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SULTAMICILLIN
AL PRODRUG
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T
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TAB
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SULTAMICILLIN
DRUG
REVIEW
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Sultamicillin is the mutual
prodrug of sulbactam and
ampicillin.
Summary
Synopsis
Sultamicillin is the mutual prodrug
of sulbactam and ampicillin. It is the
tosylate salt of the double ester of
sulbactam
plus
ampicillin.
Sulbactam is a semisynthetic ßlactamase inhibitor which, in
combination
with
ampicillin,
extends the antibacterial activity of
the latter to include some ßlactamase-producing strains of
bacteria that would otherwise be
resistant. The combination of
sulbactam plus ampicillin for
parenteral use has previously been
shown to be clinically and
bacteriologically effective in a
variety of infections. The chemical
linkage of sulbactam and ampicillin
has now produced an orally effective
compound, sultamicillin, with
antibacterial activity and clinical
efficacy which are similar to those of
the parenteral formulation.
Sultamicillin has been shown to be
clinically
effective
in
noncomparative trials in patients with
infections of the respiratory tract,
ears, nose and throat, urinary tract,
skin and soft tissues, as well as in
obstetric
and
gynaecological
infections, and in the treatment of
gonorrhoea. In a small number of
1
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controlled trials, sultamicillin has
shown comparable clinical efficacy
to
phenoxymethyl
penicillin
(penicillin V) and to amoxycillin
(alone and in combination with
clavulanic acid) in the treatment of
paediatric streptococcal pharyngitis
and acute otitis media, respectively;
to cefaclor in the the treatment of
acute otitis media in adults; and to
bacampicillin,
cloxacillin
and
flucloxacillin plus ampicillin in skin
and soft tissue infections in adults,
children and adult diabetic patients,
respectively. Sultamicillin was
superior in efficacy to bacampicillin
in the treamentof chronic respiratory
infections, to cefaclor in the
treatment of acute otitis media in
adults, and to cefadroxil in the
treatment
of
patients
with
complicated urinary tract infections.
Sultamicillin-associated diarrhoea
was generally mild and transitory.
Dosage and Administration
Sultamicillin is available in a tablet
dosage form containing 375mg
sultamicillin tosylate. The usual
adult dose is 375mg administered
orally 2 to 3 times daily, taken with
an adequate amount of water to
avoid lodgement in the oesophagus
and
potential
ulceration.
Sultamicillin is contraindicated in
patients with history of allergy to
any of the penicillins and in patients
with infectious mononucleosis, the
latter contraindication suggesting
caution in its administration to
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patients with pharyngitis of
unknown aetiology. Caution should
be exercised in administering
sultamicillin to patients receiving
allopurinol and to malnourished or
debilitated patients in whom
symptoms of vitamin K deficiency
may occur. Patients with renal
dysfunction should receive reduced
dosages
of
sultamicillin
in
accordance with the usual practice
for ampicillin.
1. Antibacterial Activity
Sulbactam is a semisynthetic ß-lactamase inhibitor which, when
combined with certain antibacterials, extends their activity against
bacteria that are normally resistant
due to production of inhibitable
ß-lactamases. Such a combination is
sulbactam plus ampicillin, which
has significantly extended the
antibacterial activity of ampicillin in
clinical practice. The poor oral
absorption of sulbactam has made it
necessary to administer this
combination parenterally. However,
a double ester linkage of sulbactam
with ampicillin has been developed
(fig. 1) to produce a prodrug,
sultamicillin, which is readily
absorbed orally and hydrolysed by
enzymes in the intestinal wall,
releasing ampicillin and sulbactam
in equimolar proportions.
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bacterial enzymes which catalyse the
hydrolysis of the ß-lactam ring to
inactive derivatives, is an important
mechanism of bacterial resistance to
ß-lactam antibacterial drugs. ßLactamases
may
be
either
chromosomally or R-factor plasmidmediated, and an increasing number
are now known to be encoded by
transposons,
genetic
elements
capable of transfer among a wide
variety of plasmids and between
plasmids
and
chromosomes
(Campoli-Richards & Brogden 1987).
