, elimination,
half-life, volume of distribution, and area under the
concentration-time curve (AUC).

10. •Pharmacodynamics
•Describe the relationship of antibiotic concentration
to pharmacologic effect or microorganism death.
• The three main pharmacodynamic parameters that
are used are the
• peak to minimal inhibitory concentration ratio
(peak/MIC), the AUC to MIC ratio (AUC/MIC)

11. •Pharmacodynamics
• The time the drug concentration remains
above the MIC (T>MIC).
• Concentration independent antimicrobials include: beta-
lactams, vancomycin, macrolides, aztreonam, carbapenems,
clindamycin, tetracyclines, quinupristin/dalfopristin,
flucytosine, and azole antifungals.

12. Pharmacodynamics
Concentration Dependent Killing
• Fluoroquinolones
– Levofloxacin
– Ciprofloxacin
– Moxifloxacin
• Aminoglycosides
– Amikacin
– Tobramycin
– Gentamicin

13. Pharmacodynamics
AUC/MIC Dependent Killing
• Vancomycin
• Linezolid
• Clindamycin
• Macrolides
– Azithromycin
– Clarithromycin
– Erythromycin

14. Keys to Success
• Antibiotic covers potential infection/bacteria
• Dose of antibiotic is appropriate for treatment
of infection and adjusted for renal/hepatic
impairment
• Antibiotic penetrates site of infection
• Antibiotic is being absorbed
• Adequate treatment duration

15. Risk Factors for Resistance
• Antimicrobial therapy in the preceding 90 days
• Current hospitalization of 5 days or more
• High resistance rates in the unit
• Residence in a nursing home or extended care facility
• Immunocompromised
• Home wound care
• Chronic dialysis

16. Gram Positive Agents
Vancomycin
Linezolid
Daptomycin

17. Gram Positive Bacteria
• Cocci
– Staphylococcus
• S. aureus
• S. epidermidis
– Streptococcus
• S. pyogenes (Group A)
• S. viridians
• S. pneumoniae
– Enterococcus
• E. faecalis
• E. Faecium
• Bacilli
– Listeria monocytogenes
– Bacillus anthracis
– Corynebacterium species
– Proprionibacterium acnes

18. Vancomycin
• Spectrum of activity
– Staph (MRSA, MSSA), strep, enterococcus, c. difficile colitis (oral)
• Mechanism of action
– Inhibits synthesis of peptidoglycan/bacterial cell wall formation
• Dosing
– Actual body weight
– Loading dose = 25-30 mg/kg
– Maintenance dose = 15-20 mg/kg
– Usual Frequency = every 8-24h
– Adjust dose for renal impairment

19. Vancomycin
• Adverse effects
– Redman syndrome
– Thrombocytopenia
– Possible nephrotoxicity ??
– Ototoxicity (rare) Ototoxicity is not associated with trough
concentrations.
• Monitoring
– Goal Trough = 15-20 mcg/mL
– Bacteremia, endocarditis, osteomyelitis, meningitis, pneumonia
– Initial: trough before 4th or 5th dose
– Maintenance: trough once weekly

20. Vancomycin with Dialysis
• Continuous renal replacement therapy (CRRT)
– 15mg/kg q24h
– Hold dose if CRRT stopped > 8h
– Trough before 4th or 5th dose
• Intermittent hemodialysis (iHD)
– Pulse dosing with iHD
– iHD removes ~25% of vancomycin
– Goal Pre-iHD level < 24 mcg/mL
– Initial dose = 15mg/kg x1 dose
– Maintenance dose based on pre-iHD levels

21. Linezolid
• Spectrum of activity
– Staph (MSSA, MRSA), strep, VRE
• Mechanism of action
– Binds to bacterial ribosomes to inhibit protein
synthesis
• Bacteristatic against staph, vre but cidal
against strep pneumon
• Time dependent killing

