Approved by P&T ID subcommittee June 2014

HMC/UWMC Treatment Guidelines for Multi-drug Resistant Organisms (MDRO)

Table 1: Proposed therapy for MDR Acinetobacter (in vitro resistance to > 3 classes of antimicrobials,
such as penicillins, cephalosporins, fluoroquinolones):

Carbapenem (imipenem or meropenem) susceptible (MIC < 2g/mL):
Meropenem 1-2 gm Q8H infused over 30 minutes
Dose depends on site of infection (2gm q8h only indicated for meningitis or cystic fibrosis).

Carbapenem (imipenem or meropenem) intermediate (MIC = 4g/mL):
Meropenem 2gm Q8H prolonged therapy infused over 3 hours
Studies have demonstrated that three hour infusion improved the cumulative probability of target attainment
compared to 30 minutes intermittent administration.
o Lee LS et al. Diagnostic Microbiology and Infectious Disease 2010;68:251.
o Kim A, et al. Clinical Therapeutics 2009;31:2765.
o Jaruratanasirikul S et al. Antimicrobial Agents and Chemotherpy 2005;49:1337.
o Jaruratanasirikul S et al. Journal of Antimicrobial Chemotherapy 2009;63:560.
o Eagye KJ et al. Critical Care Medicine 2012;40:1329.
o Keel RA et al. American Journal of Health System Pharmacist 2011;68:1619.
o Crandon JL, et al. Intensive Care Medicine 2011;37:632.

If carbapenem resistant (MIC > 8g/mL) AND colistin susceptible (MIC < 2g/mL):
Colistin (see dosing guidelines) + meropenem 2 gm Q8H infused over 3 hours despite in vitro resistance
In order to reduce amplification of heteroresistant subpopulations and decrease risk of emergent resistance, colistin
is combined with a carbapenem. The cell membrane effect of colistin may restore carbapenem activity, increasing
permeability of carbapenem into the cell.
o Garonzik, SM et al. Antimicrobial Agents and Chemotherapy 2011;55:3284.
o Dalfino L, et al. Clinical Infectious Diseases 2012;54:1720-1726.
o Zusman O et al. Antimicrobial Agents and Chemotherapy 2013;57:5104.
o Mendes RE, et al. Clinical Infectious Diseases 2008;46:1324.
o Pankuch GA, et al. Antimicrobial Agents and Chemotherapy 2008;52:333.

For isolates with carbapenem MIC > 4 g/mL, may consider the following as adjunctive therapy:
If susceptible to minocycline (MIC < 4), consider addition of minocycline 200mg x1, then 100mg IV q12h because
minocycline and carbapenem demonstrated synergy in vitro and there are clinical experiences with minocycline
although CNS penetration data is limited.
o Liang W, et al. BMC Infectious Diseases 2011;11:109.
o Chan JD, et al. J Intensive Care Medicine 2010;25:343.

If tigecycline MIC < 0.25, consider addition of tigecycline 100mg x1, then 50mg IV q12h. There are no CLSI
interpretive breakpoints available, but PK/PD analysis suggest that MIC should be <0.25 to be considered
susceptible although CNS penetration data is limited.
o Lee YT, et al. Eur J Clin Microbiol Infect Dis 2013 (32):1211.

Regardless of rifampin susceptibility result, may consider rifampin as adjunctive therapy as there is potential
implication for clinical benefit. Rifampin failed to lower 30-day mortality in prospective randomize trial (colistin
vs. colistin + rifampin) but increased Acinetobacter eradication was observed in colistin + rifampin arm.
o Durante-Mangoni E, et al. Clinical Infectious Diseases 2013;57:349.
o Aydemir H, et al. Epidemiol Infect 2013;141:1212.

If susceptible to aminoglycoside, may consider as adjunctive therapy. Extended interval dosing at 7mg/kg q24h
with monitoring parameters of Hartford nomogram.

In the setting of ventilator associated pneumonia, may consider inhaled colistin 75mg q8h to q12h as adjunctive
therapy in addition to systemic therapy. Pre-medicate with nebulized albuterol 5-10 mins to prevent potential risk
of bronchospasm.
o Kofteridis DP et al. Clinical Infectious Diseases 2010;51:1238-1244.
Approved by P&T ID subcommittee June 2014

o Tumbarello M et al. CHEST 2013;144:1768-1775.