1.1 Activity of Sulbactam In Vitro
Against ß-lactamases
The administration of a compound
which is a ß-lactamase inhibitor, in
combination with a ß-lactam
antibacterial drug of known efficacy
and safety, is one approach to the
problem of bacterial resistance. The
best known of these inhibitors are
clavulanic acid and sulbactam, the
latter a semisynthetic sulphone
derivative of the penicillin nucleus
(fig. 1). Both are progressive
competitive inhibitors of ß-lactamase in that they compete with the
ß-lactam antibacterial drug for the
active site on the ß-lactamase
enzyme. An irreversible interaction
takes place between the enzymes
and the inhibitor through the
formation of a stable complex, so
inactivating the enzyme and
destroying
the
inhibitor.
A
progressively greater effect is
produced with increasing time (Wise
1982).
The production of ß-lactamases,
In general, sulbactam is effective
2
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Synergy in vitro between
ampicillin and sulbactam
has been defined as a 4-fold
or greater decrease in the
minimum inhibitory
concentration (MIC)
against ß-lactamases of Richmond
and Sykes types II, III, IV and V, and
to much lesser degree against
Richmond and Sykes type I.
Sulbactam is also effective against
certain
ß-lactamases
from
Bacteroides fragilis, although not
against the ß-lactamases from B.
fragilis from DNA Homology Group
II.
1.2 Inhibitory Activity In Vitro
Sultamicillin is the tosylate salt of
the double ester of ampicillin plus
sulbactam in a 1:1 ratio. Mean peak
serum ampicillin concentrations
achieved following administration
of single oral doses of sultamicillin
250mg
and
500mg
are
approximately 60% greater than
sulbactam concentrations, thus
giving an in vivo serum ratio of
approximately 1.6:1 (ampicillin :
sulbactam) [Hartley & Wise 1982].
This ratio was occasionally used in
assessments of in vitro antibacterial
activity (e.g. Eliopoulos et al. 1984),
but most studies used ratios of 2:1 or
1:1. Using checkerboard dilution
techniques,
an
in
vitro
concentrations ratio of 2:1 was
reported by Wise et al. (1980) to be
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S
optimal, although little difference
has been noted betwen ratios of 1:4
to 4:1 (Campoli-Richards & Brogden
1987). The discussion of in vitro
antibacterial activity will therefore
be based on studies that used a 2:1 or
a 1:1 ratio.
Synergy in vitro between ampicillin
and sulbactam has been defined as a
4-fold or greater decrease in the
minimum inhibitory concentration
(MIC) or minimum bacterial
concentration (MBC) of both drugs,
or a fractional inhibitory or
bactericidal concentration (FIC or
FBC) of less than 0.5. Synergy has
been demonstrated against ßlactamase-producing strains of B.
fragilis from DNA Homology Group
I (Appelbaum et al. 1986), against ßlactamase-producing strains of
o
o
S
o
NH2
C CONH
H
CH3
CH3
N
o
S
CH3
CH3 o
N
O
C O CH2
O
Sultamicillin
esterase
NH2
C CONH
H
O
S
N
O
Ampicillin
O
S
CH3
CH3
CH3
CH3
N
COOH O
COOH
Sulbactam
Haemophilus influenzae, against
both
penicillin-resistant
H.
influenzae which do not produce ßlactamase (Campoli-Richards &
Brogden 1987). However, rates of
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synergy were low against R-factor
plasmid-containing
strains
of
Pseudomonas aeuroginosa, and
against P.aeruginosa strains resistant
to several other antibacterial drugs
(Campoli-Richards & Brogden 1987).
The degree of synergy against
methicillin resistant S. aureus is
probably not clinically significant
(see below), and neither sulbactam
nor clavulanic acid showed synergy
with ampicillin or several other ßlactam antibacterials against ßlactamase-producing isolates of B.
fragilis from DNA Homology Group
II (Appelbaum et al. 1986).
