Principles of Antimicrobial Therapy (2026)

Empiric vs Definitive Coverage

empiric→best guess based on body part/type of infection

definitive→based on culture+sensitivity (c+s) results
-c+s→2-3 days for final results

Resistance Patterns

look for pattens in your institution/community

Penetration

harder in bone and lung

Minimum Inhibitory Concentration (MIC)

the lowest concentration of an antimicrobial that will inhibit the visible growth of an organism

Post-Antibiotic Effect

period of time after complete removal of an antibiotic during which there is no growth of the target organism

Antimicrobial Factors

site of infection

• penetration

• minimum inhibitory concentration (MIC)

• post-antibiotic effect

patient specific factors

drug-specific factors

• iv vs po

• bacterostatic vs bacteriocidal

• cost/day

Bacterial Resistance Mechanisms

inactivation by various beta-lactamases

• “traditional” beta-lacamases→resistance

• now→carbapenemase resistance

development of new binding proteins→decreased affinity for antibiotics

decreased cell wall permeability

certain organisms→modification of cell membrane consitituents→prevents penetration of cell membrane

Broad Classes of Drugs

cell wall active→beta lactams

• penicillins

• cephalosporins

• thienamycines (“penems”)

• monobactams

cell wall active→non-beta lactam

• vancomycin

protein-synthesis active

• aminoglycosides

• tetracyclines

• macrolides

• lincosamides

other mechanisms

• DNA gyrase→fluoroquinolones

• purine synthesis inhibition→TMP-sulfa

Bacteriostatic vs Bacteriocidal Drugs

bacteriostatic

“we’re ECSTaTiC about bacteriostatic”

• Erythromycin (macrolides)

• Clindamycin

• Sulfonamides (bactrim)

• Tetracyclines

• Trimethoprim (bactrim)

• Chlroamphenicol

bacteriocidal

“Very Finely Proficient At Cell Murder”

• Vancomycin

• Fluoroquinolones

• Penicillins

• Aminoglycosides

• Cephalosporins

• Metronidazole

Penicillins (General) Method of Action (MOA)

MOA→cell wall active drugs

• inhibits certain enzymes that create cross-linking→disrupts cell wall formation
  -cross-linking enzymes→cause cell lysis+death

• divided into several subclasses

Penicillins (General) Dose Adjustment+Coverage

dose adjustment

• most→need to be dose-adjusted for CrCl→x<50 ml/min
  -some→hepatic adjustment (instead)

coverage

• most→gram postive
  -some→gram negative

Penicillins (General) Classes

natural penicillins

aminopenicillins

penicillinase-resistant (anti-staph penicillins)

beta-lactamase inhibitor combinations→includes antipseudomonal PCNs

Penicillins (General) Adverse Events

hypersensitivity reactions

neutropenia

insterstitial nephritis

CNS toxicity→seizures

Penicillins (General) Pharmacokinetics (ADME)

absorption

• most→destroyed by gastric acid

• others→absorbed in duodenum

• peak concentration→1-2 hrs

distribution

• widely distributed to many tissues+fluids

metabolism

• minimal/no metabolism by liver

elimination

• half-life→short

• excretion→kidneys (some→biliary)

Natural Penicillins Dose Adjustment+Coverage

dose adjustment

• CrCl→x<50

• decreased renal function→necessary

coverage

active against:

• streptococcal spp. (includes enterococcus spp.)

• trepodema pallidum

• peptococcus

• peptostreptococcus

• mx of choice→syphillis/strep infections

Natural Penicillins Mx

penicillin g

penicillin v

procaine

benzathine

Natural Penicillins Distribution

Distribution

• lung

• ascites

• synovium pericardium (synovial layer of pericardium)

• ascitic fluid

• soft tissues

Aminopenicillins Dose Adjustment+Coverage

dose adjustment

CrCL→x<50

coverage

natural penicillins+negative gram-coverage:

• h influenzae

• e coli

• k pneumoniae

• more active (than other penicillins)→enterococcus

• mx of choice→sensitive enterococcal infections

Aminopenicillins Mx

amoxicillin→more completely absorbed

ampicillin

Aminopenicillins Distribution

renal tissue

septic joints

ascitic fluid

CSF (inflamed meninges)

Aminopenicillins Adverse Effects

not very beta-lactamase stable

Penicillinase-Resistance PCNs Dose Adjustment+Coverage

dose adjustment

• needed for severe hepatic impairment

• nafcillin→needs big IV sodium load

coverage

• mx of choice→methicillin-sensitive s aureus infections (MSSA)
  -MSSA→different bacteria structure→normal beta lactamase can’t attack nucleus

• streptococcal spp

• staphylococcus aureus

• peptostreptococcus

key points

• no gram negative coverage

• strep→good

• staph→excellent

Penicillinase-Resistance PCNs Distribution

bone

septic joint effusions

cardiac tissue

Penicillinase-Resistant PCNs Mx

oxacillin

nafcillin

dicloxacillin

Ureidopenicillins (Anti-Pseudomonal Penicillins) Dose Adjustment+Coverage

dose adjustment

CrCl x<50 ml/min→necessary

coverage

• gram-negative→significantly improved activity
  -psudomonas
  -bacteroides

• enterococal→some

• anaerobes→some

Ureidopenicillins (Anti-Pseudomonal Penicillins) Distribution

pleural fluid

ascitic fluid

wound fluids

Ureidopenicillins (Anti-Pseudomonal Penicillins) Mx

piperacillin

Ureidopenicillins (Anti-Pseudomonal Penicillins) Adverse Effects

not very beta-lactamase stable

Beta-Lactam/Beta-Lactamase Inhibitors MOA

blocks attack of beta lactam nucleus→allows transpeptidase enzymes to bind→distrupts cell wall formation

have no antimicrobial activity

Beta-Lactam/Beta-Lactamase Inhibitors Dose Adjustment+Coverage

dose adjustment

CrCl x<50 ml/min→necessary

coverage

adds:

