Infectious Disease I

Empiric antibiotic selection is based on:

Infection site and likely organisms

Infection severity and risk of multi-drug resistant organisms

Spectrum of activity

Ability of the antibiotic to penetrate the site of infection or risk of side effects

Patient characteristics (age, body weight, allergies, renal or hepatic function, comorbid conditions, recent antibiotic use, colonization with resistant bacteria)

Treatment guidelines (IDSA, CDC)

Antibiogram

shows susceptibility patterns and can be used to monitor resistance trends over time

Gram stain

categorizes the organism by stain result and shape (morphology) and provides quick, preliminary results (does NOT identify the exact organism)

Gram-positive organism characteristics

thick cell wall 

stain dark purple or blue 

Gram-negative organism characteristics

thin cell wall

stains a pink color

Atypical organism characteristics

do NOT have a cell wall

Will not stain very well

Most common Gram-positive cocci

Clusters: Staphylococcus spp. (includes MSSA and MRSA)

Pairs & Chains: Streptococcus pneumoniae, Streptococcus spp. like pyogenes, Enterococcus spp. (including VRE)

Common gram-positive rods

Listeria monocytogenes

Corynebacterium spp.

Common gram-positive anaerobes

Peptostreptococcus 

Propionibacterium acne 

Clostridioides difficile 

Clostridium spp. 

Common gram-negative cocci

Neisseria spp.

Common gram-negative rods that colonize the gut

Proteus mirabilis

Escherichia coli

Klebsiella spp.

Serratia spp.

Enterobacter cloacae

Citrobacter spp.

Common gram-negative rods that do not colonize the gut

Pseudomonas aeruginosa 

Haemophilus influenzae 

Providencia spp.

Common gram-negative organisms that are curved or spiral shaped

H. pylori

Campylobacter spp.

Treponema spp.

Borrelia spp.

Leptospira spp.

Common gram-negative coccobacilli

Acinetobacter baumannii

Bordetella pertussis

Moraxella catarrhalis

Common gram-negative anaerobes

Bacteroides fragilis 

Prevotella spp.

Synergy of antibiotics definition

an effect greater than the sum of the individual drugs

Example: aminoglycosides and beta-lactams

Common mechanisms of resistance: Intrinsic

the resistance is natural to the organism

E. coli is naturally resistant to vancomycin because the antibiotic is too large to penetrate the cell wall

Common mechanisms of resistance: Selection pressure

resistance occurs when antibiotics kill the susceptible bacteria, leaving behind more resistant strains 

Enterococcus is part of normal gut flora, and when antibiotics are used, it can lead to more vancomycin-resistant Enterococcus (VRE) 

Common mechanisms of resistance: Acquired

Bacterial DNA containing resistant genes can be transferred between species and/or picked up from dead bacterial fragments in the environment

Common mechanisms of resistance: Antibiotic degradation

bacterial enzymes break down the antibiotic

Example: beta-lactamases break down beta-lactams before they can bind to their site of activity (combated with beta-lactamase inhibitors like clavulanate, sulbactam), or extended-spectrum beta-lactamases (ESBL) can break down both beta-lactams and most cephalosporins

Extended-spectrum beta-lactamases (ESBLs) are treated with:

carbapenems

cephalosporin/beta-lactamase inhibitor combinations

Carbapenem-resistant Enterobacterales Definition

MDR gram-negative organisms that produce enzymes capable of breaking down penicillins, most cephalosporins, and carbapenems

Requires combination of antibiotics (advanced beta-lactam/beta-lactamase inhibitor combinations, or polymyxins)

Common Resistant Organisms

Klebsiella pneumoniae

Escherichia coli

Acinetobacter baumannii

Enterococcus faecalis, Entercoccus faecium

Staphylococcus aureus

Pseudomonas aeruginosa

Antibiotics that have the highest risk of C. diff infection

broad-spectrum penicillins

cephalosporins

quinolones

carbapenems

Clindamycin (has a boxed warning)