Using a 2:1 ratio of ampicillin plus
sulbactam, a susceptibility cut-off
point of less than or equal to 8 mg/L
(ampicillin) has been recommended
(Jones & Barry 1987). In several
studies of the in vitro activity of
ampicillin plus sulbactam in a 2:1
ratio using an inoculum of 104 to 106
colony-forming units (cfu), MICs of
8 mg/L or less (based on the
ampicillin component) were found
for S. aureus (including ampicillinresistant strains), Staphylococcus
epidermidis, Klebsiella pneumoniae,
H. influenzae and various species of
Proteus and Bacteroides. MICs
several-fold lower than those for
ampicillin alone were found for most
species of Enterobacteriaceae and
methicillin-resistant staphylococci
(Campoli-Richards & Brogden 1987)
[table I]. However, it has been
recommended that all methicillinresistant
staphylococci
be
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considered resistant to ampicillin
plus sulbactam even if the MICs
indicate susceptibility (Barry & Jones
1988).
In vitro MICs of sulbactam plus
ampicillin in a 1:1 ratio were also 2to 8-fold lower than for ampicillin
alone in a study of 31 clinical isolates
of E. coli, Citrobacter koseri and
Klebsiella species (Ball et al. 1984). In
the latter study, Gram-negative rods
were variably susceptible, with
synergy demonstrated in over 80%
of strains of Proteus and Morganella
species but not against Serratia or
Pseudomonas
species.
E.coli,
Enterobacter and Klebsiella species
showed MICs below 16 mg/L for
only 50% of tested strains.
Haemophilus ducreyi was also
susceptible (MIC90 of 1 mg/L) to
ampicillin plus sulbactam in a 1:1
ratio (Jones et al. 1986).
Ampicillin plus sulbactam (in a 1:1
ratio) showed the greatest in vitro
inhibitory activity against both
ampicillin-susceptible and ampicillin
resistant
strains
of
H.influenzae and strains of S.
epidermidis, in comparison with
ampicillin
alone,
cephalexin,
cloxacillin, cefaclor, erythromycin,
piperacillin
and
latamoxef
(moxalactam). Against methicillinsusceptible strains of S.aureus the
activity of ampicillin plus sulbactam
was equal to that of cephalexin
(MIC90 = 4 mg/L) and against
methicillin-resistant strains of S.
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aureus the MIC90 of ampicillin plus
sulbactam was 16 mg/L (Eliopoulos
et al. 1982). Only 1% of 90 cefoxitinresistant strains of anaerobic bacteria
[mostly B. fragilis (n=53)] were
resistant to the 1:1 ratio of ampicillin
plus sulbactam, versus7% for the 2:1
ratio, 16% for clindamycin and 86%
for ampicillin; all 90 strains were
susceptible to chloramphenicol and
metronidazole (Jones & Barry 1988).
2. Pharmacokinetics
Sultamicillin was initially developed
to improve the oral absorption of the
ß-lactamase inhibitor sulbactam.
Initial work utilising homogenates
of intestines from the rat and dog
showed that sultamicillin was
hydrolysed
within
minutes,
liberating the active components
(Foulds & Brennan 1982). Although
the rate of hydrolysis of the prodrug
sultamicillin was shown to be dose
dependent, and the administration
of large doses resulted in incomplete
hydrolysis and the release of small
quantities of parent compound to
the portal circulation, the doses used
clinically in human patients were
well within the range of quantities
which
could
be
completely
hydrolysed by enzymes in the
intestinal wall (Schach von Wittenau
1984).
2.1
Absorption
Concentration
and
Plasma
Initial studies in human volunteers
reported by Baltzer et al. (1980)
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showed sultamicillin to be rapidly
absorbed from the gastrointestinal
tract and delivered as ampicillin and
sulbactam to the blood. Peak
concentrations in plasma occurred in
approximately 1 hour and the area
under the plasma concentrations
versus time curves (AUC) for both
ampicillin and sulbactam were
similar,
indicating
a
close
relationship
between
the
pharmacokinetic handling of the 2
components.
Experiments
in
rats
had
demonstrated more complete oral
absorption of sultamicillin than of
either sulbactam or ampicillin when
administered as single agents,
resulting in AUCs for ampicillin and
sulbactam that were 2.5 times
greater than those achieved from
their administration singly (English
et al. 1984). In human volunteers, the
increase
in
peak
plasma
concentration of ampicillin obtained
with sultamicillin in comparison
with
that
obtained
with
administration of ampicillin alone
has been confirmed (Ball et al. 1984;
Emmerson et al. 1983; Foulds et al.
