Antibiotics Review Part II: basic antimicrobial Principles including Penicillins, Cephalosporins

B-Lactam Antibiotics

Mechanism: Inhibition of Cell Wall Synthesis

• B-lactams bind Penicillin-Binding Proteins (PBPs)
• Irreversible binding • Bactericidal 

Time-dependent killing

• Time > MIC

Pregnancy Category B

Peptidoglycan Cross-Linking & PBPs

B-Lactam ring resembles this amide bond AND has a higher binding affinity for PBP than the chains. Therefore, cross-linking does NOT occur!

Susceptibility to B-Lactams 

Organism must be: 

• Actively growing and making a cell wall 
• Not producing inactivating enzymes (-ases) 
• Must be able to
• enter porin channels to reach peptidoglycan layer (gram-negatives)

Many drug classes

• Penicillin (PCN)
• Cephalosporin
• Carbapenem
• Monobactam

“Natural” Penicillin (PCN)

1928, discovered by Alexander Fleming

1940s used clinically in the US

One of his agar plates was contaminated with a mold, Penicillium notatum 

Besides mold growth, there was a 'zone of inhibition' in which the microorganism (S. aureus) had not grown

Penicillin G

• IV Penicillin Potassium or Sodium 
• IM short-acting: Procaine Penicillin 
• IM long-acting: Benzathine Penicillin 
• Dosed in ‘Million Units' instead of milligrams

Penicillin V 

PO, also called Pen VK

• More stable to gastric acid than Pen G

Case 1

28-year-old man 

Asymptomatic HIV infection, adherent to the antiretroviral regimen (Atripla) 

Two new sexual partners within the past 6 months, NOT used condoms consistently. 

PE: normal, except shotty axillary and inguinal lymphadenopathy, unchanged from previous examinations. 

Neurologic: normal. 

Labs: 

• SCr 0.8, AST 23, ALT 26, Alk Phos 84
• CD4 cell count 680 cells/uL, HIV RNA VL undetectable 
• Serum rapid plasma reagin titer is 1:16 compared with negative results 6 months ago. Results of serum fluorescent treponemal antibody absorption testing are positive

Which of the following is the most appropriate treatment?

• A. Aqueous crystalline penicillin G intravenously for 10 days
• B. Intramuscular benzathine penicillin G weekly for three doses
• C. Oral doxycycline for 14 days
• D. Single-dose intramuscular benzathine penicillin G

Different formulations for Syphillis Tx

Primary, Secondary, and Early Latent

• IM Benzathine Penicillin 2.4 MU X1

Tertiary and Late Latent

• IM Benzathine Penicillin 2.4 MU x 3 doses

Neurosyphillis

• IV Pen G (aqueous crystalline) 18-24 MU/day 
• Alternative: Procaine PCN + Probenecid

Jarisch-Herxheimer reaction

• Acute febrile reaction, headache, myalgia 
• Within 24 hrs after 1st dose

Common Medication Error! 

NEVER use Combination Long/Short-Acting!!

CORRECT PRODUCT: L-A is benzathine ONLY

INCORRECT PRODUCT: C-R is a mix of benzathine and procaine 

Antimicrobial Spectrum of Penicillin (PCN) 

Gram (+), primarily Streptococci!

• Enterococcus faecalis, >50%
• Streptococcus pneumoniae MICs

Few Gram (-)

• Neisseria meningitidis

Anaerobes, not B. fragilis

Actinomyces sp. (mouth)

Spirochetes, Treponema pallidum (syphyllis)

History of PCN Resistance

If an organism is PCN-susceptible, “natural” PCN is more effective than any of the other PCNs

• Most clinically relevant with Streptococci

Resistance to B-Lactams

Problems with PBPS

• Overproduction of PBPs 
• Production of PBPs with reduced affinity

B-Lactam Inactivating Enzymes (B-Lactamases)

Inactivation of porin channels

Efflux pumps

The purpose of this slide is to show you that there are hundreds of different B-Lactamases that cleave different B-Lactams

So what this means is:

All future B-Lactams

• 1) address problems with resistance, or 
• 2) expand the antimicrobial spectrum to cover new organisms 

Remember, PCN was very narrow!

Penicillins: Antimicrobial Spectrum

“Anti-staphylococcal” Penicillins

• Methicillin (IV) 
• Oxacillin (IV, PO) 
• Nafcillin (IV) 
• Dicloxacillin (PO) 
• Cloxacillin (PO)
• Spectrum: MSSA, Strep

Aminopenicillins

• Add Gram (-) coverage 
• Expand anaerobic coverage
• Ampicillin (IV, PO): caution Na+ in IV formulation 
• Amoxicillin (PO): more stable against gastric acid

Gram Negative Rods | SPACE Bugs

• S (also called KES): Serratia, Klebsiella, Enterobacter 
• Proteus vulgaris or Pseudomonas: Proteus mirabilis can also be an ESBL producer
• Acromobacter or Acinetobacter 
• Citrobacter
• Enterobacter

Aminopenicillins: Antimicrobial Spectrum

• Gram (-) coverage
• “Low Resistance” Enterobacteriacae (GNRs) 
• H. influenzae (non-Blactamase producing) 
• Food-derived organisms: 1. Listeria monocytogenes: Drug of Choice. 2. Salmonella sp. and Shigella sp.
• Gram (+), Streptococci and Enterococci
• Better anaerobic coverage compared to PCN