Bactericidal Mechanisms of Action

DNA/RNA inhibitors 

Cell membrane inhibitors 

Cell wall inhibitors 

Bacteriostatic Mechanism of Action

Folic Acid Synthesis inhibitors 

Protein synthesis inhibitors

DNA/RNA inhibitors

Quinolones (DNA gyrase, topoisomerase IV)

Metronidazole, tinidazole

Rifampin

Cell Membrane Inhibitors

Polymyxins

Daptomycin

Telavancin

Oritavancin

Protein Synthesis Inhibitors

Aminoglycosides

Macrolides 

Tetracyclines

Clindamycin

Linezolid, tedizolid

Cell Wall Inhibitors

Beta-lactams

Monobactams

Vancomycin, dalbavancin, telavancin, oritavancin

Folic Acid Synthesis Inhibitors

Sulfonamides

Trimethoprim

Dapsone

Hydrophilic Agent Pharmacokinetic Parameters

Small volume of distribution → less tissue penetration

Mostly renally eliminated → can lead to side effects if not dose adjusted 

Low intracellular concentration → not active against atypical pathogens

Poor bioavailability → IV:PO ratio is NOT 1:1 

Examples of Hydrophilic Agents

Beta-lactams

Aminoglycosides

Vancomycin

Daptomycin

Polymyxins

Lipophilic Agents Pharmacokinetic Parameters

Large volume of distribution → better tissue penetration

Mostly hepatically eliminated → can cause hepatotoxicity and drug-drug interactions

Achieve higher intracellular concentrations → active against atypical pathogens

Excellent bioavailability → IV:PO ratio is often 1:1

Examples of lipophilic agents

Quinolones

Macrolides 

Rifampin

Linezolid

Tetracyclines

Concentration-dependent killing antibiotics

aminoglycosides

Benefits of concentration dependent killing antibiotics

can be dosed less frequently and in higher doses to maximize the concentration above the MIC

Time dependent killing antibiotics

beta-lactams

Benefits of time dependent killing antibiotics

can be dosed more frequently and can be administered for a longer duration to maximize the time above the MIC

Beta-lactam mechanism of action

inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins, which prevents the final step of peptidoglycan synthesis

Natural penicillin bacterial activity

gram-positive cocci (streptococci and enterococci) NOT staphylococci

Gram-positive anaerobes (mouth flora)

NO gram-negative activity

Antistaphylococci penicillin bacterial activity

streptococci and methicillin-susceptible Staphylococcus aureus (MSSA)

NO activity against Enterococcus, gram-negative pathogens and anaerobes

Aminopenicillin bacterial activity

Streptococci, enterococci, and gram-positive anaerobes 

Certain gram-negative bacteria (Haemophilus, Neisseria, Proteus, E. coli) 

Aminopenicillin WITH beta-lactamase inhibitors bacterial activity

Added activity against MSSA

more resistant strains of gram-negative bacteria (Haemophilus, Neisseria, Proteus, E. coli, Klebsiella) and gram-negative anaerobes

Extended-spectrum penicillin WITH beta-lactamase inhibitor bacterial activity

Broad-spectrum activity

MSSA coverage, more resistant strains of gram-negative bacteria, gram-negative anaerobes

Expanded coverage to other gram-negatives like Citrobacter, Acinetobacter, Providencia, Enterobacter, Serratia (CAPES) and Pseudomonas

Natural Penicillin Examples

Penicillin V Potassium 

Penicillin G Aqueous 

Penicillin G Benzathine

Penicillin G Benzathine Boxed Warning

NOT for IV use; can cause cardio-respiratory arrest and death

Antistaphylococcal Penicillin Examples

Dicloxacillin 

Nafcillin

Oxacillin

Aminopenicillin Examples

Amoxicillin

Amoxicillin/Clavulanate

Ampicillin

Ampicillin/Sulbactam

Extended-Spectrum Penicillin Examples

Piperacillin/Tazobactam

Penicillin Side Effects

Seizures (with accumulation if not renally dose adjusted)

