45: Antimicrobial Therapy


CHAPTER 45
Antimicrobial Therapy


Steven B. Levy1, Alejandro Díaz Chávez2, and Amy S. Rosenberg3


1 Mount Sinai Morningside‐West, New York, NY, USA


2 Division of CHI Mercy Health, Roseburg, OR, USA


3 Icahn School of Medicine at Mount Sinai, New York, NY, USA


Background



  • Infection in ICUs is associated with considerable morbidity, mortality, and expense.
  • About 50% of patients in ICUs are infected and about 70% receive antibiotics.
  • The costs associated with infection may account for as much as 40% of total ICU expenditures.
  • When designing an antimicrobial regimen, the pharmacology of anti‐infectives involves many factors.

    • Organism: local susceptibility patterns, minimum inhibitory concentration (MIC), resistance mechanisms.
    • Drug: pharmacokinetics, pharmacodynamics (PD), tissue penetration, potential adverse effects, interactions, resistance, cost.
    • Host: source and site of infection, recent antimicrobial therapy, allergies, age, weight, organ function, comorbidities, immunocompromised state, concomitant therapy, pregnancy.

  • See Table 45.1 for guidelines regarding the empiric selection of antimicrobials for the most common infections based on the most likely organism responsible for the infection.

Table 45.1 Guide to empiric antimicrobial therapy in the critical care unit.































































Type of infection Common pathogens Empiric selection Clinical pearls
Bacterial meningitis
2–50 years old


>50 years old




Post‐neurosurgery or penetrating trauma		 Neisseria meningitidis, Streptococcus pneumoniae


S. pneumoniae, N. meningitidis, Listeria monocytogenes, aerobic Gram‐negative bacilli


Aerobic Gram‐negative bacilli (including Pseudomonas aeruginosa), Staphylococcus aureus, coagulase‐negative staphylococci		 Vancomycin plus
ceftriaxone or cefotaxime
± rifampin (with steroids only)

Ampicillin plus
vancomycin plus
ceftriaxone or cefotaxime
± rifampin (with steroids only)

Vancomycin plus
cefepime or ceftazidime or meropenem		 Duration of treatment:
Pneumococcus: 10–14 days
Listeria: ≥21 days
Intravascular catheter‐related blood stream infection
Not neutropenic or septic


Neutropenia or sepsis		 Coagulase‐negative staphylococci, S. aureus

Above plus Gram‐negative bacilli (GNB) including P. aeruginosa

Consider empiric treatment of candidemia for patients with: total parenteral nutrition, prolonged exposure to antibiotics, hematologic malignancy, organ transplantation, femoral catheterization, or colonization due to Candida species		 Vancomycin or daptomycin (if high rates of MRSA with vancomycin MIC >2 mg/L)

Vancomycin plus
cefepime or piperacillin‐tazobactam

Echinocandin (or fluconazole in selected patients)		 Catheter should be removed in sepsis and/or presence of a virulent pathogen
Clostridium difficile infection (CDI) – initial episode
Asymptomatic colonization (positive C. difficile test without diarrhea, ileus, or colitis)

Non‐severe disease (positive C. difficile test with diarrhea, WBCs ≤15 000/mm3 and serum creatinine <1.5 mg/dL)

Severe (e.g. WBCs > 15 000/mm3 or serum creatinine ≥ 1.5 mg/dL)



Fulminant (hypotension or shock, ileus, megacolon)		 Clostridium difficile No treatment



PO vancomycin or fidaxomicin



PO vancomycin or fidaxomicin



PO vancomycin plus
IV metronidazole
± vancomycin retention enema
(500 mg/100 mL normal saline every 6 hours)



Duration of treatment: 10 days


Early surgical consultation

Surgical consultation
Febrile neutropenia
Inpatient IV antibiotics (high risk – anticipated neutropenia >7days, clinically unstable or medical comorbidities)
Catheter‐related, skin and soft tissue infections, pneumonia or hemodynamic instability

Abdominal symptoms


Febrile after 4–7 days on broad spectrum antibiotics


Febrile >4 days and hemodynamically unstable		 Gram‐positive cocci (GPC) (staphylococci, streptococci)
GNB (including P. aeruginosa), rarely anaerobes

GPC, GNB, MRSA



GPC, GNB, anaerobes


GPC, GNB, fungus (Candida sp, Aspergillus sp.)


Resistant GPC, GNB, anaerobes, fungus		 Piperacillin/tazobactam or imipenem or meropenem or cefepime or ceftazidime


Beta‐lactam as above plus vancomycin



Beta‐lactam as above plus metronidazole for additional anaerobic coverage

Consider empiric antifungal coverage: echinocandin or voriconazole or amphotericin B preparation

Antifungal coverage as above
Coverage for resistant bacteria
Spontaneous bacterial peritonitis


Secondary peritonitis (e.g. bowel perforation, ruptured appendix)		 Enterobacteriaceae, S. pneumoniae, enterococci

Enterobacteriaceae, Bacteroides sp., enterococci, P. aeruginosa		 Cefotaxime or ceftriaxone or piperacillin‐tazobactam

Piperacillin‐tazobactam or
cefepime plus metronidazole or
ciprofloxacin plus metronidazole		 Can use other regimens which cover Gram‐negative aerobic and anaerobic organisms
Pneumonia
Community‐acquired pneumonia admitted to ICU









Hospital‐acquired pneumonia









Ventilator‐associated pneumonia		 S. pneumoniae, Legionella sp., Haemophilus influenzae, Enterobacteriaceae, S. aureus, atypical respiratory pathogens

Above plus risk for P. aeruginosa








Average risk of P. aeruginosa or other GNB

Risk factors increasing likelihood of P. aeruginosa or other GNB or high risk of mortality

