Beta Lactam structure
Thiazolidine ring attached to a B lactam ring that carries a secondary amino group
Pencillin MOA
PCN is a natural analog of D-ala-D-ala. PCD binding proteins (PBP’s) enzymes that remove terminal alanine to crosslink with neighboring peptide
PCDs inhibit this transpeptidation by covalently binding to PBP’s, blocking transpeptidation and inhibiting peptidoglycan synthesis within the bacterial cell wall
Leads to bacterial cell lysis and death
Bactericidal
Classes of PCN
Natural PCN
B lactamase resistant PCNs
Extended spectrum: amino-penicillins
Extended Spectrum: antipseudomomal penicillins
Natural penicillins
Penicillin G
Penicillin V
B-lactamase resistant penicillins
Methicillin
Nafcillin
Oxacillin
Dicloxacillin
Extended spectrum: amino-penicillins
Ampicillin
Amoxicillin
Extended spectrum antipseudomomal penicillin
Carbenicillin
Ticarcillin
Piperacillin
Penicillin G
natural PCN
Na or K
IV
Penicillin V
natural penicillin
PO
Benzathine Penicillin G
natural PCN
IM-long acting
Natural PCN spectrum of activity
streptococci, neisseria meningitidis, treponema pallidum, enterococcus faecalis.
Penicillinase-resistant Penicillins (penase-stable penicillins)
Methicillin (prototype)
Dicloxacillin (PO)
Nafcillin (im, IV, po)
Penicillinase resistant PCN spectrum of action
s. aureus, staph epidermidis, penicillinase producing, streptococci but NOT: MRSA MRSE Enterocci Gram - organisms
Aminopenicillins
Extended spectrum. Includes:
Ampicillin (PO, IV, IM)
Amoxicillin (PO)
Spectrum: Gram +, streptococci, enterococcus faecalis, listeria monoctytogenes, treponema pallidum. Extended gram -: h. flu, some ecoli and proteus mirabilis.
NOT: klebsiella, pseudomonas, little staph coverage, NOT MRSA, MRSE
Antipseudomonal PCNs
extended spectrum.
Carboxypenicillins: Carbenicillin (PO) and Ticarcillin (IM, IV)
Ureidopencillins: Piperacillin
Spectrum: Expanded gram - to include p. aeruginosa, E. coli, serratia, proteus mirabilis and enterobacter, kelbsiella pneumonia. Gram +: streptococci, not as good as PCN. Poor staph, NOT MRS, NOT good for enterococci
Penicillin Resistance
- Inactivation of B lactamases
- Modification of target (PBP)
- Impaired Penetration
- Efflux
Inactivation of B-lactamase
Most common. B lactamase breaks a bond in the B lactam ring of PCN to disable the molecule. Bacteria with this enzyme can resis the effects of PCN and other B lactam antibodies
Alteration in target PCN binding proteins
Alteration in target PBPs. Reduced affinity-can overcome with very high concentrations. Resistance in one organism may result from replacements of its PBP with PBO from resistant organism. MRS; streptcoccus pneumoniae and enterococci-penicillin.
PCN resistance by impaired permeability
Permeability barrier preventing penetration of antibiotic-gram - organisms.
Can down regulate porins or not make
not so critical by itself; important with b-lactamase
efflux pump - gram - organisms
Penicillins Absorption
Natural PCN: oral–poor; PCN-V more acid stable. Parenteral: PCN G usually given IV. PCN G procaine needs to be cautioned with an allergy to procaine. Penicillin G benzathine–delay absorption, low serum level sustained >7 days, used for B hemolytic step and treponema pallidum
PCN-ase resistant: nafcillin poorly absorbed PO, usually given IV. Dicloxacillin: acid stable, given on an empty stomach.
Aminopenicillins: Amoxicillin PO, can be given with food. Ampicillin, food decreases rate and extend of absorption, usually only given IV
Anti-pseudomonal–carbenicillin PO. Others IV/IM
PCN Distribution
Protein binding: nafcillin 90%, PCN G 60%, others less
adequate distribution into MOST tissues and fluids; sputum and milk 3-15% of serum; eye, prostate poor.