GI upset 

Diarrhea

Rash (including SJS/TEN)

allergic reactions/anaphylaxis

Hemolytic anemia 

Antistaphylococcal Penicillin Special Considerations

preferred for MSSA infections

NOT renally dose adjusted

Nafcillin is a vesicant (administer through a central line)

Aminopenicillin Special Considerations

Ampicillin PO has POOR bioavailability - rarely used

IV ampicillin and Zosyn are diluted in NS

Penicillin Drug Interactions

Probenecid can increase the levels of beta-lactams 

Can increase levels of methotrexate

Penicillin VK (oral) is first line treatment for:

pharyngitis (strep throat)

Amoxicillin (oral) is first line treatment for: 

acute otitis media 

Infective endocarditis prophylaxis before dental procedures 

H. pylori infections

Penicillin G Benzathine (IM) is first line treatment for:

syphilis

Amoxicillin/Clavulanate is first line treatment for:

Acute otitis media and bacterial sinusitis

First generation cephalosporin bacterial activity

gram-positive cocci (streptococci and staphylococci)

Preferred when a cephalosporin is used for MSSA infection

Some activity against gram-negative rods (Proteus, E. coli and Klebsiella)

Second generation cephalosporin bacterial activity 

staphylococci, more resistant S. pneumoniae strains

Haemophilus, Neisseria, Proteus, E. coli, Klebsiella 

Cefotetan and Cefoxitin (2nd gen) have added activity against:

gram-negative anaerobes (B. fragilis)

Third generation group 1 cephalosporin bacterial activity

resistant streptococci (S. pneumoniae and viridians group streptococci)

Staphylococci (MSSA)

Gram-positive anaerobes and resistant strains of HNPEK

Third generation group 2 cephalosporin bacterial activity

lacks gram-positive activity 

covers Pseudomonas

Fourth generation cephalosporin bacterial activity

broad gram-negative activity (HNPEK, CAPES, and Pseudomonas) 

gram-positive resistant streptococci and staphylococci

Fifth Generation cephalosporin bacterial activity

gram-negative activity against HNPEK

broad gram-positive activity

ONLY beta-lactams that cover MRSA

First generation cephalosporin examples

Cefazolin

Cephalexin

Cefadroxil

Second generation cephalosporin examples

cefuroxime

cefotetan

cefoxitin 

cefprozil

Third generation group 1 cephalosporin examples

cefdinir

ceftriaxone

cefotaxime

Cefpodoxime

Third generation group 2 cephalosporin examples

ceftazidime

Fourth generation cephalosporin examples

cefepime

fifth generation cephalosporin examples

ceftaroline fosamil

Ceftriaxone Contraindications

use in hyperbilirubinemia neonates - causes biliary sludging, kernicterus

Concurrent use with calcium-containing IV products in neonates

Cephalosporin Warnings

cross-reactivity with penicillins

Cefotetan: causes disulfiram like reaction with alcohol ingestion

Cephalosporin Side Effects

Seizures (with accumulation if not dose adjusted)

GI upset

Diarrhea

Rash (including SJS/TEN)

allergic reations/anaphylaxis

hemolytic anemia

Ceftriaxone Special Notes

Does NOT need to be renally dose adjusted

Cephalexin common use

skin infections (MSSA)

Strep throat

Cefuroxime common uses

Acute otitis media

Community-acquired pneumonia

Cefdinir common uses

acute otitis media

Cefazolin common uses

surgical prophylaxis

Cefotetan and Cefoxitin common uses

Surgical prophylaxis (GI procedures)