Risk factors for MRSA or high mortality risk

S. aureus, P. aeruginosa, Klebsiella pneumoniae, Acinetobacter sp., other Gram‐negative bacilli

Risk factors for antimicrobial resistance


Risk factors for MRSA		 A beta‐lactam (cefotaxime, ceftriaxone, or ampicillin‐sulbactam) plus either azithromycin or a fluoroquinolone


Piperacillin‐tazobactam or cefepime or imipenem or meropenem plus
ciprofloxacin or levofloxacin
or
Above beta‐lactam plus
an aminoglycoside plus
either azithromycin or a fluoroquinolone

Cefepime or piperacillin‐tazobactam or levofloxacin or imipenem or meropenem
Prescribe antibiotics from two different classes with antipseudomonal activity as above. May include an aminoglycoside or aztreonam in regimen

Above regimen plus
vancomycin or linezolid

Cefepime or ceftazidime or imipenem or meropenem or piperacillin‐tazobactam

Consider adding ciprofloxacin or levofloxacin
an aminoglycoside or polymyxin or colistin

Above plus
vancomycin or linezolid












Initial therapy should be based on knowledge of local pathogens and susceptibility patterns


Duration of treatment: 7 days

Duration of treatment: 7 days
Complicated pyelonephritis
Complicated pyelonephritis (e.g. patients with diabetes mellitus, renal failure, urinary tract obstruction, indwelling urethral catheter, stent, nephrostomy tube, urinary diversion, immunosuppression, or transplantation) Escherichia coli, other Enterobacteriaceae, P. aeruginosa, enterococci, S. aureus Mild or moderate disease: ceftriaxone or ciprofloxacin or levofloxacin

Severe disease: cefepime or piperacillin‐tazobactam or
meropenem or imipenem		 If resistance on prior urinary cultures, use broader or more appropriate agent
Ceftriaxone and cefepime do not cover enterococci
Skin and soft tissue
Necrotizing fasciitis Streptococci sp. (group A, C, G), Clostridia sp., polymicrobial (aerobic + anaerobic), S. aureus, K. pneumoniae Vancomycin or linezolid plus piperacillin‐tazobactam or a carbapenem plus clindamycin Clindamycin is added for antitoxin effects

Clinical pharmacology principles


Understanding the basic clinical pharmacology of antimicrobials will help guide therapy.


Bactericidal versus bacteriostatic pharmacodynamics



  • The relationship between antibiotic activity and various bacterial species may be characterized as bactericidal or bacteriostatic. This applies to in vitro testing for a particular microbial strain.
  • Using in vitro microbiologic techniques:

    • Bactericidal activity is defined as a ≥3‐log10 cfu/mL reduction in 24 hours or by the ratio of minimum bactericidal concentration (MBC)/MIC ≤4.
    • Bacteriostatic activity is <3‐log10 cfu/mL reduction in 24 hours or the MBC/MIC >4.

  • In general, concentrations that reach bactericidal activity are preferred for severe infections that may progress rapidly with potential lethal consequences. A disadvantage of rapid bacterial killing may be the release of cell wall components, endotoxins, and cytokines.

Key pharmacodynamic predictors of antibiotic effectiveness



  • Concentration (peak) dependent activity:

    • Serum concentration reaches an adequate peak regardless of the concentration at the end of the dosing interval (e.g. gentamicin peak concentration ≥10 times MIC).
    • Goal is to maximize peak concentration yet limit the time of exposure.
    • Common antibiotics include aminoglycosides and polymyxins.

  • Time‐dependent activity:

    • Serum concentration adequately maintained above the MIC for the entirety of the dosing interval.
    • Goal is to maximize duration of exposure.
    • Common antibiotics include penicillins, cephalosporins, and carbapenems.

  • Concentration/time‐dependent activity:

    • Another measure of exposure to an antibiotic is the area under the curve (AUC) : MIC, which is becoming more widely used as a predictor of drug effectiveness.
    • Goal is to maximize total amount of exposure.
    • Common antibiotics include fluoroquinolones, linezolid, macrolides, clindamycin, tetracyclines, and vancomycin.

Dosing principles using pharmacokinetics



  • The loading (first) dose (LD) is designed to achieve an initial serum concentration that mimics an effective steady state concentration.
  • The LD is usually a relatively higher dose than that of the maintenance dose (MD).
  • The MD regimen takes into account patient physiologic factors and microbial factors that account for the rate and extent of elimination.

    • Patient factors in the critically ill include weight, fluid shifts, renal function, liver function, extracorporeal membrane oxygenation (ECMO), and sepsis.
    • Microbial factors include susceptibility to the agent and site of infection (e.g. lung, brain, heart, urinary tract) such that different doses and serum concentrations may be needed for different sites of infection.
    • Higher MD therapy may be more appropriate in morbidly obese or neutropenic patients, in those with infection involving sites in which drug penetration is poor (e.g. meninges, heart), or in those with infection involving organisms with increased MIC susceptibility.
    • Extended infusions with shorter dosing intervals of time‐dependent killing antimicrobials (e.g. cefepime, piperacillin/tazobactam, meropenem) are being used more often because they potentially optimize attainment of target concentrations.

  • The MD regimen for concentration‐dependent agents differs from time‐dependent regimens.

    • Each dose is intended to achieve a high peak concentration relative to the MIC, with very low trough concentrations that are sometimes intended to be undetectable.
    • Higher initial doses may be needed when extracellular water is increased, such as with edema, septic shock, post‐surgery, or trauma.
    • High concentration extended‐interval aminoglycoside dosing as opposed to traditional dosing is an example of this dosing technique.

Pathophysiologic and pharmacokinetic changes in the critically ill


The primarily affected pharmacokinetic parameters are distribution and elimination.



