Download Problem Set 2: Cephalosporins: KEY Answer the following

Problem Set 2: Cephalosporins: KEY
Answer the following questions for the cephalosporins shown below:
H
S
S
H2N
H
H
S
CH 2C ON H
C
N
N
COO H
A
H
N
C
H
H
S
N
N
OCH 3
NH2
H
H
H
N
O
E
N
COO H
H
N
O
CH3
S
H2N
H
N
N
C
S
N
O
O
F
H
CON H
N
CH 3
COO H
N
N
D
S
O
N
CH 2S
O
O
COO CHOC OOCH (CH 3 ) 2
CH 3
CH 3
O
OCH 3
O
C
S
CHCON H
CON H
CH 2
COO H
CH 2C OO H
S
H2N
CH
O
O
B
S
N
N
CH 2O CO CH 3
O
H
CON H
CH3
COO H
O
Which cephalosporins are first generation agents: Answer: A and E. See notes
Which cephalosporins are third generation agents? Answer: B and F. See notes
Which cephalosporins acylate essential PBPs? Answer: All (A-F). Alkylation of
essential PBPs (1-3) is required for bactericidal action. These compounds display
differences in PBP binding preferences between members and versus the penicillins,
but the bottom line is that they all acylate essential PBPs and compromise cell wall
bioaynthesis resulting in death.
Which are classified as cephamycins? Answer: None. None of these drugs contain a 7alpha-methoxy substituent required for classification as cephamycins
Which are classified as cephalosporanic acids? Answer: A and F.
Those
cephalosporins with a 3-acetoxymethyl substituent are classified as cephalosporanic
acids. Do you recall the properties this substuent imparts?
Which are classified as aminothiazole cephalosporins? Answer: B, C and F. Do you
recall the contribution this substituent makes toward antibacterial activity?
Which are classified as alkoximino cephalosporins? Answer: B, C and F. Do you recall
the role of this substituent in antimicrobial activity and spectrum of activity?
Which can exist as cis and trans isomers? Answer: None. Technically none of these
compounds exist as cis and trans isomers. The only alkene is B and its C=C is
symmetrically substituted so cis-trans isomerism is not possible. Some of you
identified the alkoximines, but geometric isomers of these are technically referred to
as "syn" and "anti".
Which are effective against MRSA? Answer: None. See notes for discussion of
cephalosporin acitvity versus these organisms!
Which are effective against enterococci? Answer: None. See notes for discussion of
cephalosporin acitvity versus these organisms!
Which are effective against Legionella pneumophilia? Answer: None. See notes for
discussion of cephalosporin acitvity versus these organisms!
Which are effective against Stentrophomonas maltophilia? Answer: None. See notes for
discussion of cephalosporin acitvity versus these organisms!
Which are effective against Pseudomonas aeruginosa? Answer: None. See notes for
discussion of cephalosporin acitvity versus these organisms!
Are there
cephalosporins effective against this organism? If so, which ones and why?
Which are orally active? Answer: B, C and E. Only B, C and E are orally effective
(chemically stable 3-substituents and 7-substituents of acceptable stability). The two
cephalosporanic acids (A and F) have acetoxymethyl groups that are readily cleaved
in acid (and by esterases). Compound D is stable to esterases, but its Nmethylthiotetrazole group is readily cleaved in acid (see notes on Pharmacokinetics).
Which are chemically (acid) unstable? Answer: A, D, F. The two cephalosporanic
acids (A and F) have acetoxymethyl groups that are readily cleaved in acid (and by
esterases). Compound D is stable to esterases, but its N-methylthiotetrazole group is
readily cleaved in acid (see notes on Pharmacokinetics).
Which are metabolically (esterase) unstable? Answer: A, C and F. Compounds A and
F are cephalosporanic acids and will be readily hydrolyzed by esterases to desacetyl
metabolites (see question below) and cleared. Compound C is a prodrug with its
ester function at the 2-acid position. The DIFFERENCE between A and F and C is
that esterase hydrolysis of the acetoxymethyl group leads to inactivation.
Hydrolysis of an ester at position 2 leads to formation of ACTIVE cephalosporin
drug!
Which are available as monosodium salts for IV administration? Answer: A, D and F
(and maybe E). Compounds A, D and F contain a single acidic moiety which can
react with a suitable base to yield a monosodium salt. Compound B is a diacid and
thus would yield a disodium salt. Compound C has NO ACIDIC functionality and
thus would not yield a sodium salt. Compound E is a zwitterion and could be
formulated as a salt so credit was given for this answer.