Ceftriaxone common uses

CAP

Meningitis

Spontaneous bacterial peritonitis 

Pyelonephritis 

Ceftolozane/tazobactam and ceftazidime/avibactam uses

MDR gram-negative organisms including Pseudomonas

Ceftaroline common uses

active against MRSA

CAP, skin and soft tissue infections

Carbapenem Bacterial activity

MDR gram-negative infections 

includes ESBL-producing bacteria 

NO activity against atypical pathogens, MRSA, VRE, or C. difficile

Ertapenem Bacterial activity

NO activity against Pseudomonas, Acinetobacter, or Enterococcus

Carbapenems common uses

polymicrobial infections (severe diabetic foot infections)

Empiric therapy when resistant organisms are suspected

ESBL-positive infections

Resistant Pseudomonas or Acinetobacter infections

Ertapenem Special considerations

Must be diluted in NS ONLY

Carbapenem Side effects

Diarrhea

Rash/severe skin reaction (DRESS)

Higher risk of CNS effects like confusion and seizures with large doses or impaired renal function

Try to avoid in patients with a seizure disorder

Monobactam examples

Aztreonam

Aztreonam bacterial activity

many gram-negative organisms (Pseudomonas and CAPES)

NO gram-positive or anaerobic activity

Aztreonam

Azactam

Aztreonam Special considerations

can be used even if there is a penicillin allergy

Beta-lactams that can cover MRSA

Ceftaroline

Beta-lactams that can cover MSSA

Oxacillin

Nafcillin

Augmentin

Piperacillin/Tazobactam

Ampicillin/Sulbactam

Cefazolin and Cephalexin

Cefuroxime, Cefotetan, Cefoxitin

Ceftriaxone

Cefepime

Ceftaroline

Cephalosporin/beta-lactamase inhibitors

Meropenem

Ertapenem

Beta-lactams that can cover S. pneumoniae

Penicillin

Amoxicillin

Oxacillin, Nafcillin

Augmentin and Ampicillin/sulbactam 

piperacillin/tazobactam

Cefazolin and cephalexin 

Cefuroxime, cefotetan, cefoxitin 

Ceftriaxone

Cefepime

Ceftaroline

Cephalosporin/beta-lactamase inhibitors

Meropenem

Ertapenem

Beta-lactams that can cover Viridans group streptococci

Penicillin

Amoxicillin

Oxacillin, Nafcillin

Augmentin, ampicillin/sulbactam

Piperacillin/tazobactam

Cefazolin and cephalexin

Cefuroxime, cefotetan, and cefoxitin

Ceftriaxone

Cefepime

Ceftaroline

Cephalosporin/beta-lactamase inhibitors

Meropenem

Ertapenem

Beta-lactams that can cover Enterococcus (NOT VRE)

Penicillin

Amoxicillin

Amoxicillin/Clavulanate

Ampicillin/sulbactam

Piperacillin/tazobactam

Meropenem

Beta-lactams that can cover PEK (proteus, E. coli, Klebsiella)

Amoxicillin

Augmentin

Ampicillin/sulbactam

Piperacillin/tazobactam

Cefazolin and cephalexin

Cefuroxime, cefotetan, cefoxitin

Ceftriaxone, Ceftazidime

Aztreonam

Cefepime

Ceftaroline

Cephalosporin/beta-lactamase inhibitors

Meropenem

Ertapenem

Beta-lactams that can cover HNPEK (Haemophilus, Neisseria, Proteus, E. coli, Klebsiella)

Amoxicillin

Augmentin

Ampicillin/sulbactam

Piperacillin/tazobactam

Cefuroxime, cefotetan, cefoxitin

Ceftriaxone, ceftazidime

Aztreonam

Cefepime

Ceftaroline

Cephalosporin/beta-lactamase inhibitors

Meropenem

Ertapenem

Beta-lactams that can cover CAPES (Citrobacter, Acinetobacter, Providencia, Enterobacter, Serratia)

Piperacillin/tazobactam

Aztreonam

Cefepime

Cephalosporin/beta-lactamase inhibitors

Meropenem

Ertapenem