  • Changes in serum proteins affect distribution of protein‐bound agents (e.g. ceftriaxone, clindamycin, doxycycline, nafcillin, tigecycline, vancomycin).
  • Hydrophilic agents tend to have low volumes of distribution, are primarily renally eliminated, and have relatively low intracellular tissue penetration (e.g. aminoglycosides, beta‐lactams, polymyxins, vancomycin).
  • Lipophilic agents tend to have wider volumes of distribution, are primarily hepatically eliminated, and have relatively higher intracellular tissue penetration (e.g. macrolides, lincosamides, tetracyclines, tigecycline).

Specific treatments


Acute renal failure requiring IHD, CRRT, and PD



  • Factors affecting antimicrobial use include the degree and rapidity of renal impairment, type and duration of dialysis, intrinsic residual function, and drug pharmacology and interactions.
  • Common methods of continuous renal replacement therapy (CRRT) in the critically ill are continuous veno‐venous hemofiltration (CVVH), continuous veno‐venous hemodialysis (CVVHD), continuous veno‐venous hemodiafiltration (CVVHDF), and peritoneal dialysis (PD).
  • Specific factors that may influence dosing with intermittent hemodialysis (IHD)/CRRT/PD include:

    • Flow rate: increasing the blood or dialysate flow rate will increase drug clearance.
    • Membrane pore size (sieving coefficient): larger pores allow removal of drugs with larger molecular weight.
    • Protein binding: antimicrobials with low protein binding capacity in serum may be removed.
    • Distribution: reduced drug removal by IHD/CRRT occurs with agents that have larger volumes of distribution.
    • Sepsis: dosing is further affected by changes in cardiac output, fluid shifts, capillary permeability, and end‐organ dysfunction.

  • Table 45.2 includes dosing considerations for IHD/CRRT/PD:

    • For CRRT dosing ranges, higher daily doses may be needed for CVVHDF, moderate doses for CVVHD, and lower doses for CVVH.
    • Dosing regimens used with IHD cannot be consistently employed with CRRT.

  • Obtaining therapeutic drug monitoring concentrations:

    • IHD: trough preferably prior to IHD; or following a session, ≥2 hours for aminoglycosides and ≥4–6 hours for vancomycin to allow for drug redistribution.
    • CRRT: aminoglycoside peak concentration should be 2 hours after the dose and random concentrations at steady state after the third dose.
    • Monitor a 24 hour random concentration and every 3–5 days once an acceptable dosing regimen is established.

Table 45.2 Pharmacotherapy for common antibiotics in critical care.











































































































































































































































































