1982; Hartley & Wise 1982).
In human volunteers approximately
60% of the sulbactam component
and 75% of the ampicillin
component was absorbed following
administration of single 500mg oral
doses of sultamicillin, producing
mean peak plasma concentrations
(Cmax) of 4.4 mg/L and 7.1 mg/L,
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respectively (Foulds et al. 1982).
Slightly higher Cmax values were
observed by Hampel et al.(1988),
after administration of a single oral
dose of sultamicillin: 6.4 mg/L for
sulbactam and 11.1 mg/L for
ampicillin. Hartley and Wise (1982)
reported that mean peak plasma
concentrations of ampicillin were
approximately 60% greater than
sulbactam concentrations after oral
doses of sultamicillin 250mg or
500mg, giving an in vivo plasma
ratio of approximately 1.6 : 1. These
findings are at variance with those of
Rogers et al. (1983) who reported
mean peak plasma concentrations
using an HPCL assay of 9.1 and 8.9
mg/L for ampicillin and sulbactam,
respectively, after single 750mg oral
doses
of
sultamicillin.
The
bioavailability of both drugs was
greater than 80% in this study. AUC
was roughly proportional to dose in
the sultamicillin dose range of
250mg to 750mg. Hampel et al.
(1988) found the bioavailability of
ampicillin in combination with
sulbactam to be about 90%. These
investigators also examined the
pharmacokinetics of amoxycillin
/clavulanic acid and found the
bioavailability of amoxycillin to be
72% after a single oral dose of the
combination.
Foulds et al. (1982) reported no effect
of a light meal on the absorption of
sultamicillin. While Sakai et al.
(1985) found a reduction in the peak
plasma concentrations of both
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Absorption
Following oral administration
of 500 mg sultamicillin single
dose, 60% of sulbactam and
75% of ampicillin was absorbed
producing peak plasma
concentration of 4.4 mg/1 of
Sulbactam and 7.1 mg/1 of
Ampicillin.
Thus sultamicillin results in 2.5
times greater concentration of
ampicillin and sulbactam than
when given alone. This superior
pharmacokinetic profile enables
twice daily dosage of
sultamicillin unlike traditional
q.i.d. dosing of ampicillin.
sulbactam and ampicillin and a
delay of approximately 1 hour in the
time to reach the peak plasma
concentration when sultamicillin
was administered with food, other
trials showed little difference in
values obtained after administration
of sultamicillin in the fasting state or
postprandially (Okamoto et al. 1985;
Saito et al. 1985a). In all these studies
the cumulative urinary excretion
rates of sulbactam and ampicillin
were unaffected by food. The
concomitant administration of an
antacid (1g sodium bicarbonate)
reduced
mean
peak
plasma
concentrations of sulbactam and
ampicillin
and
delayed
the
6
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Table II: Some pharmacokinetic values reported for sulbactam (S) and ampicillin (A) following
single-dose oral administration of sultamicillin to healthy volunteers
several such studies are presented in
table III.
Reference
The
tissue
or
fluid/plasma
concentration ratios of both
sulbactam and ampicillin varied
widely in adult patients with various
otorhinolaryngological infections
(Mori et al. 1985) as well as in
paediatric patients with chronic
otitis media (Reilly et al. 1983;
Voelker et al. 1985). No difference
was found in penetration of drug
into middle ear effusions that were
serous as opposed to mucoid in
nature. Peak sulbactam and
ampicillin concentrations also varied
from ear to ear in the same patient
(Reilly et al. 1983) but were
considered sufficient to produce the
desired result.
Ball et al
(1984)
Baltzer et al.
(1980)
Cox et al.
