Beta-Lactam and Other Cell Wall- and Membrane-Active Antibiotics

a. Penicillins
i. Penicillin G
1. Greatest against Gram-positive organisms and Gram-neg cocci
and non-beta-lactamase-producing anaerobes
2. Susceptible to beta lactamases
ii. Antistaphylococcal penicillins (nafcillin)
1. Resistant to staph beta-lactamases
2. Staphylococci and streptococci (Gram pos)
3. Not for enterococci, anaerobic bacteria and gram neg cocci and rods
iii. Extended spectrum (ampicillin and antipseudomonal penicillins)
1. Improved activity against Gram neg organisms
2. Susceptible to beta lactamases
iv. Relatively stable in gastric acid
v. I million units = 0.6 g
1. Semisynthetic penicillins in weights rather than units
vi. MIC in mcg/mL
vii. Most penicillins are formulated as the sodium or potassium salt of the free
acid
viii. Procaine and benzathine salts of penicillin G provide repository for IM
injection
ix. Dry crystalline form stable for years at 4C
x. Solutions lose their activity rapidly (24 hrs at 20C)
xi. MOA: interfere with transpeptidation reaction of bacterial cell wall
synthesis, binds to penicillin-binding protein, beta lactam antibiotics only
kill when cell is actively growing and synthesizing cell wall
xii. Resistance: beta lactamase, modification of PBPs, impaired penetration of
drug to target PBPs, efflux
1. Beta lactamase: S. aureus, H flu, E coli prefer penicillins than
cephalosporins
2. AmpC beta lactamase (pseudomonas aeruginosa and enterobacter
sp.) and extended spectrum beta lactamases
a. Hydrolyze ceph and pens
3. Carbapenems are resistant to both penicillinases and
cephalosporinases but susceptible to metallo-beta lactamases and
carbapenemases
4. Altered PBPs
a. Basis of methicillin resistance in staphylococci and pen
resistance in pneumococci and enterococci
b. PBPs have low affinity for the antibiotics unless in higher not
achievable concentrations
5. Impaired penetration
a. Occurs in Gram neg only
b. Not a very important mechanism to confer resistance unless
beta lactamases are present (even a relatively inactive one)
or with an efflux pump
xiii. Clinical Uses
1. Penicillins should be given 1-2 hours before and after a meal, except
amoxicillin. Blood levels of pen can be raised by simultaneously
administering probenecid (0.5 g every 6hrs orally) to impair renal
tubular secretion of beta lactam compounds.

2. Penicillin
a. For streptococci, meningococci, some enterococci, penicillinsusceptible pneumococci, nonBlactamase producing
staphylococci, treponema pallidum and certain other
spirochetes, Clostridium sp, actinomyces and certain other
gram pos rods, nonBlactamase producing gram neg
anaerobes
b. Penicillin V oral form of pen. Indicated only for minor
infections because of poor bioavailability, narrow spectrum,
and need to dose 4 times a day. Amoxicillin is used instead.
c. Benz and procaine pen G for IM injection yield low but
prolonged drug levels. 1.2M units benz pen for B-hemolytic
strep pharyngitis. 2.4M units for syphilis.
3. Penicillins resistant to Staphylococcal B lactamase (methicillin,
nafcillin, isoxazolyl pens)
a. Semisynthetic
b. Indicated for infection by staphylococci
c. Listeria monocytogenes, enterococci, methicillin-resistant
strains of staphylococci
d. Drugs of choice for meth-susceptible pen-resistant
staphylococci
e. Isoxazolyl pen (oxacillin, cloxacillin, dicloxacillin)
i. 0.25-0.5 g orally every 4-6 hours
ii. For mild to moderate localized staphylococcal infections
iii. Acid stable, reasonable bioavailability
iv. Administered 1 hr before or after meals
f. For serious infections: oxacillin or nafcillin, 8-12 g/d, is given
by intermittent IV infusion of 1-2g every 4-6 hrs
4. Extended-Spectrum Penicillins (Aminopenicillins, Carboxypens,
ureidopens)
a. Better activity than pens against gram neg
b. Inactivated by many beta lactamases
c. Aminopens: ampicillin, amoxicillin
i. Amoxicillin better absorbed orally
ii. Amoxicillin for UTI, sinusitis, otitis, lower resp tract
infections
iii. Ampicillin for shigellosis (not amoxicillin)
iv. Both are the most active of beta lactam antibiotic
against pneumococci with elevated MICs
v. Ampicillin (4-12g/d) for anaerobes, enterococci, L
monocytogenes, Blactamase-negative gram neg cocci
and bacilli like E. coli. and Salmonella sp. Non betalactamase producing H flu are susceptible
vi. Ampicillin not for: Klebsiella sp., Enterobacter sp., P
aeruginosa, Citrobacter sp., Serratia marcescens,
indole-positive proteus species, other gram neg aerobes
that are often encountered in hospital acquired
infections these produce beta lactamases that
inactivate ampicillin
d. Carboxypenicillins
i. Carbenicillin