Generic name General spectrum of activity Usual initial dosing for critically ill Route of administration Renal dose adjustments Clinical pearls
Penicillins
(w/ & w/o beta‐lactamase inhibitors)
MOA: binds to penicillin‐binding proteins inhibiting peptidoglycan cell wall synthesis resulting in cellular lysis
Net effect: bactericidal activity
Ampicillin GPC
GNB		 1–2 g q4–6 h
IHD: 1–2 g q12–24 h
CRRT: load 2 g
MD 1–2 g q6–12 h		 IV Yes Higher dose for Listeria meningitis recommended
Limited Gram‐negative organism coverage
Ampicillin/sulbactam GPC
GNB (no PA)
Anaerobes		 1.5–3 g q6 h
IHD: 1.5–3 g q8–12 h
CRRT: load 3 g
MD 1.5–3 g q6–12 h		 IV Yes Sulbactam is a sulfonamide molecule that may cause allergenic cross‐reactivity with other sulfonamides
Sulbactam often maintains susceptibility to Actinetobacter baumannii
Amoxicillin/clavulanate GPC
GNB (no PA)
Anaerobes		 875 mg/125 mg q12 h PO Yes
Nafcillin GPC (MSSA) 1–2 g q4 h
IHD/CRRT: same		 IV No Recommended 12 g/day for bacteremia
Extravasation can result in tissue necrosis; may cause neutropenia
Oxacillin GPC (MSSA) 1–2 g q4 h
IHD/CRRT: same		 IV No Recommended 12 g/day for bacteremia
Reversible increase of transaminases
Piperacillin/tazobactam GPC
GNB (PA)
Anaerobes		 3.375–4.5 g q6 h
IHD: 2.25 g q8–12 h
CRRT: 2.25–3.375 g q6–8 h		 IV Yes Tazobactam is a sulfonamide molecule that may cause allergenic cross‐reactivity with other sulfonamides
Extended infusion of 4 hours q8 h may be more effective than 30 minute infusions q6 h
If MIC to Pseudonomas aeruginosa is 32–64 mg/L, consider switch to cefepime or meropenem
Cephalosporins
(w/ & w/o beta‐lactamase inhibitors)
MOA: binds to penicillin‐binding proteins inhibiting peptidoglycan cell wall synthesis resulting in cellular lysis
Net effect: bactericidal activity
Cefazolin (first generation) GPC
GNB		 1–2 g q8 h
IDH: 500 mg to 1 g q24 h
CRRT: load 2 g
MD 1 g q8 h or 1–2 g q12 h		 IV Yes Limited Gram‐negative organism coverage
Cefoxitin (second generation) GPC
GNB (no PA)
Anaerobes		 1–2 g q6–8 h IV Yes Increasing resistance to Bacteroides fragilis
Ceftriaxone (third generation) GPC
GNB (no PA)
Oral anaerobes		 1–2 g q12–24 h
IHD: 1–2 g q24 h
CRRT: load 2 g
MD same		 IV/IM No May cause biliary sludge in gallbladder
Cefpodoxime (third generation) GPC
GNB (no PA)		 200–400 mg q12 h PO Yes Possible agent to convert ceftriaxone from IV to PO
Ceftazidime (third generation) GPC
GNB (PA)		 1–2 g q8–12 h
IHD: 500 mg to 1 g q24 h
CRRT: load 2 g
MD 1 g q8 h or 1–2 g q12 h		 IV Yes
Cefepime (fourth generation) GPC
GNB (PA)		 1–2 g q12 h
IHD: 500 mg to 1 g q24 h
CRRT: load 2 g
MD 1 g q8 h or 1–2 g q12 h		 IV Yes Seizure risk with ESRD
P. aeruginosa dose 1–2 g q8 h
Ceftaroline (fifth generation) GPC (MRSA, DRSP) 600 mg q12 h
IHD: 200 mg q12 h		 IV Yes
Ceftazidime/avibactam (third generation/BLI) GPC
GNB (PA)		 2.5 g q8 h IV Yes Avibactam is a non‐beta‐lactam beta‐lactamase inhibitor that reconfers susceptibility to ceftazidime
Used for some multidrug‐resistant organisms, possibly in a multidrug regimen
Ceftolozane/tazobactam GPC
GNB		 1.5 g q8 h
IHD: 750 mg once, then 150 mg q8 h		 IV Yes Not active against KPC‐producing bacteria; active against some Enterobacteriaceae and P. aeruginosa isolates with certain mechanisms of resistance
Carbapenems
MOA: binds to penicillin‐binding proteins inhibiting peptidoglycan cell wall synthesis resulting in cellular lysis
Net effect: bactericidal activity
Ertapenem GPC
GNB (no PA)
Anaerobes		 1 g q24 h IV Yes Seizure risk
Induces valproic acid metabolism – avoid concomitant use
Imipenem/cilistatin GPC
GNB (PA)
Anaerobes		 500 mg q6 h
IHD: 250–500 mg q12 h
CRRT: load 1 g
MD 500 mg 6–8 h		 IV/IM Yes Seizure risk
Induces valproic acid metabolism – avoid concomitant use
Meropenem GPC
GNB (PA)
Anaerobes		 1 g q8 h or
500 mg q6 h
IHD: 500 mg q24 h
CRRT: load 1 g
MD 500 mg to 1 g q8–12 h
PD: recommended dose q24 h		 IV Yes Seizure risk
Induces valproic acid metabolism – avoid concomitant use
Extended infusion of 1 g over 3 hours q8 h may be more effective than 500 mg over 30 minutes q6 h or 1 g over 30 minutes q8 h
Monobactam
MOA: binds to penicillin‐binding proteins inhibiting peptidoglycan cell wall synthesis resulting in cellular lysis
Net effect: bactericidal activity
Aztreonam GNB (PA) 1–2 g q8 h
IHD: 500 mg q12 h
CRRT: load 2 g
MD 1 g q8 h or 1–2 g q12 h		 IV Yes Alternative for beta‐lactam allergy; confers no activity against Gram‐positive organisms or anaerobes
Fluoroquinolones
MOA: inhibits DNA‐gyrase thus not allowing supercoiled DNA uncoiling and promotes double‐strand DNA breakdown
Net effect: bactericidal activity
Ciprofloxacin MSSA
GNB (PA)
Atypical lung pathogens		 400 mg q8–12 h
IHD: 200–400 mg q24 h
CRRT: 200–400 mg q12–24 h
PD: 500 mg q24 h		 IV
PO 		Yes Prolongs QTc interval
Excellent tissue penetration
Enteral absorption interactions with di‐ or trivalent cations, multivitamins, antacids, tube feeds
Ciprofloxacin is the most reliable for empiric P. aeruginosa coverage
Levofloxacin GPC
GNB (PA)
Atypical lung pathogens		 750 mg q24 h
IHD: 250–500 mg q48 h
CRRT: load 500–750 mg
MD 250–750 mg q24 h		 IV
PO 		Yes
Moxifloxacin GPC
GNB
Anaerobes
Atypical lung pathogens		 400 mg q24 h
IHD/CRRT: same		 IV
PO 		No
Lincosamide
MOA: binds to the 50S ribosomal subunit (reversibly), preventing peptid–bond formation and inhibiting protein synthesis
Net effect: bacteriostatic activity
Clindamycin GPC
Anaerobes		 600–900 mg q8 h
IHD/CRRT: same		 IV
PO 		No Good tissue penetration including bone, minimal CSF penetration; among the most common offenders of C. difficile infections
Macrolides
MOA: inhibits protein synthesis at the chain elongation step and binds to the 50S ribosomal subunit
Net effect: bacteriostatic activity
Azithromycin GPC
Atypical lung pathogens		 Load: 500 mg × 1
Mtce: 250 mg q24 h
IHD/CRRT: same		 IV
IV/PO 		No May have some activity against some Gram‐negative organisms
Prolongs QTc interval (rare); minimal to no CYP450 interactions
Sulfonamides
MOA: individually block two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria
Net effect: bacteriostatic activity
Sulfamethoxazole/trimethoprim GPC
GNB		 5–20 mg TMP/kg per day, divided q6–12 h
IHD: 2.5–10 mg TMP/kg q24 h
CRRT: 2.5–7.5 mg TMP/kg q12 h		 IV
PO 		Yes No activity against group A Streptococcus
Dose calculated based on trimethoprim component
Tetracyclines and glycylcycline
MOA: binds to the 30S and possibly the 50S ribosomal subunits resulting in inhibited protein synthesis
Net effect: bacteriostatic activity
Doxycycline GPC
GNB (no PA)
Anaerobes
Atypicals		 100 mg q12 h
IHD/CRRT/PD: same		 IV
PO 		No Good tissue penetration with minimal CSF penetration
Absorption interaction with di‐ or trivalent cations
Covers mycoplasma, chlamydia, rickettsiae; resistance in Gram‐negative aerobic organisms is very common
Tigecycline GPC (MRSA, VRE, DRSP)
GNB (no PA)
Anaerobes
Atypicals		 Load: 100 mg
MD: 50 mg q12 h
IHD/CRRT: same		 IV No Very broad spectrum except Morganella morganii, Proteus mirabilis, Providencia sp. and P. aeruginosa
Not recommended for bloodstream infections due to high volumes of distribution and low serum concentrations
Not recommended for hospital‐acquired or ventilator‐associated PNA
Polymyxins
MOA: increase permeability of the bacterial cell membrane leading to death of the cell
Net effect: bactericidal activity
Polymyxin B GNB (PA) 7500–12 500 units/kg q12 h IV Yes Useful for multidrug‐resistant P. aeruginosa and A. baumannii
Renal dose adjustments may not be necessary according to recent literature
Colistin methanesulfate
(polymyxin E)		 GNB (PA) Load: 270 mg
MD: 135 mg q12 h
IHD: 1.5 mg/kg q24–48 h
CRRT: 2.5 mg/kg q48 h		 IV Yes Useful for multidrug‐resistant P. aeruginosa and A. baumannii
Nebulization may be used as an adjuvant for VAP
Aminoglycosides
MOA: binds to the 30S and possibly the 50S ribosomal subunits resulting in inhibited protein synthesis
Net effect: bactericidal activity
Amikacin GNB (PA) 5–7.5 mg/kg q8 h
or
Extended interval: 15 mg/kg q24–48 h
IHD: 5–7 mg/kg q48–72 h
CRRT: load 10 mg/kg
MD 7.5 mg/kg q12–24 h		 IV Yes Use ideal body weight (IBW) for dosing. If actual weight (AW) is >125% of the IBW, use adjusted body weight (ABW): ABW = IBW + 0.4 × (AW – IBW)

