Inappropriate combinations of

antimicrobial agentsMunzur Morshed, Pharm D.

candidate 2011Arnold & Marie Schwartz College of Pharmacy

and Health SciencesNorth Shore- Long Island Jewish Health System

Infectious Diseases-Advanced Pharmacy Practice

Bacterial Targets for Antimicrobials

Resistant Nosocomial Pathogens.

Staphylococcus AureusStreptococcus Pneumonia.Enterococcus SpeciesPseudomonas aeruginosaEnterobacter SpeciesAcinobacter SpeciesKlebsiella Pneumonia - Extended Spectrum Beta-Lactamase

producing. - Carbapenem resistant (KPC) John Papadopoulos- Pharmacodynamic Principles of Antimicrobial

Pharmacotherapy.

New Antimicrobials in the pipeline

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John Papadopoulos- Pharmacodynamic Principles of Antimicrobial Pharmacotherapy.

Risk factor of developing bacterial resistance

Inappropriate prescribing-overprescribing, under prescribing and wrong dose

Prior use of the same antimicrobial Prolonged administrations of antimicrobial Hospital Stay-Length of stay and prior

hospitalization Use of invasive devices Lack of patient compliance Sub-Optimal antibiotic concentration in the

critically-ill patients Inadequate infection control practice

Inappropriate Antimicrobial Combinations

Beta-Lactams Plus

Beta-LactamsZosyn + Unasyn

Zosyn + Primaxin/Meropene

mCeftazadime +

ZosynCeftazadime +

primaxin/ Meropenem

Cefoxitin + Zosyn

Cefoxitin + Primaxin/Meropene

mNaficillin + Cefazolin

Lincosamide Plus

Beta-LactamsClindamycin +

UnasynClindamycin +

Primaxin/Meropenem

Clindamycin + Zosyn

Clindamycin PO +Augmentin

FluoroquinolonePlus

MacrolidesMoxifloxacin + Erythromycin

Moxifloxacin + Azithromycin

GlycopeptidesPlus

Oxazolidinone

Lincosamide

PlusNitroimidaz

oleVancomycin + Linezolid

Clindamycin + Flagyl

Spectrum of ActivityPenicillins

Cephalosporins

Carbapenems

Staphylococci (+)

MSSA -1st gen. Ceph.

MSSA(+)

Streptococci (+)

Streptococci (+) Streptococci (+)

Enterococci (+) Haemophilus Influenza (-)

C-Difficile (+)

Bacteroides Fragilis (-)

Bacteroides Fragilis (-)

Bacteroides Fragilis (-)

Borellia Burgdoferi (A spirochete)

E-Coli (-) Fusobacterium(-)

Peptostreptococci (Gram -)

Serratia, Klebsiella and Proteus

Peptostreptococci (Gram -)

Pseudomonas(Gram -)

Pseudomonas(Gram -)

Pseudomonas (-)(At high doses)

β-lactamase inhibitors- in conjunction with the penicillins.

Same Spectrum of activity as the first column

Spectrum of Activity cont…

Fluoroquinolones

Macrolides

Lincosamide

Glycopeptide

Oxazolidinone

Nitroimidazole

Streptococci (+)

Strep. (+)

MSSA (+) MRSA (+) MRSA (+) C-Difficile(-)

Staphylococci (+)

Moraxella Catarrhalis(-)

Streptococci(+)

C-Difficile (+)

VRE Bacteroides SP.(-)

Pseudomonas (-)

Neisseria (-)

C-Difficile (+)

Bacteroides sp. (-)

Penicillin ResistantPneumococci

GardnerellaVaginalis(-)

Entero-Bacteriaceae (-)

H. Influenza(-)

Fusobacterium(-)

Beta-Lactams plus Beta-Lactams

Subclasses of Beta-Lactam AntibioticsPenicillins- Ampicillin, Piperacillin, NafcillinCephalosporins- Ceftazidime, Cefazolin, CefoxitinCarbapenems- Imipenem/Cilastatin (Primaxin),

Meropenemβ-lactamase inhibitors- Tazobactam, Sulbactam/

Unasyn, Zosyn

MOA- Inhibits or disrupts the synthesis of the peptidoglycan layer hence inhibition of cell-wall growth

Beta-Lactams plus Beta-Lactamscont…

 Zosyn plus Unasyn Avoid use b/c of therapeutic Duplication Same MOA and same class and same spectrum of activity Clinical Trials-Zosyn more efficacious than Unasyn if empiric treatment is

desired- Pseudomonal Coverage

Zosyn plus Primaxin/Meropenem or Unasyn plus Primaxin/ Meropenem

Combination of a Beta-Lactam and Carbapenem Same class but different Sub-Class Avoid use▪ Major Drug Interactions- Antagonistic Effect▪ Carbapenems inhibits the destruction of Beta-Lactamases▪ Carbapenems induces the production of Beta-Lactamases▪ Zosyn/Unasyn induces the destruction of the Beta-Lactamase producing

organism

Clinical Trial- Zosyn is as effective as Primaxin and it constitutes a good choice as an initial empiric monotherapy.

Beta-Lactams plus Beta-Lactamscont…

Ceftazidime plus Zosyn or Cefoxitin plus Zosyn Combination of a cephalosporin and a Beta-Lactam Same class but different Sub-Class Ceftazadime- Third Generation; Cefoxitin- Second Generation Ceftazadime SOA- serious gram (+) infections, DRSP, pseudomonas,

nosocomial pneumonia. Cefoxitin SOA- Anaerobes-Bacteroides Fragilis; gram (-) such as

Proteus, Klebsiella, E-Coli Avoid use ▪ Both combo represents therapy duplication; similar spectrum of

activity Clinical Trial

▪ Each antimicrobial in both combo’s are equally efficacious▪ Same spectrum of activity▪ Eradication rate of each antimicrobial in both combo for the

corresponding pathogens are similar

.