Which are prodrugs designed to enhance oral bioavailability? Answer C. Both C and D
are cephalosporin prodrug forms, but only C (cefpodoxime proxetil) is designed to
be administered for enahnced absorption (enhanced lipophilicity). Compound D is
the cefamandole prodrug which is designed as a pharmaceutically stable derivative
(see notes on these two drugs).
Which exists as anions at physiologic pH? Answer A, B, D, F and maybe C, if you
consider it to have hydrolyzed to the acid. Compounds A, B, D and F are acids or
diacids with pKas in the 3-5 range and thus will be ionized at physiologic pH.
Compound E is a zwitterion and will exist as a zwitterion, not an anion. Compound
C would yield an acid after esterase action (prodrug) and this active form would be
ionized at physiologic pH.
Which is most highly bound by plasma proteins? Answer D. As further illustrated in
several problems below, only D contains a 3-N-methylthiotetrazole substituent
which enhances plasma protein binding by a direct contribution to binding.
Compounds A, B, C, E and F do not contain a substituent (heterocycle) which
enhances interactions with plasma proteins.
Which may be metabolized to desacetyl metabolites? Answer: A and F. Compounds A
and F are cephalosporanic acids and will be readily hydrolyzed by esterases to
desacetyl (alcohol) metabolites which may cyclize to lactones. These metabolic
products are significantly less active than the parent drug and are cleared.
Compound C does NOT give rise to a desacetyl metabolite but rather an active acid.
Note the difference in the position and nature of attachment of the ester group in C
versus A and F.
Which has the longest half-life? Answer: D.
Compounds A and F are
cephalosporanic acids and will be readily hydrolyzed by esterases and cleared.
Compounds B, C and E do not have a metabolically unstable 3-substituent, but they
also do not contain a substituent (heterocycle) which facilitates interactions with
plasma proteins. Only D contains a metabolically stable 3-substituent which also
enhances plasma protein binding - the N-methylthiotetrazole group. Can you draw
the structure of an analog of D which would have an even longer half-life?
Which are eliminated primarily by renal mechanisms? Answer: All. All of the
cephalosporins are cleared renally by TS and GF. Which cephalosporins are
cleared hepatically to a greater extent?
Which oral agent is most susceptible to beta-lactamase inactivation? Answer E. Only B,
C and E are orally effective (chemically stable 3-substituents and 7-substituents of
acceptable stability). Of these three drugs, B and C have alkoximino substituents to
protect from beta-lactamases to some degree. E contains only a small, polar
functionality in the 7-side chain (amino) which affords only minimal protection
from beta-lactamase inactivation.
Which oral agent is least susceptible to beta-lactamase inactivation? Answer: B. Only
B, C and E are orally effective (chemically stable 3-substituents and 7-substituents
of acceptable stability). Of these three drugs only B and C have alkoximino
substituents to protect from beta-lactamases and generally the acidalkoximino
group of B is more effective.
Which two cephalosporins generally have the highest activity against gram positive
cocci? Answer: A and E. these are first generation agents with the highest affinity
for gram positive PBPs, etc.
Which may produce a disulfiram reaction with alcohol? Answer: D. The 3-Nmethylthiotetrazole cephalosporins are capable of inhibiting the enzymes of alcohol
metabolism and thus allow for acetaldehyde levels to accumulate like disulfiram
treatment? Under which therapeutic conditions is this reaction of concern?
Which may prolong PT times? Answer: D. The 3-N-methylthiotetrazole
cephalosporins are capable of producing hypoprothrombinemia. Do you recall the
general mechanism?
Cephalosporin Thought Question:
The first-generation cephalosporin cefazolin is still considered by many authoritative
sources to be the antibacterial drug "of choice" for prophylactic administration prior to an
initial incision in numerous surgical procedures, including coronary artery bypass graft
surgery (CABG). However, several clinical studies beginning in the late 1980s found
that the overall post-surgical infection rate for CABG was consistently and significantly
lower when the second-generation cephalosporin cefamandole was administered
prophylactically. Subsequent well-designed studies showed an even lower infection rate
with cefuroxime. The most common etiologic agent of a post-surgical wound infection in
this setting is Staphylococcus aureus. Use your knowledge of the pathogen and the
various cephalosporins involved to provide a brief, logical explanation for the results.
Answer: To quote your notes: "A few studies have shown second-generation
cephalosporins (cefamandole, cefuroxime) to be slightly superior to cefazolin with
respect to overall infection rate when they are used for surgical prophylaxis in clean
procedures (cardiovascular and orthopedic surgery). This phenomenon, if it is real,
may reflect the somewhat greater stability of second-generation cephalosporins to one
or more beta-lactamases which are hyperproduced by some strains of staphylococci."