22. Linezolid
• Adverse Effects
– Myelosupression (pancytopenia, thrombocytopenia)
– GI upset
– Serotonin syndrome
• Drug interactions
– Monoamine oxidase inhibitors (MAOI’s)
– Selective serotonin reuptake inhibitors (SSRI’s)
• Dosing
– 600mg IV/PO q12h

23. Linezolid
• Clinical Pearls
– May be used for vancomycin failure or intolerance
– Oral & IV formulations
– Bacteriostatic
– No renal adjustment
– May have prescribing restrictions
– Expensive

24. Daptomycin
• Spectrum of activity
– Staph (MSSA, MRSA), strep, enterococcus (VRE)
• Mechanism of action
– Causes bacterial membranes to depolarize leading to inhibition of
protein, DNA, and RNA synthesis
• Typical Dosing
– Adjust with renal impairment
– 4-6 mg/kg (actual weight) q24-48h
• Adverse Effects
– Arthralgia
– Myalgia
– CPK elevations

25. Daptomycin
• Clinical Pearls
– Not for treatment of pneumonia
– Can use doses of 8-10 mg/kg for severe infections
– Monitor CPK at baseline and weekly
– Can falsely elevate INR
– May have prescribing restrictions
– Takes 30-60 minutes to reconstitute
– Expensive

26. Gram Negative Agents
Aminoglycosides
Aztreonam

27. Gram Negative Bacteria
Cocci
• Neisseria gonorrhoeae
• Neisseria meningitidis
• Moraxella catarrhalis
Bacilli
• Pseudomonas aeruginosa
• Acinetobacter species
• Citrobacter species
• Enterobacter species
• Klebsiella pneumoniae
• E. Coli
• H. influenzae
• Proteus mirabilis
• S. maltophilia

28. Aminoglycosides
• Spectrum of activity
– Only gram negative, gram positive synergy
• Mechanism of action
– Bind bacterial ribosome and inhibit protein synthesis
• Adverse effects
– Nephrotoxicity
– Ototoxicity
– Prolonged neuromuscular blockade
Medications
Gentamicin Tobramycin Amkicacin

29. • Aminoglycoside antibiotics possess
nondepolarizing neuromuscular blocking
activity, which is additive or synergistic with
the effects of the nondepolarizing
neuromuscular blocking agents used in
anesthesia .
• Aminoglycosides cause presynaptic inhibition
of acetylcholine release and postsynaptic
reduction in sensitivity

30. Aminoglycosides
• Clinical Pearls
– Used for
• Nosocomial infections
• Double gram negative coverage
• Endocarditis (synergy)
– Two dosing schemes
• Traditional dosing
• Extended interval dosing/once daily dosing
– Levels must be monitored
• Traditional = peak & trough around 3rd dose
• Extended interval = trough before 2nd dose
– Monitor Scr daily

31. Aztreonam
• Class
– Monobactam
• Spectrum of activity
‒ Gram positive: none
‒ Gram negative: most, except S. maltophilia
• Mechanism of action
– Inhibit cell wall synthesis
• Dosing
– Usual: 1-2g IV Q8h
– Meningitis: 2g IV Q6-8h
• Adverse effects (rare)
– Transient eosinophilia
– LFT elevations
– Thrombocytopenia
**Can be used with
penicillin allergy**

