1. Critical Care Antibiotics
Kelli A. Rumbaugh, PharmD, BCPS
Surgical ICU Clinical Pharmacist
Vanderbilt University Medical Center
Nashville, TN

2. Objectives
To define terminology used to describe antimicrobials and bacteria
To review the mechanism of action, pharmacodynamics, adverse effects, and antimicrobial spectrum of commonly used antibiotics in the intensive care unit
To describe the incidence and treatment approach to penicillin allergic patients

3. Definitions Minimum Inhibitory Concentration Gram Stain Acid fast
Antimicrobial concentration that inhibits visible microbial growth in artificial media
Gram Stain
Gram positive
Gram negative
Acid fast
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
Fail to account for the fact that drug concentrations change throughout the dosing interval
Does not capture interpatient pharmacokinetic variability
Does not provide info on post-antibiotic effects
Gram staining, also called Gram's method, is a method of differentiating bacterialspecies into two large groups (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 theircell walls by detecting peptidoglycan, which is present in a thick layer in gram-positive bacteria.[1] 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.
Acid-fastness is 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.

4. Pharmacodynamics Beta-Lactams Time Dependent Killing Penicillin
Cephalosporins
Piperacillin-Tazobactam
Carbapenems
Meropenem
Ertapenem
Pharmacokinetics versus pharmacodynamics
Pharmacokinetics mathematically describe the relationship of antibiotic concentration to time.
Terminology that is typically associated with pharmacokinetics includes: absorption, distribution,
metabolism, elimination, half-life, volume of distribution, and area under the concentration-time
curve (AUC).
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), and
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.
Braz. J. Microbiol. 2007;38(2).

5. Concentration Dependent Killing
Pharmacodynamics
Concentration Dependent Killing
Fluoroquinolones
Levofloxacin
Ciprofloxacin
Moxifloxacin
Aminoglycosides
Amikacin
Tobramycin
Gentamicin
Braz. J. Microbiol. 2007;38(2).

6. Pharmacodynamics Vancomycin Linezolid Clindamycin Macrolides
AUC/MIC Dependent Killing
Vancomycin
Linezolid
Clindamycin
Macrolides
Azithromycin
Clarithromycin
Erythromycin
Braz. J. Microbiol. 2007;38(2).

7. 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

8. 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
Am J Respir Crit Care Med. 2005;171:388–416.
Clin Infect Dis. 2012;54(4):470–8.

9. Vancomycin Linezolid Daptomycin
Gram Positive Agents
Vancomycin
Linezolid
Daptomycin

10. 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

11. Am J Health-Syst Pharm. 2009; 66:82-98.
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 = mg/kg
Maintenance dose = mg/kg
Usual Frequency = every 8-24h
Adjust dose for renal impairment
Am J Health-Syst Pharm. 2009; 66:82-98.

12. Am J Health-Syst Pharm. 2009; 66:82-98.
Vancomycin
Adverse effects
Redman syndrome
Thrombocytopenia
Possible nephrotoxicity ??
Ototoxicity (rare)
Monitoring
Goal Trough = mcg/mL
Bacteremia, endocarditis, osteomyelitis, meningitis, pneumonia
Initial: trough before 4th or 5th dose
Maintenance: trough once weekly
Ototoxicity is not associated with trough concentrations.
Am J Health-Syst Pharm. 2009; 66:82-98.

13. 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

14. Linezolid Spectrum of activity Mechanism of action Adverse Effects
Staph (MSSA, MRSA), strep, VRE
Mechanism of action
Binds to bacterial ribosomes to inhibit protein synthesis
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
******* Bacteristatic against staph, vre but cidal against strep pneumon*****
Time dependent killing
Product Information: ZYVOX(R) Pharmacia and Upjohn Company, New York, NY, 2008.

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

16. Clin Infect Dis 2011; 52(3):e18-e55.
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
Product Information: CUBICIN® Cubist Pharmaceuticals, Inc, Lexington, MA, 2010.
Clin Infect Dis 2011; 52(3):e18-e55.

17. 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 minutes to reconstitute
Expensive - $$$

18. Aminoglycosides Aztreonam
Gram Negative Agents
Aminoglycosides
Aztreonam

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

20. Aminoglycosides Spectrum of activity Mechanism of action
Medications
Gentamicin
Tobramycin
Amkicacin
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
Aminoglycoside antibiotics possess nondepolarizing neuromuscular blocking activity, which is additive or synergistic with the effects of the nondepolarizing neuromuscular blocking agents used in anesthesia (Foldes et al, 1963). Aminoglycosides cause presynaptic inhibition of acetylcholine release and postsynaptic reduction in sensitivity (Levanen & Nordman, 1975; Warner & Sanders, 1971; Pittinger et al, 1970). Respiratory depression or prolonged apnea has been well documented with combinations of aminoglycosides and nondepolarizing neuromuscular blockers (Hasfurther & Bailey, 1996; Pridgen, 1956; Geha et al, 1976; Bennett et al, 1975; Chapple et al, 1983). Respiratory depression has occurred following various aminoglycoside routes of administration, including intravenous, intraperitoneal, intramuscular, oral, intraluminal, intrapleural, and irrigation.