1. First antipseudomonal carboxypen

2. Not used anymore
ii. Ticarcillin
1. Less active than ampicillin against enterococci
e. Ureidopenicillins, Piperacillin, mezlocillin, azlocillin
i. Active against selected gram neg bacilli, such as
Klebsiella pneumoniae
f. In the treatment of P aeruginosa, aside from an
antipseudomonal penicillin, an aminoglycoside or
fluoroquinolone is used in combination for pseudomonal
infections outside the urinary tract
g. Ampicillin, amoxicillin, ticarcillin, piperacillin are available in
combination with one or more B-lactamase inhibitors
i. Clavulanic acid, sulbactam, tazobactam
ii. Extends activity to b-lactamase producing S aureus and
some B-lactamase producing gram neg bacteria
xiv. Adverse Reactions
1. Hypersensitivity
2. Allergic reactions include anaphylaxis (0.05%), serum-sickness type
reactions (now rare urticarial, fever, joint swelling, angioneurotic
edema, intense pruritus, respiratory compromise occurring 7-12
days after exposure), and a variety of skin rashes
3. May occur: oral lesions, fever, interstitial nephritis (autoimmune
reaction to penicillin-protein complex), eosinophilia, hemolytic
anemia, hematologic disturbances, vasculitis
4. Alternative drugs can be given
a. Exception is for enterococcal endocarditis or neurosyphilis
desensitization can be achieve by slowly increasing dosage
5. Patients with renal failure
a. High doses can cause seizures
6. Nafcillin neutropenia
7. Oxacillin hepatitis
8. Methicillin interstitial nephritis (no longer used for this reason)
9. Large doses GI upset, nausea, vomiting, diarrhea
10. Ampicillin pseudomembranous colitis
11. Secondary infections vaginal candidiasis
12. Ampicillin and amoxicillin skin rashes not allergic in nature
a. Usually occur when aminopens are prescribed for a viral
infection
b. Cephalosporins and cephamycins
i. Similar to pens but more stable to many B-lactamases > broader
spectrum
1. However there are strains of Klebsiella and E. coli expressing
extended-spectrum B-lactamases.
ii. Not active against Enterococci and L monocytogenes
iii. First Generation (Cefazolin, Cefadroxil, Cephalexin, Cephalothin,
Cephapirin, Cephradine)
1. Very active against Gram-pos cocci such as pneumococci,
streptococci, staphylococci

2. Traditional cephs are not active against methicillin-resistant

strains of staphylococci but new compounds have been
developed
3. Active against: E coli, K pneumoniae, Proteus mirabilis, anaerobic
cocci like peptococci and peptostreptococci (usually sensitive)
4. Poorl against: P aeruginosa, indole-positive proteus species,
Enterobacter sp, S marcescens, Citrobacter sp, Acinetobacter sp,
Bacteroides fragilis
5. Probenecid can increase serum levels
6. Dosage must be reduced in pts with impaired renal function
7. Oral
a. Cephalexin, cephradine, cefadroxil are absorbed in the gut
to a variable extent. Filtered and secreted into urine.
8. Parenteral
a. Cefazolin is the only first-gen parenteral ceph still in
general use. IV infusion of 1 g and reach peak level of 90120 mcg/mL. Can also be administered IM
9. Clinical Uses
a. Oral
i. UTI, staphylococcal and streptococcal infections like
cellulitis and soft tissue abscess
ii. Not for serious systemic infections
b. Cefazolin
i. Penetrates tissues well
ii. Surgical prophylaxis
iii. Alternative to an antistaphylococcal penicillin for
patients allergic to pen
c. A choice in infections for which it is the least toxic drug
(penicillinase-producing E coli or K pneumoniae) and in pts
with staphylococcal and streptococcal infections with Hx of
pen allergy
d. Not for meningitis does not enter CNS
iv. Second Generation (Cefaclor, Cefamandole, Cefonicid, cefuroxime,
cefprozil, loracarbef, ceforanide and structurally related cephamycins
cefoxitin, cefmetazole, cefotetan which have activity against anaerobs)
1. Active against organisms inhibited by first-gen cephs with
extended Gram-neg coverage
2. For
a. Klebsiella sp (inc. resistant to cephalothin)
b. Cefamandole, cefurozime, cefonicid, ceforanide, cefaclor
i. H flu but not serratia or B fragilis
c. Cefoxitin, cefmetazole, cefotetan
i. B fragilis and some serratia but less for H flu
3. Not for:
a. Enterococci and P aeruginosa (like 1st gen)
b. Enterobacter
4. Oral
a. Cefaclor, cefuroxime axetil, cefprozil, loracarbef
b. 10-15 mg/kg/d in two to four divided doses
c. Children: 20-40 mg/kg/d to a max of 1g/d