32. Mixed Spectrum Agents
Cephalosporins
Piperacillin-Tazobactam
Carbapenems

33. Spectrum of Activity Primary Use
First Generation
Cefazolin (Ancef) (IV)
Cephalexin (Keflex) (PO)
• Simple Gram (+) , simple gram (-) , no
anaerobes. No ceph gets enterococci.
• Simple SSTI, surgical prophylaxis
Second Generation
Cefotetan (Cefotan) (IV)
Cefoxitin (Mefoxin) (IV)
Cefuroxime (Ceftin) (IV)
Cefaclor (Ceclor) (PO)
Cefprozil (Cefzil) (PO)
• Same spectrum as 1st Generation
• Cefotetan and Cefoxitin cover anaerobes
• Surgical prophylaxis if anaerobes,
URTI, UTI
Third Generation
Ceftriaxone (Rocephin) (IV)
Cefotaxime (Claforan) (IV)
Ceftazadime (Fortaz) (IV)
Cefpodoxime (Vantan) (PO)
Cefdinir (Omnicef) (PO)
Cefixime (Suprax) (PO)
• Better gram (-)
• Ceftazadime-pseudomonas • PNA, meningitis
Fourth Generation
Cefepime (Maxipime) (IV)
• Good gram (+), nosocomial gram (-)
including pseudomonas
• No anaerobes
• Sepsis, HAP, neutropenic fever
Fifth Generation
Ceftaroline (Teflaro)
• MRSA, MSSA, E. faecalis, s.pneumoniae,
• Some gram (-), NO pseudomonas
• Pneumonia, SSTI
Cephalosporins

34. • CABP pathogens, ceftaroline has activity
against the Gram-positive organisms S.
pneumoniae, S. aureus and Streptococcus
pyogenes, and Gram-negative species
(Haemophilus influenzae and CABP
pathogens, ceftaroline has activity against the
Gram-positive organisms S. pneumoniae, S.
aureus and Streptococcus pyogenes, and
Gram-negative species .

35. Cephalosporins
• Clinical Pearls
– Do not cover enterococcus (except ceftaroline)
– ↑ gram negative coverage with higher generations
– Used for surgical prophylaxis
– Anaerobic coverage
• Cefoxitin
• Cefotetan
– Pseudomonas coverage
• Ceftazidime
• Cefepime

36. Fluoroquinolines
Medications
Ciprofloxaci
n
Levofloxacin Moxifloxacin
Gemifloxaci
n
Mechanism
of Action
Inhibit DNA gyrase and topoisomerase IV inhibiting DNA synthesis
Spectrum of
Activity
• Gram Negative: Enterobacteriaceae, Haemophilus spp,
Neisseria spp and M. Catarrhalis
• Atypicals
Pseudomonas
Pseudomonas
S. pneumoniae
Anaerobes
S. pneumoniae
- - -
Clinical Use
Gram (-)
infections,
Bone/Joint
PNA, UTI
PNA
NOT: UTI
PNA

37. Piperacillin-Tazobactam
• Spectrum of activity
– Gram negative: P. aeruginosa, Enterbacteriaceae
– Gram positive: MSSA, Enterococci, Strep
– Anaerobes
• Mechanism of action
– Inhibit cell wall synthesis
• Adverse effects
– Gastrointestinal intolerance
– C. difficle colitis
– Interstitial nephritis

38. • Mechanism of Action:
•Inhibit mucopeptide synthesis in the bacterial cell
wall, thus results in formation of defective cell walls
and osmotically unstable organisms susceptible to cell
lysis
•Tazobactam acts as a beta-lactamase inhibitor and
inactivates both plasmid and chromosome mediated
beta-lactamases

39. Carbapenems
Meropenem
(Merem®)
Ertapenem
(Invanz®)
Imipenem -
Cilastatin
(Primaxin®)
Doripenem
(Doribax®)
Mechanism of
Action
Inhibit cell wall synthesis
Spectrum of
Activity
Broad Spectrum: Gram (+), Gram (-), ESBL, Anaerobes
NOT: MRSA
--
NOT: Pseudomonas,
Enterococcus,
Acinetobacter
-- --
Adverse Effects
↓ Platelets
Drug Fever
Seizure
↓ Platelets
Drug Fever
Common Use Meningitis Intra-abdominal Nocardia NOT: Pneumonia

40. Carbapenems
• Clinical Pearls
– First line agent for extended spectrum beta-lactamase
(ESBL) producing bacteria
– Extended infusion meropenem
• ↑ time above MIC
– Reserved for severe infections
– May have prescribing restrictions