In the setting of CNS infection, may consider intrathecal or intraventricular administration of aminoglycosides
(gentamicin 4-8mg daily or tobramycin 4-8mg daily) or colistin (10mg daily) in addition to systemic therapy.
o Kim BN, et al. Lancet Infectious Diseases 2009;4:245.
o Cascio A, et al. International Journal of Infectious Diseases 2010;14:e572.

For isolates with carbapenem MIC > 8 g/mL, may also consider the following as adjunctive therapy in
addition to options above:
Consider the addition of vancomycin. Retrospective study of ICU patients with MDR infections (60% with MDR
Acinetobacter) showed that combination of a glycopeptide > 5 days is a protective factor for 30-day mortality
(adjusted HR of 0.42, 95% CI: 0.18-0.93) in patients who received colistin + glycopeptide compared to patients
who did not receive glycopeptide without a higher risk of nephrotoxicity.
o Petrosillo N, et al. Antimicrobial Agents and Chemotherapy 2014;58:851.


Approved by P&T ID subcommittee June 2014

Table 2: Proposed therapy for MDR Pseudomonas (in vitro resistance to > 3 classes of antimicrobials,
such as penicillins, cephalosporins, fluoroquinolones):

Carbapenem (imipenem or meropenem) susceptible (MIC < 2g/mL):
Meropenem 1-2 gm Q8H infused over 30 minutes
Dose depends on site of infection (2gm q8h only indicated for meningitis or cystic fibrosis).
Carbapenem (imipenem or meropenem) intermediate (MIC = 4g/mL):
Meropenem 2gm Q8H prolonged therapy infused over 3 hours
Studies have demonstrated that three hour infusion improved the cumulative probability of target attainment
compared to 30 minutes intermittent administration.
o Lee LS et al. Diagnostic Microbiology and Infectious Disease 2010;68:251.
o Kim A, et al. Clinical Therapeutics 2009;31:2765.
o Jaruratanasirikul S et al. Antimicrobial Agents and Chemotherapy 2005;49:1337.
o Jaruratanasirikul S et al. Journal of Antimicrobial Chemotherapy 2009;63:560.
o Eagye KJ et al. Critical Care Medicine 2012;40:1329.
o Keel RA et al. American Journal of Health System Pharmacist 2011;68:1619.
o Crandon JL, et al. Intensive Care Medicine 2011;37:632.

If carbapenem resistant (MIC > 8g/mL) AND colistin susceptible (MIC < 2g/mL):
Colistin (see dosing guidelines) + meropenem 2 gm Q8H infused over 3 hours despite in vitro resistance
In order to reduce amplification of heteroresistant subpopulations and decrease risk of emergent resistance, colistin is
combined with a carbapenem. The cell membrane effect of colistin may restore carbapenem activity, increasing
permeability of carbapenem into the cell.
o Garonzik, SM et al. Antimicrobial Agents and Chemotherapy 2011;55:3284.
o Dalfino L, et al. Clinical Infectious Diseases 2012;54:1720-1726.
o Zusman O et al. Antimicrobial Agents and Chemotherapy 2013;57:5104.
o Bergen PJ et al. Antimicrobial Agents and Chemotherapy 2011;55:5685.
o Bergen PJ, et al. Antimicrobial Agents and Chemotherapy 2011;55:5134.
o Pankuch GA, et al. Antimicrobial Agents and Chemotherapy 2008;52:333.

For isolates with carbapenem MIC > 4 g/mL, may consider the following as adjunctive therapy:
Regardless of rifampin susceptibility result, may consider rifampin as adjunctive therapy as there is potential
implication for clinical benefit. The majority of rifampin data surrounds around MDR Acinetobacter infections, but
the data can be extrapolated to MDR Pseudomonas infections.
o Durante-Mangoni E, et al. Clinical Infectious Diseases 2013;57:349.
o Aydemir H et al. Epidemiol Infect 2013;141:1212.
o Crusio R, et al. Scandinavian Journal of Infectious Diseases 2014; 46:1.

If susceptible to aminoglycoside, may consider as adjunctive therapy. Extended interval dosing at 7mg/kg q24h with
monitoring parameters of Hartford nomogram.

In the setting of ventilator associated pneumonia, may consider inhaled colistin 75mg q8h to q12h as adjunctive
therapy. Pre-medicate with nebulized albuterol 5-10 mins to prevent potential risk of bronchospasm. Other
inhalation therapy such as tobramycin or aztreonam can also be considered.
o Kofteridis DP et al. Clinical Infectious Diseases 2010;51:1238.
o Tumbarello M et al. CHEST 2013;144:1768.

