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

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

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.

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).

Concentration Dependent Killing Pharmacodynamics Concentration Dependent Killing Fluoroquinolones Levofloxacin Ciprofloxacin Moxifloxacin Aminoglycosides Amikacin Tobramycin Gentamicin http://dx.doi.org/10.1590/S1517-83822007000200001  Braz. J. Microbiol. 2007;38(2).

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

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

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.

Vancomycin Linezolid Daptomycin Gram Positive Agents Vancomycin Linezolid Daptomycin

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

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 = 25-30 mg/kg Maintenance dose = 15-20 mg/kg Usual Frequency = every 8-24h Adjust dose for renal impairment Am J Health-Syst Pharm. 2009; 66:82-98.

Am J Health-Syst Pharm. 2009; 66:82-98. Vancomycin Adverse effects Redman syndrome Thrombocytopenia Possible nephrotoxicity ?? Ototoxicity (rare) Monitoring Goal Trough = 15-20 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.

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

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.

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

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.

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 - $$$

Aminoglycosides Aztreonam Gram Negative Agents Aminoglycosides Aztreonam

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

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.

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

**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**

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

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

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

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.

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

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;26:1320-32. Lodise. Clin Infect Dis 2007;44:357-63.

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

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.

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.

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. 2013. 

Fluoroquinolones Macrolides Tetracyclines Atypical Agents Fluoroquinolones Macrolides Tetracyclines

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

References

Commonly Encountered Infectious Disease Issues

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):000-000.

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):000-000.

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 2457043) 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.

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.

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

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