41. Tigecycline
• Spectrum of activity
– Enterococcus (including VRE), MSSA, MRSA, MRSE, anaerobes
– Not pseudomonas, proteus, providencia
• Mechanism of action
– Binds to bacterial ribosomes to inhibit protein synthesis
• Dose
– 100mg IV x 1 dose
– 50mg IV q12h
• Adverse effects
– Nausea and vomiting
– Hyperbiliruminemia

42. •Tigecycline has a spectrum of activity
that includes anaerobes, many gram-
positive cocci and gram-negative
bacilli w/ the exception of
Pseudomonas, Proteus, and
Providencia.
•N/V may occur in up to 2/3rds of
patients

43. Tigecycline
• Clinical Pearls
– No renal adjustment
– Hepatic dose adjustment (Child Pugh C)
• 100mg IV x 1, then 25mg IV Q12h
– Used for resistant infections
– Do not use for
• Ventilator associated pneumonia
• Bacteremia
– Can be used for
• Intra-abdominal infections
• Skin & soft tissue infections

44. •All-cause Mortality:
•An increase in all-cause mortality has been observed
•The cause of this mortality risk difference has not
been established.
•Tigecycline should be reserved for use in situations
when alternative treatments are not suitable.
•Death resulted from progression of infection
•Especially in ventilator associated pneumonia
•Reserve for use when other agents are not an
option

45. Atypical Agents
Fluoroquinolones
Macrolides
Tetracyclines

46. Atypical Bacteria
Agents
• Fluoroquinolones
– Levofloxacin
– Ciprofloxacin
– Moxifloxacin
– Gemifloxacin
• Macrolides
– Azithromycin
– Erythromycin
– Clarithromycin
• Tetracyclines
– Tetracycline
– Doxycycline
– Minocycline
Bacteria
• Mycoplasma
• Legionella pneumoniae
• Chlamydia pneumoniae
• Richettsia
• Actinomyces

47. Commonly EncounteredInfectiousDisease
Issues

48. Clostridium Difficile
Antimicrobials per IDSA Guidelines

49. Clostridium Difficile
• IDSA Recommendations
– No probiotics - ↑ Bloodstream infections
– Stop causative antimicrobials
– Repeat testing during the same episode is discouraged
– Vancomycin taper after second reoccurrence
– Dual antimicrobials
• Ileus = IV metronidazole + vancomycin enema
**PO vancomycin is only used to treat c. diff infection**

50. • There is no evidence to support administration of
combination therapy to patients with uncomplicated
CDI.
• Although hampered by its low statistical power, a
recent trial did not show any trend toward better
results
when rifampin was added to a metronidazole
regimen.
• There is no evidence to support use of a combination
of oral metronidazole and oral vancomycin.

51. Allergic Reactions
• IgE reactions
– Anaphylaxis
– Bronchospasm
– Angioedema
– Pruritic rash
– Uticaria
– Hypotension

52. Penicillin Allergy
Avoid Use
Incidence of
Reaction
May Use
Cephalosporins
• 1st/2nd generation
cephalosporin
2% • Aztreonam
• 3rd/4th generation
cephalosporin
Carbapenems
• None? 0-11% • All carbapenems?
• Aztreonam
• Graded challenge or PCN
skin test

53. •Penicillin-cephalosporin cross-reactivity studies that
confirmed penicillin allergy by skin testing are superior
in design compared with those that diagnosed
penicillin allergy by history alone.
•Another group of studies evaluated patients with
positive penicillin skin tests (to penicilloyl polylysine
[PPL], penicillin G, and/or the minor determinant
mixture [MDM]) who were challenged with
cephalosporins and found an overall reaction rate of
3.4 percent .

54. •If this analysis is limited to studies published after
1980 (when cephalosporins were no longer
contaminated with penicillin), the reaction rate is
reduced to 2 percent.
•Thus, approximately 2 percent of patients with skin-
test proven sensitivity to penicillin can be expected to
react to cephalosporins.
•Range for cephalosporin reaction was 0-12% reported
in the literature.

55. Treatment Approach

56. GOOD LUCK
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO
elansarysamir@yahoo.com