Poor penetration into cerebrospinal fluid when BBB intact: both passive transport and active transport out of CSF along with other organic compounds
Poor entry into CSF, difficulty crossing BBB; hydrophilic and active transport out
“Adequate” CSF concentrations 3-5% penetration attained during inflammation
CSF: probenecid–inhibits transport out of CSF; uremia–organic cmpds accumulate in CSF compete for transport; can accumulate and cause seizures
All cross placenta; risk category B
PCN Elimination
Primarily renal for most, both glomerular filtration (10%) and tubular secretion (90%) (probenecid inhibits)
half-life < 1hr (except benzathine PCN)
severe renal insufficiency t½ up to 10 hrs
Significant non-renal elimination for a few agents, no adjustment in renal insufficiency:
Nafcillin: primarily biliary
Oxacillin, diclox, clox: both renal and biliary
PCN G Clinical Use
Infections caused by Streptococci (S pneumoniae, MIC < 0.1 mcg/ml, viridans group streptococci), including upper and lower respiratory infections (pneumonia), arthritis, endocarditis, septicemia, meningitis
- *meningococcus meningitis
- *Syphilis (Treponema pallidum - DOC for all stages and forms) **Oral anaerobes (peptococcus, peptostreptococcus) and clostridia
PCN V Clinical Uses
Strep pharyngitis
Benzathine PCN Clinical use:
syphilis
Single injection to treat beta-hemolytic strep pharyngitis
Penicillinase-resistant PCN’s Clinical Use
Infections caused by Staph aureus or Staph epidermidis
NOT MRSA or MRSE, not enterococcal infections
Aminopenicillins Clinical Use
Used to tx otitis media, upper respiratory tract infections, sinusitis, meningitis
Infections due to susceptible strains of Haemophilus influenzae, Proteus mirabilis, and E coli
DOC for Strep Grp B, uncomplicated enterococcus UTI, Listeria monocytogenses (+AG) , Lyme disease
Oral anaerobes
Antipseudomonal PCN’s Clinical Uses
For serious infections caused by Gr (-) bacteria: bacteremias, pneumonias, bone, skin, intra-abdominal, gynecologic, infections following burns and UTI due to organisms resistant to PCN-G and ampicillin, especially Pseudomonas aeruginosa
Benzathine PCN Dose
**Given IM
PCN G Dose
**Given IV
PCN V Dose
250 – 500mg PO bid, tid, qid
** Given PO
Dicloxacillin
125 - 500mg q6h, PO*
Nafcillin Dose
1-2 gm q4-6h IV**
Amoxicillin dose
500mg q8h PO or 875mg q12h
Peds: UD=usual dose: 40-45 mg/kg/d div q12h or q8h HD=high dose: 80-90 mg/kg/d div q12h or q8h raised because of strep resistance
Ampicillin dose
250-500 mg q6h PO; 1-2 gm q3-4hr IV
Piperacillin Dose
3-4gm IV q4-6h (12 gm/day for most organisms, but for Pseudomonas 18-24 gm/day
B-lactam inhibitors
Clavulanic acid, sulbactam, tazobactam
No antimicrobial activity, acts as a bodyguard
Inhibit many but not all bacterial betalactamases; protect hydrolysable PCN’s against inactivation by these enzymes
Goal is to extend spectrum of activity for the companion beta lactame
Examples of B-lactam inhibitors
Fixed combos:
Amoxicillin + Clavulanic acid 125 mg = Augmentin PO
Ampicillin + Sulbactam = Unasyn (IV)
Ticarcillin + Clavulanic acid 100mg = Timentin (IV)
Piperacillin + Tazobactam = Zosyn (IV)
** Enhanced activity against beta-lactamases produced by s. aureus (Not MRSA), h. flu, e. coli, klebsiella pneumonia, n. gonorrhoeae, salmonella, shigella
**Inhibit chromosomal B-lactamases: legionella, bacteroides, branhamella
*no enhanced activity against AmpC B-lactamases
Spectrum of Action with B-lactamase inhibitor
expands coverage of parent PCN. good against s. aureus, staph epidermidis (NOT MRSA, MRSE), strep, ok for enterocci. proteus, e. coli, klebsiella penumoniae, h. flu, moraxella, catarrhalis
NOT PSEUDOMONAS
Dosing with B lactamase inhibitor
Augmentin: 875/125 bid PO; 500/125 or 250/125 tid PO
Zosyn: 2.25gm = Pip 2g, Tazo 250mg; 2.275 Pip 3g, Tazo 375mg; 4.5gm Pip = 4g, Tazo 500mg. Given IV q6h
Cephalosporins Classification/Spectrum of Action
More stable to beta-lactamase than PCN; produced by cephalosporium mold.