(1982)
No. of
Dose
subjects (mg)
Cmax
(mg/L)
tmax
(min)
(S)
(A)
(S)
6.1
7.0
10.9
9.3
9.7
11.1
60-90 60-90
6
500
750
475
10
16
250
500
3.6
5.1
2.6
8.7
16
51
(A)
38
750
8.3
11.0
Hampel et al. 10
(1988)
294(S)
+440(A)
6.4
11.1
40.9 42.3
Hartley &
250
2.2
3.2
60
40
6
Wise (1982)
AUC 0 – ∞
(mg/L * h)
t1/2
(h)
(S)
(S)
(A)
Vd
(L)
(A)
(S)
% recovery in
urine (h)
(A)
(S)
(A)
18.6
13.6
75(24) 67(24)
3.9
6.6
4.4 0.70
11.0 0.70
1.24
0.74
50
52
69
72
11.5
14.7 0.69
0.79
49
62
10.9
17.2 0.65
1.33
60(12) 66.9(12)
1.10
1.20
62(8)
62()
1.20
1.00
500
4.0
5.6
60
60
52(8)
80(8)
Nakayama et
(1985b)
4
750
5.8
7.1
41
41
13.6
17.1 1.02b 1.07b
31.7
39.7 49(8)
57(8)
Okada et al
al. (1985)
10
375
3.9
5.9
45
42
8.4
12.4 1.03
0.89
27.9
24.4 60(8)
69(8)
Rogers et al
(1983)
6
750
8.9
9.1
58
55
16.7
17.8 1.11
0.96
Saito et al
(1985b)
5
375
2.8
2.4
53
55
5.7
4.3
0.68
0.77
66(8)
55(8)
Sawae et al
(1985)
4
750
3.6
4.3
30
48
8.0
11.5 1.11
1.16
41(8)
46(8)
58
64
a. Small number of volunteers - number not stated.
b. Calculated from Kel
Abbreviations : Cmax = maximum (peak) plasma drug concentration; tmax = time to peak concentration; AUC 0 – ∞ = area under
plasma concentration-time curve from time zero to infinity; t1/2 = elimination half life ; Vd = volume of distribution
2.2 Distribution
incubated at 37ºC for 20 minutes and
using the centrifugal ultrafiltration
method (Kano et al. 1985). The mean
volume of distribution of ampicillin
was similar to that of sulbactam in
healthy
volunteers
after
administration of single oral doses of
sultamicillin (see table II).
The in vitro protein binding values
of sulbactam and ampicillin in
human sera have been reported to be
29.2 and 25.6%, respectively, at a
drug concentration of 34 mg/L,
Concentrations of sulbactam and
ampicillin have been measured in
various body tissues and fluids after
single-dose
administration
of
sultamicillin to patients. Data from
achievement of peak plasma
concentrations to 3 hours after
administration of a 750mg dose of
sultamicillin;
again,
urinary
excretion rates at 6 hours were not
affected (Okamoto et al. 1985).
7
Bile
concentrations
of
both
sulbactam and ampicillin as
measured during T-tube drainage
were 2 to 3 mg/L (Yamamoto et al.
1985a). Ampicillin concentration in
bile after a 750mg oral dose of
sultamicillin was 2.5 to 3 times
higher than that obtained after a
500mg oral dose of ampicillin alone
(Yura et al. 1985). During
cholecystectomy detectable concentrations of both ampicillin and
sulbactam were noted in gallbladder
and common duct bile as well as in
gallbladder wall (Sawada et al.
1985).
Purulent
exudates
from
the
appendix and wound exudates from
postmastectomy sites also contained
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N
Metabolism
More than 75% of both
Ampicillin & Sulbactam in its
active form were recovered in
the urine. Urine concentration
after 750 mg daily dose were
Ampicillin (400mg/1) and
Sulbactam (200 mg/1).
amounts
of
sulbactam
and
ampicillin for a considerable period
after administration of sultamicillin
(Sakai et al. 1985; Sawada et al. 1985)
Transfer of sulbactam and ampicillin
to amniotic fluid and cord plasma
has been demonstrated in 30
pregnant women (Cho et al. 1985;
Takase et al. 1985) and both drugs
have been detected in maternal milk
samples from 5 patients. Milk
concentrations for both sulbactam
and ampicillin of 0.04 mg/L were
detected at 3 hours after a 375 mg
oral dose of sultamicillin, with mean
peak milk concentrations at 4 hours
of 0.10 and 0.072 mg/L, respectively,
and persistence in milk sampled for
up to 6 hours after the dose (Takase
et al. 1985).