21. Aminoglycosides Clinical Pearls Used for Two dosing schemes
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

22. **Can be used with penicillin allergy**
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**

23. Cephalosporins Piperacillin-Tazobactam Carbapenems
Mixed Spectrum Agents
Cephalosporins
Piperacillin-Tazobactam
Carbapenems

24. Cephalosporins 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
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
and Gram-negative species (Haemophilus influenzae and

25. 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

26. Fluoroquinolines Medications Ciprofloxacin Levofloxacin Moxifloxacin
Gemifloxacin
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
S. pneumoniae
Anaerobes
- - -
Clinical Use
Gram (-) infections,
Bone/Joint
PNA, UTI
PNA
NOT: UTI
Jl of Antimic Chemo. 2003;51:S1, 13–20.

27. 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
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

28. Piperacillin-Tazobactam
Clinical Pearl
Extended infusion = 3.375g Q8h
Clinical Pearls
False positive galactomannan antigen assay
Not used for c. difficle infections
Extended infusion dosing
Figure A on the left:
Showing the probability of target attainment with the target being the time above MIC. Goal time above MIC is 50% of the time.
Figure on the right:
Comparison of 14 and 30 day mortality comparing extended infusion and traditional dosing. Traditional dosing is over 30minutes.
The study was looking at treatment of pseudomonas
Total of 111 patients
As you can see, the extended in
Lodise. Pharmacotherapy 2006;26:
Lodise. Clin Infect Dis 2007;44:

29. Imipenem - Cilastatin (Primaxin®)
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
Common Use
Meningitis
Intra-abdominal
Nocardia
NOT: Pneumonia

30. Pharmacotherapy 2006;26(9):1320–1332.
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
Pharmacotherapy 2006;26(9):1320–1332.

31. Tigecycline Spectrum of activity Mechanism of action Dose
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
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
Product Information: TYGACIL(R) Wyeth Pharmaceuticals, Inc, Philadelphia, PA, 2013.

32. 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
All-cause Mortality: An increase in all-cause mortality has been observed in a meta-analysis of 13 Phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator. The cause of this mortality risk difference of 0.6% (95% CI, 0.1, 1.2) 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
FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. U.S. Food and Drug Administration (FDA). Rockville, MD  

33. Fluoroquinolones Macrolides Tetracyclines
Atypical Agents
Fluoroquinolones
Macrolides
Tetracyclines

34. Atypical Bacteria Agents Bacteria Mycoplasma Legionella pneumoniae
Fluoroquinolones
Levofloxacin
Ciprofloxacin
Moxifloxacin
Gemifloxacin
Macrolides
Azithromycin
Erythromycin
Clarithromycin
Tetracyclines
Tetracycline
Doxycycline
Minocycline
Mycoplasma
Legionella pneumoniae
Chlamydia pneumoniae
Richettsia
Actinomyces
Mycoplasma vs. mycobacteria
Clinical Pearls
Uses
Community acquired pneumonia
Opportunistic infections
Tic born illness
COPD exacerbations

35. References

36. Commonly Encountered Infectious Disease Issues

37. Clostridium Difficile
Antimicrobials per IDSA Guidelines
The criteria proposed in Table 3 for defining severe or complicated CDI are based on expert opinion. These criteria may need to be reviewed in the future, on publication of prospectively validated severity scores for patients with CDI.
Infect Control Hosp Epidemiol. 2010;31(5):

38. 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
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.
**PO vancomycin is only used to treat c. diff infection**
Infect Control Hosp Epidemiol. 2010;31(5):

39. Allergic Reactions IgE reactions Anaphylaxis Bronchospasm Angioedema
Pruritic rash
Uticaria
Hypotension
Limitations of the literature:
Diagnosis of pcn allergy: skin test vs. self report vs. radioabsorbant testing (blood)
Most are unblinded open studies
Most lack a control group
Early studies in the 1970’s looking at pcn and cephalosporins had know contaimination of pcn in the cephalsporins produced at the time. No contamination after 1980
Early reports did not state the nature of the reaction
Only 10-15% on patients who have a stated PCN allergy will have a positive skin test.
Patients with an allergy a long time ago will more than likely tolerate a non-R1 side chain cephalosporin. IgE levels decrease over time.
Carbapenems:
Base on skin testing (which is not validated), there was a 50% (10/20) reaction rate to carbapenems with a reported PCN allergy (PMID )
Carbapenems (ie, imipenem, meropenem, doripenem, and ertapenem) share a common beta-lactam ring with penicillins and hence the potential for allergic cross-reactivity
J Emerg Med. 2012;42(5):612–620.

40. J Antimicrob Chemother. 2004;54(6):1155.
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?
Graded challenge or PCN skin test
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 (table 3). 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.
J Chemother. 2008;20(2):233.
Clin Infect Dis. 2000;31(6):1512.
Clin Infect Dis. 2004;38(8):1102
Pharmacotherapy. 2007;27(1):137.
J Antimicrob Chemother. 2004;54(6):1155.
J Emerg Med. 2012;42(5):612–620.

41. Treatment Approach
Clin Infect Dis. 2002; 35:26–31.

42. Critical Care Antibiotics
Kelli A. Rumbaugh, PharmD, BCPS
Surgical ICU Clinical Pharmacist
Vanderbilt University Medical Center
Nashville, TN