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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. 
    • 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

    • 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



    • 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 
    • 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 
    • 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 

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

    • 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 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

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


    MIT (Methylthiotetrazole) side chain
    • Cefotan, Cefmandole, Cefoperazone, Cefmetazole 
    • Vitamin K-antagonism -> increased bleeding risk 
    • Disulfiram-type reaction

    Cephalosporin Food & Drug Interactions

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

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

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