2.3 Metabolism and Elimination
Sulbactam has been shown to be
excreted primarily in the urine, and
metabolism has not been reported in
man. Coadministration of ampicillin
with sulbactam did not affect the
renal elimination (see Campoli8
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Table III Concentrations of sulbactam (S) and ampicillin (A) In various tissues and fluids after
single-dose administration of sultamicillin to patients
Tissue or fluid/
Reference
Tissue/body fluid
Type of patient
No. of Dose
Peak tissue or fluid
tmaxa
patinents (mg)
Sputum
Tonsil
patients (mg)
(h)
(mg/kg; mg/L)a
ratioa
(s)
(A)
(s)
A)
4-6
1.5-4
3.8-17.3
2.1-3.8
1-1.5
11.8-92.3 6.9-16.7
Bronchiectasis
1
Chronic respiratory 4
tract Infection
750
750
0.2-1.3
0.93
0.13-0.52
Otorhinolaryngological
infections
750
0.5-0.96
0.24-0.60
7
plasma concentration
6.4-14.9
4
Sinus aspirate
Acute sinusitis
3
750
0.57-4.6
0.67-5.2
1.5-2
Bile
T-tube drainage
3
1
2
4
750
375
375
1125
1.2-2.8
2.4
0.42-0.7
0.1-1.8C
0.15-2.3e
6.6-7.9
2.74
3.1-4.6
0.44-3.4C
0.01-9.5e
2-5
2.4b
5
1.5-4d
1.5-4d
13
12
1
8
Cholecystectomy
5.7-35.1
5
10
3
Gallbladder wall
Cholecystectomy
4
1125
0.3-0.4
0.01-0.59
1.5-4d
8
Appendix wall
Cholecystectomy/
appendectomy
3
1125
0.4-0.43
0.05-1.32
1.5-4d
8
Purulent ascites
Appendectomy
2
1125
1.04-2.7
1.92-4.45
1.25-3.3d
8
Wound exudate
Mastectomy (breast 4
cancer)
750
2.9-3.8
2.2-4.7
4-6
7
Middle ear fluid
Chronic otitis media 10
In children
32
50mg/kg 0.3-2.7
50mg/kg
0.16g
0.2-5.2
2
9-43
5->100
6
0.53g
0.5-2f
3.3
9.1
11
Intrapelvic genital
organs
obstetricc Infection 1
750
2.45h
0.2-1.0l
2.60h
0.1-1.2l
3.5h
2
2
Umbllical cord
blood
Pregnancy
1
29
750
375
1.6
0.97
1.16
0.76
4-5
1.1.5b
2
9
Amniotic fluid
Pregnancy
1
29
750
.75
8.95
0.52
7.5
0.56
10
6.4b
2
9
Maternal milk
Postpartum
5
375
0.10
0.072
4
9
f
f
f
f
f
a - A range of values is given for the patients studied unless otherwise noted.
b - tmax sulbactam, tmax ampicillin.
c - Common duct bile concentration.
d - Samples taken at various times during surgery.
e - Gallbladder bile concentration.
f - Sample times after the dose, not necessarily representing the peak tissue concentration.
g - Mean values for all patients studied.
h - Uterine arterial plasma.
i - uterine tissues Including endometrium, myometrium, perimetrium, ovary, oviduct, vagina, cervix.
areferences: 1 Aoki et al. (1985):2 Choet al. 1985); 3 Jones et al. (1985); 4 Mori et al. (1985;5 Nasu et
al. (1985); 6 Reilly
et al. (1983); 7 Sakai et al. (1985); 8 Sawada et al. (1985); 9 Takase et al. (1985; 10 Tamita et al. (1985;
11 Voelker et al. (1985); 12 Yamamoto et al. (1985a); 13 Yura et al. (1985).
9
S
U
L T A M
Richards & Brogden 1987).
Percentage recovery of sulbactam in
urine within 8 hours after
administration of single oral doses of
sultamicillin (250 to 750 mg) to
healthy volunteers has been
reported to range from 41 to 66%,
and
percentage
recovery
of
ampicillin ranged from 46 to 80%
(table
II).
Peak
urinary
concentrations of sulbactam and
ampicillin were 200 mg/L and 400
mg/L, respectively (Foulds et al.