Conventional; target peak concentrations (after third dose):
26–40 mg/L: life‐threatening
21–25 mg/L: serious infections
15–20 mg/L: UTI
Trough concentration (prior to next dose) <5 mg/L

IHD: redose when pre‐HD concentration <10 mg/L or post‐HD <6–8 mg/L
CRRT: target peak concentration 15–30 mg/L; redose when concentration <10 mg/L
Use ideal body weight (IBW) for dosing. If actual weight (AW) is >125% of the IBW, use adjusted body weight (ABW): ABW = IBW + 0.4 × (AW – IBW)
Gentamicin Tobramycin GNB (PA)GNB (PA) 1–1.7 mg/kg q8 h
or
Extended interval: 7 mg/kg q24–48 h
IHD: load 2–3 mg/kg, then 1–2 mg/kg q48–72 h
CRRT: load 2–3 mg/kg, then:
UTI: 1 mg/kg q24–36 h
Serious: 1–1.5 mg/kg q24–36 h
Life‐threatening: 1.5–2.5 mg/kg q24–48 h		 IV
IV		 Yes
Yes		 Conventional; target peak concentrations (after third dose):
8–10 mg/L: life‐threatening
6–8 mg/L: serious infections
4–6 mg/L: UTI
Trough concentration (prior to next dose) <1 mg/L


IHD: redose when pre‐HD concentration <1–2 mg/L
CRRT: redose based on severity and random concentration:
<1 mg/L: UTI
<1.5–2 mg/L: serious infection
<3–5 mg/L: life‐threatening infection
Glycopeptide
MOA: binds to peptidoglycan precursors blocking glycopeptide polymerization resulting in inhibited cell wall synthesis
Net effect: bactericidal activity
Telavancin GPC (MRSA, VRE, DRSP) 10 mg/kg q24 h IV Yes
Vancomycin GPC (MRSA, DRSP) Load: 15–25 mg/kg or
25–30 mg/kg
(severe infection)
MD: 15–20 mg/kg q8–12 h (infuse 1 g over 1 hour to avoid ‘red man syndrome’)
IHD: load 15–25 mg/kg, then 5–10 mg/kg post‐HD
CRRT: load 15–25 mg/kg
Susp/caps: 125–250 mg q6 h		 IV












PO 		Yes












No 		Use actual body weight for dosing

Target trough concentrations (prior to fourth doses):
≥10 mg/L: always optimal to prevent resistance
12–15 mg/L: less complicated infections (SSI, UTI)
15–20 mg/L: complicated infections (IE, CNS, OM, PNA)
Dosing adjustment based on trough

Nephrotoxicity and ototoxicity are rare without a concomitant offending agent



For C. difficile treatment
Oxazolidinone
MOA: binds to the 23S ribosomal RNA of the 50S subunit, thus inhibiting translation and protein synthesis
Net effect: bacteriostatic activity
Linezolid GPC (MRSA, VRE) 600 mg q12 h
IHD/CRRT: same		 IV/PO No MAOI, interacts with catecholamines; lactic acidosis; myelosuppression; peripheral and optic neuropathy
Not recommended for bloodstream infections
Tedizolid GPC (MRSA) 200 mg q24 h IV/PO No MAOI, interacts with catecholamines
Cyclic lipopeptide
MOA: binds to bacterial cell membranes and causes causing a rapid depolarization of membrane potential thus inhibiting protein synthesis
Net effect: bactericidal activity
Daptomycin GPC (MRSA, VRE) 6‐8 mg/kg q24 h
IHD: 4–6 mg/kg q48 h
CRRT: 4–6 mg/kg q48–72 h
PD: dose based on CrCl <30 mL/min		 IV Yes Deactivated by surfactant in lungs, thus ineffective for PNA
Monitor CPK weekly, consider stopping statins due to risk of myopathy; eosinophilic pneumonia (risk usually with >2–4 weeks of treatment)
Nitroimidazole
MOA: penetrates cellular cytoplasm along with free radicals, inhibits DNA synthesis and interacts with DNA to cause DNA degradation thus inhibiting protein synthesis leading to death of the bacteria
Net effect: bactericidal activity
Metronidazole Anaerobes 500 mg q6–8 h
IHD: 500 mg q8–12 h
CRRT: 500 mg q6–12 h
PD: 500 mg q8–12 h		 IV/PO No Disulfiram‐like reaction with ethanol; peripheral, autonomic, and optic neuropathy (generally with high doses or prolonged treatment)