But, resistance continued and these agents became ineffective. Coverage was needed for even more pathogens, such as Pseudomonas SPACE/SPICE bugs

B-lactamase Inhibitors

Clavulanic Acid 

Sulbactam 

Tazobactam

• None are available as single-agents in the USA

Little intrinsic antimicrobial activity

• Sulbactam: Acinetobacter

May increase side effect profile 

• Clavulanic Acid: 9 Gl side effects, cholestasis: Max Dose/day = 500mg

B-lactam/ B-lactamase Inhibitors Combination Agents 

• Amoxicillin/Clavulanic Acid (Augmentin, PO) 
• Ampicillin/Sulbactam (Unasyn, IV) 
• Ticarcillin/Clavulanic Acid (Timentin, IV) 
• Piperacillin/Tazobactam (Zosyn, IV)
• Protects the primary B-lactam from cleavage by a variety B-lactamases via suicide inhibition (irreversible binding): Therefore, may broaden the antimicrobial spectrum of the primary ß-lactam

Clinical Pearls regarding B-Lactamase Inhibitors

Protection against B-Lactamases!

• Staphylococcus aureus (MSSA) 
• H. influenzae and M. catarrhalis 
• Many GNRs!!! Including SPACE Bugs

Non B-Lactamase Resistance Issues

• S. pneumoniae, Enterococcus, MRSA (PBP changes)

Zosyn: nosocomial pathogens 

Timentin: Strentrophomonas maltophilia

Case 2

42-year-old man, admitted for CAP 

PMH: HTN (chlorthalidone), 25-pack-year smoker 

Inpatient Medications: Ceftriaxone + Azithromycin 

Microbiology: 

• Day 2 Blood cultures 2/2 gram-positive cocci in pairs and chains. The ceftriaxone is continued and the azithromycin is stopped
• Day 3 Blood culture result is Streptococcus pneumoniae, susceptible to penicillin

Day 3: feeling better, eating and drinking well

• RR 16, O2 sat 97% RA, HR 88/min, BP 140/80 mm Hg, Temp 37.0 °C 98.6 °F

Which of the following is the most appropriate management? 

• A. Discharge on oral levofloxacin to complete 7 days of therapy 
• B. Discharge on oral amoxicillin to complete 14 days of therapy
• C. Discharge on oral amoxicillin to complete 7 days of therapy 
• D. Switch to oral amoxicillin and discharge tomorrow, if stable

B-Lactam (Penicillins) | Food & Drug Interactions 

Food

• reduction of the oral absorption of PCN V, amoxicillin, dicloxacillin, cloxacillin

Drug

• Birth control pills (esp. PCN and aminopenicillins) 
• Warfarin: Nafcillin/Dicloxacillin: strong CYP3A4 Inducers 
• Probenecid: inhibits tubular secretion of PCN and increases the T 1/2

Penicillin (PCN) Allergy

• Cross-reactivity with other B-Lactams
• 1st Gen. Cephalosporins 5-10% 
• 2nd & 3rd Gen. Cephalosporins 1-5% 
• Carbapenems ~1-5% 
• Monobactams, rare

Newer data suggest that cross-reactions occur between chemical functional groups, but across drug classes 

• Example, Aztreonam and Ceftazidime have a high cross-reactivity and the same functional group

Cephalosporins

Cephalosporins available today (1st -> 5th Generations) have NO activity against Enterococcus, Listeria, Atypicals

3rd Generation Cephalosporins | Intravenous

• Ceftriaxone and Cefotaxime have identical spectrum, but very different pharmacokinetics 
• Ceftriaxone is dosed once-daily due to 1 protein-binding 
• Ceftriaxone is NOT for use in Neonates (< 3 months old) due to kernicterus (too much unbound bilirubin): Use Cefotaxime instead 
• Both penetrate the CNS = Meningitis Treatment (S. pneumoniae) at high doses: example, Ceftriaxone 2g IV q12h 
• Both are “Drugs of Choice” for Community-Acquired Pneumonia (CAP) (+/- a macrolide) and Gonorrheal infections 

Many Other Cephalosporins are in Development

Ceftobiprole (IV): PDUFA TBD

• MRSA + Pseudomonas + Enterococcus faecalis + Streptococcus pneumonia

Ceftolozane/Tazobactam (IV): PDUFA Dec 2014 

• Stable against ESBLs 
• Activity against Pseudomonas

Ceftazidime/Avibactam (IV): PDUFA Q1 2015

Ceftaroline/Avibactam (IV): PDUFA 2015

• Promising against ESBLs, KPCs and other Blactamases 
• Avibactam is the first non-Blactam blactamase inhibitor

Cephalosporin Adverse Reactions

Common 

• Rash, diarrhea, allergic reactions & hypersensitivity
• Biliary sludge with Ceftriaxone 
• Clostridium difficile colitis = documented with all B-Lactams

Rare

• Seizures, hematologic issues, interstitial nephritis

MIT (Methylthiotetrazole) side chain

• Cefotan, Cefmandole, Cefoperazone, Cefmetazole 
• Vitamin K-antagonism -> increased bleeding risk 
• Disulfiram-type reaction

Cephalosporin Food & Drug Interactions

Food 

• Rate of absorption can be reduced with food intake in some agents 

Drug

• MTT side-chain: Warfarin, Alcohol 
• Probenecid: when tubular secretion occurs