Beta-Lactams plus Beta-Lactamscont…

Ceftazadime plus Primaxin/Meropenem or Cefoxitin plus Primaxin/Meropenem Combination of a cephalosporin and a carbapenem Same class but different Sub-Class Avoid use ▪ Major Drug Interactions- Antagonistic effect▪ Carbapenems inhibits the destruction of Beta-Lactamases ▪ Carbapenems induces the production of Beta-Lactamases ▪ Ceftazadime/ Cefoxitin induces the destruction of the Beta-

Lactamase producing organisms Clinical Trials

▪ Primaxin- enhanced efficacy in tx. of both gram (+) and gram (-) infections

▪ Ceftazadime has greater pseudomonal coverage- advantage

Beta-Lactams plus Beta-Lactamscont…

Naficillin plus Cefazolin Same class, but different sub-class Naficillin- a penicillinase resistant penicillin▪ SOA- mostly gram (+)- staph, strep▪ Common therapy for skin and soft tissue infection,

Endocarditis, Bacteremia Cefazolin- 1 st generation cephalosporin.▪ Mainly gram (+) coverage- Staph, strep, NO enterococci▪ Partial Gram (-) coverage- E.Coli, Proteus, Klebsiella▪ Commonly used as surgical prophylaxis

Avoid use Represents Therapy Duplication Same MOA at the bacterial site

Fluoroquinolone plus Macrolides

Fluoroquinolones Avelox-Moxifloxacin▪ MOA- Inhibts DNA gyrase , which maintains the

superhelical structure of DNA and necessary for DNA replication, transcription, and DNA repair; hence inhibition of the synthesis of DNA

▪ BBW- Tendon Rupture Macrolides

Erythromycin-Erythrocin Azithromycin-Zithromax, Zmax MOA- Inhibits the ribosomal protein synthesis by

inhibiting the 50s ribosomal subunits, resulting in blockage of transpeptidation

QT prolongation

Fluoroquinolone plus Macrolides cont…

Avelox plus Erythromycin or Avelox plus Azithromycin Combination of a fluoroquinolone and a

macrolide Avelox SOA- Pseudomonas, Strep. , Staph.

Enterobacter Erythro./Azithro. SOA- Strep. , Moraxella

Catarrahalis, Chlamydia pneumonia. Avoid use ▪ Major Drug Interactions- additive effect▪ Causes QT interval prolongation-Life threatening

ventricular arrhythmias

Lincosamide plus Beta-Lactam

Clindamycin plus Unasyn, or Clindamycin PO plus Augmentin or Clindamycin plus Zosyn, or Clindamycin plus Primaxin/Meropenem Combination of 1st and 2nd line agents Clindamycin- has excellent bone penetration ability-osteomyelitis,

dental surgery▪ MOA- binds to 50S ribosomal subunit of the bacteria and therefore interfering

with protein synthesis▪ SOA- mostly gram (+)-Excellent MSSA, strep, bacteroides▪ BBW- colitis and excessive GI upset and diarrhea (C. Difficile associated)

Augmentin- beta –lactam/ beta-lactamse inhibitor combinations▪ Mainly gram (+) coverage- MSSA, Bacteroides, strep.▪ No pseudomonas coverage

Avoid use The Beta-lactam’s are cross-sensitive with penicillin Clindamycin is a substitute for patients who is unable to take the Beta-

lactam’s Usage of both can lead to developing significant resistance

Lincosamide plus Nitroimidazole

Clindamycin plus Metronidazole Metronidazole- Drug of choice for Mixed infections, Trichomonas,

and alternative for C-Difficile▪ SOA- Bacteroides, streptococci, C-Difficile, Gardnerella Vaginalis▪ Avoid alcohol- Good for alcoholics( Disulfiram reaction- nausea, vomiting,

tachycardia) Clindamycin- has excellent bone penetration ability-osteomyelitis,

dental surgery▪ MOA- binds to 50S ribosomal subunit of the bacteria and therefore

interfering with protein synthesis▪ SOA- mostly gram (+)-Excellent MSSA, strep, bacteroides▪ BBW- colitis and excessive GI upset and diarrhea (C. Difficile associated)

Avoid use Therapeutic Duplication Metronidazole- alternative for clindamycin induced C-Diffcile

associated diarrhea Usage of both can lead to developing significant resistance

Glycopeptides plus Oxazolidinone

Vancomycin plus Linezolid Vancomycin-Bactericidal agent; works by inhibiting the cell wall

synthesis, resulting in cell death▪ SOA- Gram (+), Penicillin resistant Pneumococci, Gram positive

anaerobes,no gram (-) coverage▪ DOC for MRSA, PCN allergy gram (+) infection, C-Difficile Colitis

alternative to Metronidazole Linezolid- inhibits protein synthesis by binding to the 23s

ribosomal subunit; Preventing them from multiplying▪ 1:1 IV to Po conversion (advantage)▪ SOA- VRE, Gram (+) aerobes, anaerobes, MRSA, Penicillin resistant

pneumococci Avoid use

Therapy duplication; Equally efficacious Clinical Trials- Linezolid effective alternative to vancomycin for

the tx. of cSSTI caused by MRSA . Vancomycin DOC of hospital acquired C-Dif

Thank You!

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