BLI, beta‐lactamase inhibitor; BSA, body surface area; CNS, central nervous system; CPR, cardiopulmonary resuscitation; CrCl, creatinine clearance by Cockcroft‐Gault equation; CRRT, continuous renal replacement therapy; CSF, cerebrospinal fluid; DRSP, drug‐resistant Streptococcus pneumoniae; ESRD, end‐stage renal disease; FDA, Food and Drug Administration (USA); GI, gastrointestinal; GNB, Gram‐negative bacilli; GPC, Gram‐positive cocci; IE, infectious endocarditis; IHD, intermittent hemodialysis; IM, intramuscular; IV, intravenous; KPC, Klebsiella pneumoniae carbapenemase; MAOI, monoamine oxidase inhibitor; MIC, minimum inhibitory concentration; MD, maintenance dosing; MOA, mode of action; MSSA, methicillin‐sensitive Staphylococcus aureus; MRSA, methicillin‐resistant Staphylococcus aureus; OM, osteomyelitis; PA, Pseudomonas aeruginosa; PNA, pneumonia; PO, oral (or enteral route); SSI, skin and soft tissue infection; TMP, trimethoprim; UTI, urinary tract infection; VRE, vancomycin‐resistant enterococci; VAP, ventilator‐associated pneumonia. Consult a pharmacist for peritoneal dialysis dosing.


Extracorporeal membrane oxygenation



  • Changes in pharmacokinetic parameters associated with ECMO result from sequestration of the drug, increase in distribution, changes in renal and hepatic blood flow, and flow rate from the system.
  • The pharmacokinetic effects have been minimally studied and mostly reported as case series in neonates.
  • Effects of ECMO seem to increase distribution of vancomycin, gentamicin, and cefoxitin. However, the extent of clearance appears unchanged.
  • Individualized antimicrobial regimens and therapeutic drug monitoring of vancomycin and aminoglycosides should be employed.

Inhaled antibiotic therapy



  • Current evidence suggests that the improved clinical outcomes with adjunctive inhaled antibiotic therapy in certain patients with hospital‐acquired pneumonia (HAP) and ventilator‐associated pneumonia (VAP) outweigh the potential harms and increased costs.
  • Consider inhaled colistin, tobramycin, or gentamicin in conjunction with systemic antibiotics in the treatment of patients with VAP due to gram‐negative bacilli only susceptible to polymyxins or aminoglycosides
  • Consider inhaled colistin in conjunction with systemic antibiotics in the treatment of patients with HAP and VAP due to:

    • Acinetobacter species only susceptible to polymyxins.
    • Carbapenem‐resistant pathogens only susceptible to polymyxins.

  • Adjunctive inhaled antibiotic therapy may also be considered as salvage therapy in VAP patients not responding to intravenous antibiotics alone, whether or not the pathogen is multidrug resistant.
  • Current cystic fibrosis guidelines state that there is insufficient information to recommend for or against the continued use of inhaled antibiotics in patients with cystic fibrosis treated with the same antibiotics intravenously for the treatment of an acute exacerbation of pulmonary disease.

Treatment of resistant organisms



  • There is an increasing incidence of infections due to multidrug‐resistant (MDR) gram‐positive cocci and gram‐negative bacilli in critical care settings.

    • Gram‐positive organisms: methicillin‐resistant and vancomycin‐intermediate Staphylococcus aureus, vancomycin‐resistant enterococci, and penicillin‐resistant Streptococcus pneumoniae.
    • Increasingly encountered gram‐negative‐resistant organisms: extended‐spectrum beta‐lactamase (ESBL) producing Enterobacteriaceae (e.g. Klebsiella species, Escherichia coli, and Enterobacter species), carbapenem‐resistant Enterobacteriaceae (CRE), including those due to Klebsiella pneumoniae carbapenemase, and MDR Pseudomonas aeruginosa and Acinetobacter species.

  • ESBL organisms:

    • Carbapenems are the treatment of choice. In patients with bacteremia due to these organisms, improved survival is seen with imipenem or meropenem. Although they test susceptible to cephamycins (e.g. cefoxitin, cefotetan), there are few data demonstrating efficacy.
    • Ceftolozane‐tazobactam and ceftazidime‐avibactam are newer beta‐lactam/beta‐lactamase inhibitors, which have activity against most ESBL‐producing Enterobacteriaceae. Limited clinical data show promise.

  • For serious infections due to CRE, combination therapy with two or more agents should be used. Generally a polymixin‐based regimen (if susceptible) is given, plus other agents including:

    • Tigecycline, aztreonam, or an aminoglycoside such as gentamicin (based on susceptibility testing).
    • Ceftazidime‐avibactam (limited clinical experience, used as an alternative agent as part of a combination regimen).
    • A carbapenem such as meropenem, as in vitro and animal studies have demonstrated synergistic killing.

  • For MDR Acinetobacter baumannii and Pseudomonas aeruginosa infections, a polymixin‐based regimen in combination with another agent should be used.

Gram‐negative resistance due to beta‐lactamase production



  • Beta‐lactamases are bacterial enzymes that inactivate beta‐lactam antibiotics by hydrolyzing the beta‐lactam ring.
  • The Ambler classification system classifies beta‐lactamases into four groups (A–D) based on their amino acid sequences.

Extended‐spectrum beta‐lactamases



  • ESBLs are class A beta‐lactamases that hydrolyze penicillins, most cephalosporins, and monobactams (aztreonam). They are inactive against the cephamycins (e.g. cefoxitin, cefotetan) and the carbapenems.
  • Risk factors include the prior use of beta‐lactam antibiotics, the presence of indwelling devices or previous invasive procedures, admission from a long‐term care facility, and comorbidities.