In the setting of CNS infection, may consider intrathecal or intraventricular administration of aminoglycosides
(gentamicin 4-8mg daily or tobramycin 4-8mg daily) or colistin (10mg daily) in addition to systemic therapy.
o Tunkel AR, et al. Clinical Infectious Diseases 2004:39:1267.
For isolates with carbapenem MIC > 8 g/mL, may also consider the following as adjunctive therapy in
addition to options above:
Consider the addition of vancomycin. Retrospective study of ICU patients with MDR infections (19% with MDR
Pseudmonas) showed that combination of a glycopeptide > 5 days is a protective factor for 30-day mortality
(adjusted HR of 0.42, 95% CI: 0.18-0.93) in patients who received colistin + glycopeptide compared to patients who
did not receive glycopeptide without a higher risk of nephrotoxicity.
o Petrosillo N, et al. Antimicrobial Agents and Chemotherapy 2014;58:851.
Approved by P&T ID subcommittee June 2014


Drug Dosing Guidelines for MDRO
Drug Dose for Normal Renal
Function
CrCl (mL/min)
10-50
CrCl mL/min)
<10
Hemodialysis
Ceftaroline

600mg q12h

Endocarditis
600mg q8h
31-50: 400mg q12h
15-30: 300mg q12h

31-50: 400mg q8h
15-30: 300mg q8h
<14: 200mg q12h


<14: 300mg q12h
Same as CrCl <14


Same as CrCl <14
Cidofovir
1
(I = induction dose)
(M = maintenance dose)
*Use Ideal Body Weight*
5mg/kg qwk x2wks (I)
5mg/kg q2wk (M)

During therapy:
Increase in SCr 0.3-0.4mg/dL:
3mg/kg q2wk (M)
Increase in SCr >0.5mg/dL:
Discontinue
55, SCr >1.5, 2+ proteinuria:
Contraindicated
Contraindicated Contraindicated
Foscarnet
(I = induction dose)
(M = maintenance dose)
*Use Ideal Body Weight*
CMV treatment
90mg/kg q12h (I)
90mg/kg q24h (M)
CrCl
(mL/min/kg)
3
Induction Maintenance
>1.4 90mg/kg q12h 90mg/kg q24h
>1.0-1.4 70mg/kg q12h 70mg/kg q24h
>0.8-1.0 50mg/kg q12h 50mg/kg q24h
>0.6-0.8 80mg/kg q24h 80mg/kg q48h
>0.5-0.6 60mg/kg q24h 60mg/kg q48h
>0.4-0.5 50mg/kg q24h 50mg/kg q48h
<0.4 Not recommended Not recommended
45-60mg/kg on HD days (I)
22.5-30mg/kg on HD days (M)
Telavancin
*Use Total Body Weight*
10mg/kg q24h 30-50: 7.5mg/kg q24h
10-29: 10mg/kg q48h
Not recommended Not recommended
1
Probenecid 2g 3h prior to cidofovir dose, 1g at 2h and 8h after completion of cidofovir infusion (total 4g)
CrCl = (140 age) x weight (kg) / (72 x SCr in mg/dL) (for females, multiply by 0.85)

Drug Dose normalized CrCl mL/min)
<10
Hemodialysis
Colistin
(L = loading dose)
(M = maintenance dose)
*Use Ideal Body Weight*

USE ONLI NE SANFORD
CALCULATOR
Not for CF patients
Dose (max 475mg) = Css,av x 2.0 x IBW, where Css,av is 3.5mg/L (L)

Daily dose (max 475mg) = Css,av x (1.5 x normalized CrCl* + 30),
divided q12h to start 12h after loading dose (M)

*Normalized

CrCl (mL/min/1.73m
2
) = CrCl normalized to body
surface area of 1.73m
2
Give loading dose, then give
total daily maintenance dose
q24h
Give loading dose, then 50mg
q12h

Add supplemental 30mg after
each HD session
Polymyxin B
(L = loading dose)
(M = maintenance dose)
*Use Actual Body Weight*
3mg/kg x 1 (L)
1.5mg/kg q12h (M)
No changes No changes

Prolonged Infusion Antibiotics for Multi-Drug Resistant Infections
(Use intermittent dosing guidelines for patients with renal insufficiency)

