β-LACTAMS - Penicillins / ©2009 Mark Tuttle
Name / Target Organism / Mechanism / Side effects / Absorption / Excretion / Resistance
PENICILLINS / - β-lactam ring interferes with transpeptidation in peptidoglycan cell wall assembly.
- Thus, need dividing bacteria
- BacterioCIDAL
- β-Lactamase sensitive / 1. Hypersensitivity
Rash, serum sickness, anaphylaxis in 1/10,000 (10% die)
2. Coombs-positive hemolytic anemia
10% of patients with dose > 6g/day
3. Interstitial nephritis
Mostly just methicillin
4. Neurotoxicity
Seizures or coma
Usually w/high doses
5. Cation Toxicity
When administered as Na+ or K+ salt
Worse if heart problems, preexisting electrolyte problems
6. Fluid/Electrolyte loss
w/High doses – hypokalemic acidosis
7. Herxheimer reaction
With spirochetes (Borrelia, Treponema) / - / - Mostly via kidney / -
Penicillin G / Gram + cocci
- Strep. Pyogenes,
Strep. Pneumonia (but 40% are resistant), Viridans Strep., Enterococcus faecalis
Gram – cocci
- Neisseria gonorrheam (some res.), meningitides
Gram – rods
- Bacteroides (not fragilis) ONLY, NO other GNRs / - IV
- Repository
o  Procaine
o  Benzathine
- not acid stable – would be destroyed in stomach if administered orally
- Less consistent absorption than pen V across people / - Weak acid group is ionized in blood, actively secreted and then sequestered in urine. Cannot be reabsorbed due to horrible PC. (20% bioav)
- T1/2 = 20-30 minutes
- Combine with acid probenicid competes for renal active secretion / - Staph. Aureus
- Enterococcus faecalis
(like Streptogramins)
- All Gram – rods resistant except non-fragilis Bacteroides
- Chlamydia
Penicillin V
Phenoxymethyl-penicillin / - Less active versus Neisseria than Pen G / - Oral
- Useful for mild infections where consistent absorption from GI tract is important / - / -
Broad spectrum / Aminopenicillins
Ampicillin / - E. coli, Proteus mirabilis, Salmonella, Haemophilus / - Diarrhea, pseudomembranous colitis (C. difficile)
- Maculopapular rash / - Oral and parentral use / - / -
Amoxicillin / - Better absorbed orally, less GI disturbance / - / - NOT effective vs. Shigella, Listeria
Carboxypenicillin
Carbenicillin indanyl ester, ticarcillin / - Includes Pseudomonas!, indole-positive Proteus / - Bleeding: inhibition of platelet aggregation / - / - Concentrated in urine so useful for UTIs / -
Ureidopenicillin
Piperacillin, mezlocillin / - Similar to ticarcillin but also Klebsiella pneumoniae / - / - / - / -
Narrow Spectrum spectrum / Methicillin
No longer used / - Penicillin G-resistant Staph. aureus ONLY
- Less active against other things. / - β-Lactamase resistant because of bulkier R-group / - Renal toxicity – interstitial nephritis / - / - / - MRSA
Nafcillin / - / - / - Billiary excretion- less chance of CNS toxicity than other penicillins / -
Oxacillin, Cloxacillin, Dicloxacillin
β-Lactamase Inhibitors
Clavulanate / - Negligible antimicrobial activity, used in combination with a β-lactam / - Affect plasmid-borne type A β-Lactamases:
Staph, H. influenza, Gonoccoccus, Salmonella, Shigella, E. coli (TEM-1), Klebsiella pneumonia (SHV-1) / - / - / - / - Class C β-Lactamases are RESISTANT:
Pseudomonas, Enterobacter, Citrobacter, Serratia
β-LACTAMS - Cephalosporins / ©2009 Mark Tuttle
Name / Target Organism / Mechanism / Side effects / Pharmacokinetics
CEPHALOSPORINS
Cephem core (β-lactam ring + adjoined sulfur, acid ring) + side chains at C3 (X) and C7 (R) / - Broader spectrum than penicillin G
Useful for K. pneumonia, E. coli
- Resistant to many β-lactamases
Determined via R groups (C7) / - Its Cephem core includes a β-lactam ring like to penicillin’s and has the same affect: inhibiting peptidoglycan transpeptidation
- Side chains at C7 (R) affects spectrum and stability to β-lactamases
- BacteriaCIDAL like penicillin / - Toxicity affected by C3 (X) side chain
- Same as with penicillin but kidney damage has NOT been observed (direct tubular necrosis) with Cephalexin (1st gen oral)
- 10% incidence of cross-hypersensitivity with penicillins – those with history of penicillin hypersensitivity can’t have cephalosporins
- May INDUCE β-lactamase expression (like induction of methylation of ribosome in macrolides) / - Affected by C3 (X) side chain in structure
- All generations have an oral and a parentral form
o  Oral: α-amino at C3 (X)
Dipeptide transport in gut
1st Generation / Cephalexin / - Effective against many gram +/- / - / - Orally administered
2nd Generation / Group A
Cefuroxime, Cefonicid
(Parenteral) / - Increased activity against Hemophilus influenzae / - / - Cefuroxime: only 1st/2nd gen cef to reach CNS at therapeutic levels but is not DOC for meningitis
Group B: Cephamycins
Cefoxitin, Cefotetan
(Parenteral) / - Increased activity against Bacteroides fragilis
- Unaffected by ESBLs like in K. pneumonia, E. coli, Pseudomonas, Proteus, Citrobacter / Cefotetan (+ others with NMTT):
- N-methylthiotetrazole (NMTT) side chain (C3):
o  Blocks vitamin K epoxide reductase à hypothrombinemia
o  Blocks aldehyde dehydrogenase à alcohol intolerance / -
3rd Generation / Cefotaxime
Ceftizoxime
(~xime)
Aminothiazole oxime group (@ C7) / - Oxime ether group (C7): stable vs. Enterbacteriaceae β-lact’ase
- High activity against E. coli, H. influenza, K. pneumonia, Salmonella, Shigella, Proteus miribalis
- Also, Pseudomonas, Serratia / - Aminothiazole ring (C7) affects binding to PBPs and entry into periplasm (Gram negs)
- May induce resistance in Enterobacter, Citrobacter, Serratia
Ceftriaxone
(IM) / - Especially: Gonorrhea/meningitis
- HACEK Endocarditis organisms / - 50% billiary excretion.