MOA: like PCN
First Gen Cephalosporins
Cephalothin
Cefazolin (Ancef, Kefzol) Parenteral; surg prophylaxis; skin infections not caused by MRSA
Cephalexin (Keflex) Oral
Cepharadine
Secondary Gen Cephalosporins
Cefaclor Cefuroxime Cefonicid Cefoxitin Cefotetan
Third Gen Cephalosporins
Ceftriaxone Cefotaxime Ceftzoxime Cefixime Cefdinir Ceftazidime Cefpodoxime Cefditoren
Fourth Gen Cephalosporins
Cefepime
MRSA Activity Cephalosporins
Ceftaroline
Cephalosporins First Gen Spectrum of Action
S. aureus, NOT MRSA, streptococci–aerobic and anaerobic; E. coli, K. pneumoniae, P. mirabilis
Resistant: enterococci sp, MRSE< MRSA, p. aerugenosa, b fragilis
First Gen ceph clinical use
Cefazolin used for surgical prophylaxis
Cephalexin used for UTI, cellulitis, skin and soft tissue infections, mastitis
Second Gen Ceph Oral agents:
Cefaclor (ceclor)
cefuroxime axetil (Ceftin)
Cefprozil (Cefzil)
Secon Gen Ceph parental agents
Cefuroxime (Zinacef)
Cefotetan (Cefotan)
Cefoxitin (Mefoxin)
Second Gen Ceph spectrum of action
Most important: stretpcocci (aerobic and anaerobic) less than G1, but varies by drug; m. catarrhalis, klebsiella better than G1
Cefuroxime, cefaclor: h. flu but not serratia or b. fragilis
Cefoxitin/cefotetan: bacteroides frafillis and some serratia, less against h. flu
*NOT MRSA, MRSE, ENTEROCCI, P. AERUGENOSA
Second Gen Ceph clinical uses
PO for sinusitis, otitis media, LRI
Surgical prophylaxis for “dirty” surgeries–GI, hysterectomy: cefoxitin, cefotetan
Peritonitis or diverticulitis: cefoxitin, cefotetan
Third Gen Ceph oral agents
Cefixime (Suprax)
Cefpodoxime (Vantin)
Cefibuten (Cedax)
Cefdinir (Omnicef)
Third Gen ceph parenteral agents
Ceftazidime (Fortaz)
Ceftriaxone (Recephin)
Third gen ceph B. fragilis group
Cefotaxime (Claforan)
Ceftrizoxime (Ceftizox)
Third gen ceph spectrum of action
Neisseria gonorrhea: ceftriaxone, cefixime
expanded activity for most enterobacteriaceae (e. coli, klebsiella, serratia)
p. aeruginosa–limited to ceftazidime ‘
PCN reistant streptococcus pneumoniae–ceftrixaone or cefotaxime
some b. fragilis limited to ceftaxime
*NOT enterococci sp, listeria, MRSA or MRSE
Third Gen ceph Clinical use
Respiratory, UTI, meningitis—crosses BBB
Ceftriaxone 125mg IM or cefixime 400mg x 1 for n. gonorrhea
pseudomonas infections
serious infections in hospital patients
intraabdominal infection
Fourth Gen ceph
Cefepime (Maxipime) – parenteral
Fourth gen ceph spectrum of action
streptococci–better than G2, G3
Gram - organisms like G3
p. aeuruginosa like ceftazidime
Resistant: enteroccia MRSA, MRSE, listeria monocytogenes
Fourth Gen ceph clinical use
like G3,, ? less effect on SPICE B-lactamase induction
Cefaroline (Teflaro)
New IV celphalosporin with activity against MRSA; other microbial coverage similar to ceftriaxone.
MOA: binds to penicillin-binding proteins to inhibit cell wall synthesis; high affinity to PBP2a (encoded by MedA gene in MRSA)
Use: skin and skin structure infections; not established for PNA tx.