Prolonged Infusion Dose for Normal Renal
Function
CrCl (mL/min)
10-50
CrCl mL/min)
<10
Hemodialysis
Cefazolin
*Dilute in 250mL of D5W or NS*
Stability at room temp is 24h
1.5-3g (over 12h) q12h <30: Not recommended Not recommended Not recommended
Cefepime
*Dilute in 250mL of D5W or NS*
Stability at room temp is 24h
2g (over 4h) q8h 30-59: 2g (over 4h) q12h
11-29: 2g (over 4h) q24h
Not recommended Not recommended
Ceftazidime
*Dilute 6g in 500mL or 2-4g in
250mL of NS*
Stability at room temp is 24h
No clinical data
6g (over 24h) q24h 31-50: 4g (over 24h) q24h
10-30: 2g (over 24h) q24h
Not recommended Not recommended
Doripenem

*Dilute in 100mL of NS*
Stability at room temp is 12h
500mg (over 4h) q8h 30-50: 250mg (over 4h) q8h
10-29: 250mg (over 4h) q12h
Not recommended Not recommended
Imipenem/Cilastatin
*Dilute in 250mL of NS*
Stability at room temp is 4h
No clinical data
1g (over 3h) q8h Not recommended Not recommended Not recommended
Meropenem
*Dilute in 250mL of NS*
Stability at room temp is 4h
2g (over 3h) q8h 30-49: 1g (over 3h) q8h
10-29: 1g (over 3h) q12h
Not recommended Not recommended
Approved by P&T ID subcommittee June 2014

References
Ceftaroline
1. Ho TT, Cadena J, Childs LM, et al. Methicillin-resistant Staphylococcus auerus bacteraemia and endocarditis treated with
ceftaroline salvage therapy. J Antimicrob Chemother 2012; 67:1267-70.
2. Lin JC, Aung G, Thomas A, et al. The use of ceftaroline fosamil in methicillin-resistant Staphylococcus auerus endocarditis
and deep-seated MRSA infections: a retrospective case series of 10 patients. J Infect Chemother 2013; 19(1):42-9.
Colistin
3. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in
critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob
Agents Chemother 2011; 55(7):3284-94.
Foscarnet
4. Aweeka FT, Jacobson MA, Martin-Munley S, et al. Effect of renal disease and hemodialysis on foscarnet pharmacokinetics
and dosing recommendations. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20(4):350-7.

Prolonged Infusion
Cefazolin
5. Zeller V, Durand F, Kitzis M, et al. Continuous cefazolin infusion to treat bone and joint infections: clinical efficacy,
feasibility, safety, and serum and bone concentrations. Antimicrob Agents Chemother 2009; 53(3):883-7.
Cefepime
6. Bauer KA, West JA, OBrien JM, et al. Extended-infusion cefepime reduces mortality in patients with Pseudomonas
aeruginosa infections. Antimicrob Agents Chemother 2013; 57(7):2907-12.
7. Nicasio AM, Ariano RE, Zelenitsky SA, et al. Population pharmacokinetics of high-dose prolonged-infusion cefepime in
adult critically ill patients with ventilator-associated pneumonia. Antimicrob Agents Chemother 2009; 53(4):1476-81.
Ceftazidime
8. In: Gilbert DN, Moellering RC, Eliopoulos GM, Chamber HF, Saag MS editor. The Sanford Guide to Antimicrobial Therapy
2013. 43
rd
ed. Sperryville, VA: Antimicrobial Therapy, Inc; 2013.
9. Nicolau DP, McNabb J, Lacy MK, et al. Continuous versus intermittent administration of ceftazidime in intensive care unit
patients with nosocomial pneumonia. Int J Antimicrob Agents 2001; 17(6):497-504.
10. Pea F, Viale P, Damiani D, et al. Ceftazidime in acute myeloid leukemia patients with febrile neutropenia: helpfulness of
continuous intravenous infusion in maximizing pharmacodynamic exposure. Antimicrob Agents Chemother 2005;
49(8):3550-3.
Doripenem
11. Chastre J, Wunderink R, Prokocimer P, et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in
ventilator-associated pneumonia: a multicenter, randomized study. Crit Care Med 2008; 36(4):1089-96.
Imipenem/Cilastatin
12. Eagye KJ, Banevicius MA, and Nicolau DP. Pseudomonas aeruginosa is not just in the intensive care unit anymore:
implications for empirical therapy. Crit Care Med 2012; 40(4):1329-32.
13. Sakka SG, Glauner AK, Bulitta JB et al. Population pharmacokinetics and pharmacodynamics of continuous versus short-
term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial. Antimicrob Agents Chemother
2007; 51(9):3304-10.
Meropenem
14. Crandon JL, Ariano RE, Zelenitsky SA, et al. Optimization of meropenem dosage in the critically ill population based on
renal function. Intensive Care Med 2011; 37:632-38.