• h influenzae

• m catarrhalis

• n gonorrhoeae

• b fragilis

• extends gram positive+gram negative+gram negative anaerobes

• good for “mixed” infections→broad empiric coverage

Beta-Lactam/Beta-Lactamase Inhibitors Distribution

good throughout all tissues

Beta-Lactam/Beta-Lactamase Inhibitors Mx

ampicillin-sulbactam (unasyn)

amoxicillin-clavulanate (augmentin)

piperacillin-tazobactam (zosyn)

new combination

• BLI+cephalosporin

• BLI+penem

Penicillins Summary

general monitoring

• C/S

• CBC/diff

• LFTs

• RFTs

pregnancy/lactation

• generally compatible

• cross placenta

• excreted in milk

peds

newborns→more susceptible to SEs

geriatrics

• more susceptible to SEs

• watch LFTs+RFTs

critically ill

no specific recommendations

renal impairment

dose adjustment CrCl→x<50-60

hepatic impairment

penicillin g→dose adjustment for renal+hepatic

obesity

no specific recommendations

Cephalosporins (General) Method of Action (MOA)

MOA→cell wall active drugs

• inhibits certain enzymes that create cross-linking→disrupts cell wall formation
  -cross-linking enzymes→cause cell lysis+death

• divided into several subclasses

Cephalosporins (General) Dose Adjustment+Coverage

dose adjustment

CrCl x<50 ml/min→necessary

coverage

• varies

• none cover enterococcus

• gen 1→extremely gram positive

• gen 5→extremely gram negative

• move from 1st to 5th→gain gram negative coverage

Cephalosporins (General) Classes

gen 1-5

gram positive→gram negative coverage

Cephalosporins (General) Adverse Effects

some→contain methyltetrazolethiol (MTT) side chain

prolongs prothrombin time/INR

cefotetan→disulfiram reaction with alcohol

PCN cross sensitivity→1-3%
-depends on reference
-some say even less

Cephalosporins (General) Pharmacokinetics (ADME)

absorption

rapidly+throughly absorbed

distribution

penetrates well into most tissues+fluids

metabolism

ceftriaxone→40% metabolized by liver

elimination

• half-life→short
  -exception→ceftriaxone

• excreted unchanged in urine
  -some→undergo biliary excretion

1st Generation Cephalosporins Mx

cefazolin (IV)

cephalexin

cefadroxil (PO)

1st Generation Cephalosporins Dose Adjustment+Coverage

dose adjustment

CrCl x<50 ml/min→necessary

coverage

• streptococcal spp→very active

• MSSA→very active

• gram negative→limited

• anaerobic coverage→none

• CSF penetration→poor

1st Generation Cephalosporins Distribution

bone tissue

synovial fluid

pleural fluid

wound fluids

ascitic fluid

inflammatory exudate

2nd Generation Cephalosporins Mx

“2 furry foxes drinking tea on the floor”

divided into 2 groups

group 1

• cefufoxime

• cefaclor

group 2

• cefoxitin

• cefotetan

2nd Generation Cephalosporins Dose Adjustment+Coverage

dose adjustment

decreased renal function→necessary

coverage

group 1

• strep spp→very active

• MSSA→very active

• gram negative→significantly improved

• gram negative anaerobes (b fragillis)→none

• CSF levels→variable

group 2

• strep spp→inferior

• MSSA→inferior

• gram negatives→enhanced (compared to other cephalosporins)

• bacteroides spp (b fragillis)→good

2nd Generation Cephalosporins Distribution

penetrates into various tissues/fluids

lung

• female genital tract

• kidney

• synovial fluid

• pericardial/peritoneal fluid

• pleural fluid

cephamycins

“dirty surgery”

cefuroxime

penetrates well into the CSF

3rd Generation Cephalosporins Mx

anti pseudomonal→ceftazadime

ceftriaxone

cefotaxime

cefixime

cefpodoxime

proxetil

3rd Generation Cephalosporins Dose Adjustment+Coverage

dose adjustment

• decreased renal function→necessary

• decreased hepatic function→necessary

coverage

ceftazadime:

• p aeruginosa→excellent

• streptococcal spp→adequate (slightly less than other cephalosporins)

• negative anaerobes→poor (cover under 50% of b fragillis)

ceftriaxone:

• CSF levels→excellent

general/all:

• MSSA→weak

3rd Generation Cephalosporins Distribution

extensive for all

4th Generation Cephalosporins Mx

cefepime

4th Generation Cephalosporins Dose Adjustment+Coverage

dose adjustment

decreased renal function

coverage

• staph+strep→similar to previous gens

• gram negative→superior

• p aeuruginosa→good

• MRSA→none

4th Generation Cephalosporins Distribution

extensive for all

5th Generation Cephalosporins Mx

ceftaroline

ceftobiprole

5th Generation Cephalosporins Coverage

coverage

ceftaroline:

• gram positive coverage

• gram negative coverage

• aerobic coverage

• anaerobic→limited

• respiratory infections→effective

• MRSA→effective

• s pneumo→effective

• pseudomonas→none

ceftobiprole:

• pseudomonas→yes

5th Generation Cephalosporins Summary