- Long half life (8 hrs)
Ceftazidime (larger R)
Has an extra -OCH3 at C7 / - Especially: Pseudomonas (+ aminoglycoside for Pseud. meningitis) / -
4th Generation / Cefepime (Maxipine®) / - Stable to plasmid-encoded β-lactamases: TEM-1, TEM-2, SHV-1, NOT TEM-3
- TEM-1: E. coli
- SHV-1: K. pneumoniae / - Unlike other cephalosporins, is a poor inducer of type I chromosomal β-lactamases and some extended-spectrum β-lactamases
- Also, is resistant to these β-lactamases / -
Other β-Lactams / ©2009 Mark Tuttle
Name / Target Organism / Side effects / Pharmacokinetics
CARBAPENEMS / - Broad spectrum – useful in emergency treatment
- No cross-resistance with other β-lactams. Not well recognized by β-lactamases / - / -
Imipenem-cilistatin / - / - Cilastatin prevents kidney toxicity of imipenem by blocking active uptake by renal tubule cells, HOWEVER:
- CNS toxicity: decreased consciousness and myoclonic jerking. May be result of inhibited imipenem transport out of CSF by cillistatin / - Cilistatin inhibits renal dehydropeptidase-1, enzyme which inactivates imipenem
Maropenem / - Less active vs. Gram +
- More active vs. Gram - / - Less CNS toxicity than imipenem/cilastatin because no cillastatin!
- Possibly increased renal toxicity / - NOT hydrolyzed by dehydropeptidase-1
MONOBACTAMS
Aztreonam / - Binds to PBP-3 ONLY IN Gram Negative Aerobes
- Not sensitive to plasmid or chromosomal β-lactamases and does not induce their expression
- However, if β-lactamases induced by other β-lactams, these will prevent it from binding to PBP-3 (doesn’t destroy the drug but prevents it from acting) ex. Treating Pseudomonas with tircillin (a carboxypenecillin) induces chromosomal β-lactamase that will nullify subsequent use of Monobactams / - Little cross-allergy with other β-lactams (penicillins or cephalosporins) / -
β-Lactam Substitutes
Name / Target Organism / Mechanism / Side effects / Absorption / Resistance
Spectinomycin
(Aminoglycoside-like) / - Penicillin-resistant Neisseria / - Target 30S ribosomal subunit
- Similar structure as Aminoglycosides / - Low toxicity
- Nausea, chills, fever, dizziness / - IM injection / -
Vancomycin / - Methicillin-resistant Staph. aureus (MRSA) (IV)
- Backup drug vs. Clostridium difficile (oral) Pseudomembranous colitis
- Little activity vs. Gram – rods / - Blocks D-ala-D-ala transpeptidation of peptidoglycan cell wall / 1. Ototoxic: deafness (can be irreversible)
2. Nephrotoxic: blood + protein in urine
3. Thrombophlebitis (clots in blood) 10% of patients
4. Hypotension & “red man” syndrome because it releases histamine
à Give antihistamines 2 hrs before giving drug / - IV
- Oral / - Will not block D-ala-D-lac transpeptidation
New agents for resistant Gram +
Name / Target Organism / Mechanism / Side effects / Absorption / Resistance
Quinopristin/Dalfopristin
(Streptogramins) / - Vancomycin-resistant, multi-drug resistant Enterococcus faecium
- NOT active against Enterococcus faecalis / - Inhibit protein synthesis (streptogramins) / - Muscle and joint pain
- Inhibits Cyp3A4 (50% of drugs that are oxidized are done by this à important for drug interaction) / - / - NOT active against Enterococcus faecalis
Linezolid / - Effective against Enterococcus feacalis and Faecium / - Binds 23S ribosomal RNA – no cross-resistance with other protein synth inhibitors / - Thrombocytopenia possible – platelet counts should be monitored if treatment > 2 weeks
- Inhibits MAO: avoid food rich in tyramine or drugs metabolized by MAO / - IV and oral / -
Daptomycin
A cyclic lipopeptide / - Indicated for skin infections caused by:
- Staph. aureus (including MRSA), Strep. pyogenes, Strep. agalactiae, Strep. Dysgalactiae subspecies: Equisimilis, E. faecalis (Vanc-sensitive
- BacterioCIDAL / - Inserts in cell membrane via lipid-like portion and causes rapid depolarization via pore portion
- Disrupts membrane potential needed for bacteria to make ATP / - Rhabdomyolosys: Monitor patients for muscle pain/weakness, discontinue if blood CPK>1000 u/L
Consider temporary discontinuation of Statins (HMG-CoA Reductase Inhibitors)
- Paresthesias at high doses / - IV / -