1982), suggesting the potential
usefulness of sultamicillin in the
treatment of urinary tract infections
(see section 3.3). Neither food nor
antacid was found to affect the rate
or extent of urinary elimination of
either sulbactam or ampicillin
(Okamoto et al. 1985; Saito et al.
1985a). Urinary excretion of both
sulbactam and ampicillin was
similar over all sampling times in
multiple-dose studies of up to 15
days' duration (Hartley & Wise 1982;
Okada et al. 1985b).
Since renal clearance of sulbactam
exceeds the normal glomerular
filtration rate in humans, excretion
of sulbactam by tubular secretion is
probably of major importance
(Foulds 1986.)
In studies in which sulbactam was
administered parenterally, either
alone or with ampicillin, non renal
clearance ranged from 1.8 to 3.6 L/h
but active secretion of sulbactam
was not demonstrated.
In a
I C I
L L I
N
multiple-dose
study
of
oral
sultamicillin administered to 4
human volunteers (375mg twice
daily for 15 days) sulbactam was
detected in only 2 of 12 faecal
samples, one at day 9 and the other
at day 16 of the study (Okada et al.
1985b).
2.3.1 Elimination Half-Life
The mean elimination half-life of
sulbactam ranged from 0.65 to 1.20
hours, and that of ampicillin ranged
from 0.74 to 1.33 hours, in studies of
oral sultamicillin administered to
healthy volunteers (table II). These
values are not different from those
reported
for
either
drug
administered alone.
2.1 Influence of Disease and Age on
Pharmacokinetics
2.4.1 Renal Dysfunction
Patients with renal failure who were
administered parenteral doses of
sulbactam plus ampicillin had
increased plasma concentrations and
delayed excretion of both drugs.
Single oral doses of sultamicillin
(750mg) administered to 4 groups of
5 patients with varying degress of
renal impairment produced similar
results (Boelaert et al. 1983) [table
IV]. Additionally, in a clinical trial of
oral sultamicillin in 30 patients
(mean age 62 years) with acute
exacerbations of chronic bronchitis,
increases in mean AUCs and
prolonged half-lives for both
sulbactam and ampicillin were
10
S
U
L T A M
I C I
L L I
N
Table IV Pharmacokinetic values reported for sulbactam (S) and ampicillin (A) following single-dose oral administration of
sultamicillin (750mg) to 4 groups of 5 patients with varying degrees of renal dysfunction (after Boelaert et al. 1983)
Group
1
2
3
4
Creatinine
clearance
(ml/min)
Cmax
(mg/L)
AUC 0 – ∞
(mg/L * h)
t1/2
(h)
24-hour urinary
recovery (%)
(S)
(A)
(S)
(A)
(S)
(A)
(S)
(A)
80-144
25-69
6-12
<5
5.7
8.2
7.6
8.5
8.6
12.0
14.0
16.0
14
38
111
24
63
224
0.9
2.3
8.1
2.4*
1.3
2.6
8.5
3.3*
55
30
19
66
40
25
a During haemodialysis.
b Calculated from Ket.
Abbreviations : Cmax = maximum (peak) plasma drug concentration; AUC 0 – ∞ = area under plasma concentration-time curve from
time zero to infinity; t1/2 = elimination half life ;
found in comparison with healthy
volunteers; these findings were
attributed to decreased renal
clearance since 10 of the 30 patients
had elevated plasma creatinine
concentrations (Davies et al. 1984).
Since both sulbactam and ampicillin
appear to be affected similarly in
patients with impaired renal
function (Boelaert et al. 1983) dosage
alterations for sultamicillin may
prove similar to those for ampicillin
alone.
2.4.2 Hepatic Dysfunction
Little information is available on the
use of sultamicillin in patients with
hepatic dysfunction. Studies in liverdamaged rats showed reduced
serum concentrations and higher
urinary recoveries of both sulbactam
and ampicillin (Kano et al. 1985). In 2
patients with obstructive jaundice, 1
from cancer of the bile duct and the
other from liver cirrhosis, who were
administered single doses of
sultamicillin 375mg, absorption and
biliary excretion of ampicillin were
11
slower than those of sulbactam, and
urinary recovery in 12 hours was
44.4% and 35.7%, respectively (Aoki
et al. 1985).