Cephalosporins Pharmacokinetics
Distibution: Ceftazidime or cefepime are DOS for meningitis caused by pseudomonas. MICs are sufficiently low; CSF concentration are higher
Elimination: Renally eliminated >7-% via active tubular secretion and GFR. EXCEPT ceftriaxone–biliary elimination
T1/2 for most = 2 hrs except CEFTRIAXONE = 8 HOURS
Cephalosporin Dosing
IV: Cefazolin: 500 mg to 2 gm IV, IM q8h
Ceftriaxone: 500mg-2g IV, IM w/ lido q24h
Cefepime: 1-2g IV q12h
PO: Cephalexin: 250-500mg q6hr or 500mg q12h
PCN and ceph hypersensativitiy
both usually tolerated well
PCN hypersens most common–5-8%, but only 5-10% have reaction with reexposure
Ceph: in pts w/ pcn, ~7%, w/o 1-2%
4 types of hypersensitivity
“ampicillin rash” 9% of pts–not true allergy
Type I sensativity: IgE mediatied
Immediate: <1%, anaphylaxis
Accelerated: 1-72 hrs, uticaria
Avoid ceph in pts with recent h/o immediate reaction to PCN
skin testing can help prevent or predict sensativity
Type II: cytotoxic IgM and IgG antibody mediated
hematologic
+coombs test (3%)
small # of pts develop hemolytic anemia
Type III: Immune complex of PCN and IgG or IgM
1-7% of patients
Serum sickness (fever, malaise, uticaria)
usually 6-10 days after start of PCN, 2nd, 3rd gen ceph
Type IV: T-cell mediated; delayed/late
48+ hours, dermatologic maculopapular rash
most common with PCN G
PCN and ceph ADRs
Diarrha (esp amp, amox, ceftriaxone, cefoperozone)
IM-pain, sterile abscess, redness
IV: phlebitis, pain, burning, redness
Hepatitis: rare. *Pseudocholelithiasis (biliary sludging) – seen with ceftriaxone
seizures–rare
potassium load (PCN G)
sodium load (ticarcillin)
N-methyltetrazole ring–cefotetan
antabuse reactions–MTT-containing cephs
Jarisch-hexheimer reaction–PCN G with syphilis
PCN-ceph Drug interactions
Probenecid-blocks secretion at renal tubules
Aminoglycosides-PCN
Wafarin: dicloxacillin and nafcillin reduce warfarin effect, cephs with MTT side chain
Ceftaroline
Teflaro
pharmacokinetics: primarily rental elimination half life=2.6 hours
ADR: N/D, rash, coombs conversion
Preg Cat B
Carbapenems Drugs
Imipenem/cilastatin (Primaxim)
Meropenem (Merrem IV)
Ertapenem (Invanz)
Doripenem (Doribax)
Carbapenems Spectrom of Action
Gram +, Gram -, enterobacteria, p.aerginosa
NOT ertapenem
B fragilis
Carbapenem Resistance mechanisms
Porin loss
Carbapenemase
Carbapenem clinical use
Reserve for serious infections caused by resistant organisms
UTI, septicemia, GYN infections, intra-abdominal
High PCN resistant pneumococci and enterobacter
Carbapenem pharmacokinetics
Usually IV
Wide distribution–inflamed meninges
cilastatin inhibits renal dehydropeptidase–decreased hydrolzation of imipenem in kidney
primarily renal; reduce dose in renal insufficiency
Carbapenem ADRs
hypersensativity reactions: rash, fever, pruritis, up to 50% cross sensativity with PCN (higher than cephs)
seizures
GI
Monobactam
Aztreonam (Azactam) IV (also IM and inhalation)
elimination is primarily renal
Monobactam spectrum of action
Aerobic Gram - Only
e. coli, klebsiella, p. mirabilis, serratia
Monobactam clinical use
in pts with renal insufficiency, pcn or ceph allergy. not thought to cross react hypersensativities
use not well definied
Vancomycin MOA:
Glycopeptide; Binds to d-ala-d-ala in Stage 1, prevents further growth of peptidoglycan and cross-linking
Vancomycin resistance
modification of the D-ala-D-ala site; terminal D-ala replaced by D-lactate
Vancomycin SOA
Bacteriocidal for Gram +
MRSA, c. diff
NO Gram - activity
Vancomycin Pharmacokinetics
GIVE IV Not absorbed PO IM creates sterile abscess, not absorbed\ Elimination: renal--1/2=4-8 hours normal adjust dose in renal insufficiency
Vancomycin clinical use
Serious infections such as sepsis, endocarditis, MRSA, MRSE
Vanco ADRs
Red Man syndrome–histamine release–infuse slowly (1-2hrs)
Sterile abscess with IM
Ototoxicity–serum level >60 mcg/mL
Nephrotoxicity
Vanco Dose
Adults: 15-20mg/kg/dose q8-12h
Desired levels: trough 15-20mcg/mL, peak 20-50
Daptomycin
(Cubicin)
First cyclic lipopeptide antimicrobial agent
Use: skin infections caused by s. auerus including MRSA and strep
Excreted renally; reduce dose when CrCl <30ml/min q48 hours
ADE: anemia, myopathy
IV ONLY
Fosfomycin
Use: tx of uncomplicated UTI in women caused be e.coli or e. faecialis
Mix 3gm in warm water
Bacitracin
Topical use only
Cycloserine
Use: TB
Ceftobiprole
new cephalosporin, MRSA coverage, dosed 8 hrs