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