Carbapenemases



  • Carbapenemases hydrolyze carbapenems in addition to other beta‐lactams.
  • Bacteria with carbapenemases often have additional resistance mechanisms that confer resistance to most antibiotics. The most important carbapenemases are:

    • Klebsiella pneumoniae carbapenemase (KPC) – class A:

      • The most common carbapenemase in the USA.
      • Found in many Enterobacteriaceae and Pseudomonas aeruginosa.

    • New Delhi metallo‐beta‐lactamase (NDM‐1) – class B:

      • The incidence is low but increasing.
      • NDM‐1 is found in Klebsiella species, E. coli, other Enterobacteriaceae, and Acinetobacter species.
      • NDM‐1 inactivates first to fourth generation cephalosporins and carbapenems but not aztreonam.

    • The OXA group – class D:

      • Another emerging carbapenemase.

Antimicrobial stewardship programs (ASP)



  • Thirty to 60% of antibiotics given in ICUs are unnecessary, inappropriate, or suboptimal.
  • The goal of an ASP is to optimize clinical outcome while minimizing unintended consequences of antimicrobial use.
  • Core members of an ASP as defined by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America include an infectious disease (ID) physician, an ID clinical pharmacist, a clinical microbiologist, an information systems specialist, an infection control professional, and a hospital epidemiologist.
  • Antimicrobial stewardship is important because it:

    • Improves patient outcomes.
    • Decreases the incidence of drug‐resistant organisms.
    • Reduces the adverse effects of drug therapy.
    • Reduces costs.

  • Antimicrobial stewardship is especially important in critical care because:

    • A large percentage of patients receive antimicrobials in critical care units.
    • There are many complicated and difficult to treat infections.
    • Clinicians may be more likely to start and less likely to discontinue antimicrobials, including broad spectrum antibiotics, in critically ill patients.
    • Patients may be more at risk of developing adverse effects from antimicrobials when critically ill.

  • As part of critical care antimicrobial stewardship, clinicians should:

    • Diagnose and identify pathogens as early and rapidly as possible.
    • Initiate empiric regimens based on the most likely organism(s) to be causing a specific infection, local susceptibility patterns, previous antibiotic therapy, cost effectiveness, and the likelihood of resistance developing.
    • Ensure sufficient concentration of the antimicrobial at the site of the infection.
    • At 48–72 hours, reassess therapy.
    • Apply concepts of de‐escalation: decrease the spectrum of the antimicrobial regimen by tailoring it to the site and susceptibility of the identified organisms. Stop therapy altogether if infection is deemed unlikely at the time of reassessment.

      • Stop vancomycin and linezolid if methicillin‐resistant Staphylococcus aureus (MRSA) is not found unless the patient is allergic to beta‐lactams or has an infection with gram‐positive bacteria susceptible only to one of these agents.
      • Broad spectrum agents such as the carbapenems, piperacillin‐tazobactam, and cefepime should be continued only if culture results yield organisms susceptible to these agents alone.

    • Convert medications as soon as possible from the intravenous to the enteral route. Antimicrobials such as fluoroquinolones, oxazolidinones (e.g. linezolid), clindamycin, trimethoprim‐sulfamethoxazole, metronidazole, fluconazole, and voriconazole have high oral bioavailability.
    • Use the evidence‐based duration of therapy for defined infections.

  • Biomarkers may have a role in the decision to stop the antibiotic therapy of certain diseases.

    • Current guidelines recommend using procalcitonin levels plus clinical criteria rather than clinical criteria alone in the decision to discontinue antibiotics in patients with HAP and VAP.
    • Procalcitonin may be used to help determine the timing of discontinuation of antibiotics in the empiric treatment of sepsis in patients who subsequently show no evidence of infection.

Antifungal and antiviral therapy (Tables 45.1–45.4)


Table 45.3 Pharmacotherapy of most common antifungals for critical care.


























































































Generic name General spectrum of activity Usual initial dosing for critically ill Route of administration Renal dose adjustments Clinical pearls
Azoles
MOA: interferes with fungal cytochrome P450 activity, decreasing ergosterol synthesis and therefore inhibiting cell membrane synthesis
Fluconazole Blastomycosis, candidiasis (not Candida krusei, C. glabrata), coccidioidomycosis, cryptococcosis Load: 400–800 mg
MD: 200–400 mg q24 h
IHD: 200–400 mg q48–72 h or 100–200 mg q24 h
CRRT: 200–800 mg q24 h		 IV
PO 		Yes Excellent oral bioavailability
Moderate inhibitor of CYP 3A4, thus interacts with substrates
Isavuconazole Aspergillosis, mucormycosis Load: 200 mg q8 h × 6 doses
MD: 200 mg q24 h		 IV
PO 		No
Itraconazole Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis 200–400 mg q24 h
IHD/CRRT: 200 mg q12 h × 4, then 200 mg q24 h		 PO Yes
Posaconazole Aspergillosis, candidiasis, mucormycosis Load: 300 mg q12 h, day 1
MD: 300 mg q24 h
Tabs: 300 mg q12 h, day 1
MD: 300 mg q24 h
Susp: 200 mg q6 h, day 1
400 mg q12 h with disease stabilization		 IV

PO

PO 		No Capsules and oral suspension not interchangeable due to unpredictable absorption (consider monitoring serum concentrations)
Strong CYP 3A4 inhibitor
IV not recommended with CrCl <50 due to accumulation of SBECD, a toxic vehicle
Strong CYP 3A4 inhibitor
Voriconazole Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis (no mucormycosis) Load: 6 mg/kg q12 h, day 1
MD: 4 mg/kg q12 h
Weight >40 kg: 200 mg q12 h
Weight <40 kg: 100 mg q12 h
IHD/CRRT: 400 mg q12 h × 2, then 200 mg q1 2h		 IV