d. Not predictably active against penicillin-non-susceptible

pneumococci
i. Except for cefuroxime axetil
e. Cefaclor
i. Susceptible to B-lactamase hydrolysis than other
agents
5. Parenteral
a. 1g IV infusion > serum levels 75-125 mcg/mL for most 2nd
gen
b. IM administration is painful and avoided
c. All renally cleared
6. Clinical Uses
a. Oral - active against B-lactamase-producing H flu or
Moraxella catarrhalis. Used to treat sinusitis, otitis, and
lower resp tract infections
b. Because of their activity against anaerobes (including
many B fragilis strains), they (cefoxitin, cefotetan,
cefmetazole) are used to treat mixed anaerobic infections
such as peritonitis, diverticulitis, and pelvic inflammatory
disease
c. Cefuroxime community-acquired pneumonia because it is
active against B-lactamase-producing H flu and K
pneumoniae and some penicillin-non-susceptible
pneumococci
i. Can pass BBB but not as effective as ceftriaxone or
cefotaxime for meningitis so dont use for meningitis
v. Third Generation (Cefoperazone, Cefotaxime, Ceftazidime, Ceftizoxime,
Ceftriaxone, Cefixime, Cefpodoxime proxetil, Cefdinir, Cefditoren
pivoxil, Ceftibuten, Moxalactam)
1. Expanded Gram neg coverage compared to 2nd gen, some are
able to cross BBB
2. Active against:
a. Citrobacter, S marsescens, Providencia (resistance can
emerge in Tx_
b. Beta-lactamase-producing strains of haemophilus and
Neisseria
c. P aeruginosa (only ceftazidime and cefoperazone)
d. B fragilis (Ceftizoxime, Moxalactam)
3. Not for
a. Enterobacter sp
4. Hydrolyzed by constitutively produced AmpC beta lactamase
(like 2nd gen)
5. Serratia, Providencia, Citrobacter can produce a chromosomally
encoded cephalosporinase that can confer resistance when
constitutively expressed
6. Ceftizoxime and moxolactam active against B fragilis.
7. Cefixime, cefdinir, ceftibuten, cefpodoxime proxetil are oral
agents with similar activity except cefixime and ceftibuten are
much less active against pneumococci and have poor activity
against S aureus.

8. Penetrate body fluids and tissues well. Except for cefoperazone

and all oral cephs, achieve levels in CSF sufficient to inhibit most
pathogens including Gram-neg rods, except pseudomonas
9. Strains with extended-spectrum B-lactamases are not
susceptible.
10.
Avoid treatment of enterobacter even if susceptible in vitro
because of emergence of resistance
11.
Ceftriaxone and cefotaxime for meningitis caused by
pneumococci, meningococci, H flu, and susceptible enteric Gramneg rods but not L monocytogenes
a. These two are also for serious infections from penicillin
resistant strains of pneumococci
b. But vancomycin is added in meningitis caused by these
strains (pneumococci with penicillin MICs > 1mcg/mL)
12.
Empirical therapy of sepsis of unknown cause in both
immunocompetent and immunocompromised pt and treatment
of infections where cephs are the least toxic drug available
13.
3rd gen cephs used with aminoglycosides: pts who are
neutropenic, febrile and immunocompromised
vi. Fourth Generation (Cefepime
1. Resistant to hydrolysis by chromosomal B-lactamases (by
enterobacter)
2. Hydrolyzed by extended-spectrum beta-lactamases
3. Good activity against P aeruginosa, enterobacteriaceae, S
aureus, S pneumoniae
4. Highly active against Neisseria and hemophilus
5. Penetrates well to CSF
6. Cleared renally half life of 2 hours
7. Pharmacokinetic properties similar to ceftazidime
a. Except cefepime has good activity against most penicillin
resistant strains of streptococci
b. May be useful against enterbacter
vii. Cephalosporins active against Methicillin-resistant staphylococci
1. Under development
2. Ceftaroline
3. Fosamil
4. Ceftobiprole medocaril
5. Against enterococci and has broad Gram-neg coverage
6. Neither is active against extended spectrum B lactamaseproducing strains
viii. Adverse Effects of Cephs
1. Allergy
2. Toxicity
c. Other Beta-Lactams