PO

PO 		No IV not recommended with CrCl <50, IHD, and CRRT due to accumulation of SBECD, a toxic vehicle
Strong CYP 3A4 inhibitor
Do not use for urinary tract infections
Transient visual changes; hallucinations; photosensitivity; rash
Echinocandins
MOA: non‐competitive inhibitor of 1,3‐β‐d‐glycan synthase resulting in reduced formation of 1,3‐β‐d‐glycan, essential for stability of the fungal cell wall
Anidulafungin Aspergillosis, candidiasis Load: 100–200 mg × 1
ND: 50–100 mg q24 h
IHD/CRRT: same		 IV No Does not treat urine or CNS fungal infections
Caspofungin Load: 70 mg × 1
MD: 50–70 mg q24 h
IHD/CRRT/PD: same		 IV No Does not treat urine or CNS fungal infections; hepatic dose adjustment recommended to maintenance of 35 mg q24 h
Micafungin 50–150 mg q24 h
IHD/CRRT/PD: same		 IV No
Polyenes
MOA: binds to ergosterol, altering cell membrane permeability causing leakage of cell components with subsequent cellular death
Amphotericin B deoxycholate Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis 0.3–1 mg/kg q24 h
Max: 1.5 mg/kg q24 h
IHD/CRRT: same		 IV No Infuse over 4–6 hours to prevent infusion‐related adverse effects (nausea, vomiting, fever, rigors); may cause nephrotoxicity, electrolyte imbalance
Amphotericin B lipid complex 5 mg/kg q24 h
IHD/CRRT/PD: same		 IV No Infuse over 2 hours; risk of nephrotoxicity is less than amphotericin B deoxycholate; do not use an in‐line filter
Liposomal amphotericin B 3–6 mg/kg q24 h
IHD/CRRT/PD: same		 IV No Infuse over 2 hours using a 1.0 micron in‐line filter; risk of nephrotoxicity is less than amphotericin B deoxycholate; infusion‐related adverse effects may include chest pain, dyspnea, hypoxia, abdominal pain, urticaria

CNS, central nervous system; CRRT, continuous renal replacement therapy; IHD, intermittent hemodialysis; IV, intravenous; MD, maintenance dosing; MOA, mode of action; PD, peritoneal dialysis; PO, oral (or enteral route); SBECD, sulfobutylether‐β‐cyclodextrin.


Table 45.4 Pharmacotherapy of most common antivirals for critical care.






































Generic name General spectrum of activity Usual initial dosing for critically ill Route of administration Renal dose adjustments Clinical pearls
Acyclovir HSV type 1, 2
VZV		 5–10 mg/kg q8 h
IHD: 2.5–5 mg/kg q24 h
CRRT: 5–10 mg/kg q12–24 h

200–800 mg 5 × daily		 IV

IV


PO 		Yes Nephrotoxicity with IV administration may be prevented with adequate hydration
Ganciclovir CMV Initial: 5 mg/kg q12 h
IHD: 1.25 mg/kg q48–72 h, then 0.625 mg/kg q48–72 h
CRRT:
CVVH: 2.5 mg/kg q24 h, then 1.25 mg/kg q24 h
CVVHD/CVVHDF: 2.5 mg/kg q12 h, then q24 h		 IV Yes Infusion over 1 hour; monitor for myelosuppression
Valacyclovir HSV
VZV		 500 mg–2 g q12–24 h
(2 g q12 h × 1 day for oral HSV)		 PO Yes Prodrug: converted to acyclovir; risk of TTP/HUS in immunocompromised patients receiving 8 g/day
Valganciclovir CMV Initial: 900 mg q12 h
MD: 900 mg q24 h		 PO Yes Prodrug: converted to ganciclovir

CMV, cytomegalovirus; CRRT, continuous renal replacement therapy; CVVH, continuous veno‐venous hemofiltration; CVVHD, continuous veno‐venous hemodialysis; CVVHDF, continuous veno‐venous hemodiafiltration; HSV, herpes simplex virus; IHD, intermittent hemodialysis; IV, intravenous; MD, maintenance dosing; PD, peritoneal dialysis; PO, oral (or enteral route); TTP/HUS, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome; VZV, varicella‐zoster virus.


Reading list



  1. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy 2009; 29(5):562–77.
  2. Kaki R, et al. Impact of antimicrobial stewardship in critical care: a systematic review. J Antimicrob Chemother 2011; 66:1223–30.
  3. Mehrad B, et al. Antimicrobial resistance in hospital‐acquired gram‐negative bacterial infections. Chest 2015; 147(5):1413–21.
  4. Nicolau DP, et al. Experience with a once‐daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39(3):650–5.
  5. Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram‐positive bacterial infections. Clin Infect Dis 2004; 38:864–70.
  6. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 2009; 37(3):840–51.
  7. Vincent JL, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302(21):2323–9.

Guidelines


National society guidelines
































Title Source Date and reference
Management of Adults With Hospital‐acquired and Ventilator‐associated Pneumonia: 2016 Clinical Practice Guidelines Infectious Diseases Society of America and the American Thoracic Society 2016
Clin Infect Dis 2016;63:e61–111
Implementing an Antibiotic Stewardship Program Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America 2016
Clin Infect Dis 2016;62(10):e51–77
Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) 2018
Clin Infect Dis 2018;66(7):e1–48
Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update Infectious Diseases Society of America 2011
Clin Infect Dis 2011;52(4):e56–93
Therapeutic Monitoring of Vancomycin in Adult Patients: A Consensus Review American Society of Health‐System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists 2009
Am J Health‐Syst Pharm 2009;66:82–98
Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update Infectious Diseases Society of America 2014
Clin Infect Dis 2014;59(2):e10–52
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Nov 20, 2022 | Posted by in ANESTHESIA | Comments Off on 45: Antimicrobial Therapy

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