2.4.3. Paediatric Patients
In 20 infants and children (8 to 69
months of age, mean 27 months)
administration of sultamicillin as a
suspension containing 25 mg/kg
ampicillin
and
17.5
mg/kg
sulbactam resulted in peak plasma
concentrations of ampicillin which
were greater at 20, 40, 60 and 90
minutes after the dose than were the
concentrations when ampicillin 25
mg/kg was administered as a single
agent. The AUC for ampicillin was
39% greater when administered as
sultamicillin than was the AUC for
ampicillin alone. Coadministration
of sultamicillin with milk increased
the plasma concentration but not the
AUCs of sulbactam and ampicillin
(Ginsburg et al. 1985). The
pharmacokinetic disposition of
ampicillin was similar to that of
sulbactam in these studies and did
S
U
L T A M
not differ greatly from values found
in healthy adult volunteers.
2.4.4 Geriatric Pateints
Some pharmacokinetic values in
elderly patients (number of patients
not specified; mean age 81.6 years)
administered a single dose of
sultamicillin 500mg were altered
slightly in comparison with values
reported for younger patients (Lode
et al. 1989). Ampicillin and
sulbactam AUC values were 47.0
and 20.3 mg/L * h, respectively,
Cmaxs were 11.4 and 5.5 mg/L,
respectively, and t1/2 ≤ s were 2.33
and 2.57 hours, respectively. This
indicates that enhanced absorption
and
delayed
elimination
of
sultamicillin are likely to occur to
some extent in elderly patients.
3. Therapeutic Trials
The
therapeutic
efficacy
of
sultamicillin has been demonstrated
in a number of non-comparative
therapeutic trials in patients with a
variety of infections. These include
respiratory
tract
infections,
otorhinolaryngological infections,
urinary tract infections, gonorrhoea,
skin and soft tissue infections,
obstetric
and
gynaecological
infections,
osteomyelitis/septic
arthritis, and infections arising from
ophthalmological and oral surgery.
The overall clinical efficacy
sultamicillin, defined as
percentage of patients having
excellent or good response,
of
the
an
as
I C I
L L I
N
compiled by the manufacturer from
the non-comparative trials, was
89.8% of 2,187 clinically assessable
patients.
The
bacteriological
eradication rate assessed in a world
wide survey including data obtained
in the US, Europe and Japan from
non-comparative and comparative
trials was 86.8% of 2,947 strains (Pitts
et al. 1989).
In addition, comparative studies
including 2,159 patients treated with
sultamicillin have assessed the
therapeutic efficacy of sultamicillin
in comparison with alternative
antibacterial drugs in the treatment
of various infections. Overall clinical
efficacy was 84.9% for pneumonia,
lung abscess and various chronic
respiratory tract infections, 92.4% for
acute streptococcal pharyngitis,
tonsillitis and acute otitis media,
86.3% for complicated urinary tract
infections and gonorrhoea, and
89.4% for skin and soft tissue
infections (Pitts et al. 1989).
3.1 Respiratory Tract Infections
3.1.1 Non-Comparative Results
The clinical efficacy of sultamicillin
in various infections of the lower
respiratory tract has been reported
in several non-comparative clinical
trials Patient gropus were small
(maximum 33) and the types of
infection being treated were varied,
including pneumonia, acute and
chronic bronchitis, bronchiectasis,
diffuse panbronchiolitis, emphy12
S
U
L T A M
Respiratory Tract
Infections
Sultamicillin gave excellent
results in lower respiratory
infection including pneumonia,
acute and chronic bronchitis,
bronchiectasis, infected
emphysema and lung abscess.
The most causative organisms
were H. influenza, Strep
pneumoniae, B. catarrhalis, and
Staph aureus.
sema with infection, infected
pulmonary fibrosis, and lung
abscess. The most common causative
organisms
were
Haemophilus
influenzae, Streptococcus pneumoniae, Staphylococcus aureus and
Pseudomonas aeruginosa. Overall
clinical efficacy, expressed as the
percentage of patients having a good
to excellent response at the end of
treatment, ranged from 83 to 100%.
The wide variation in response rate
is not unexpected, given the variety
of infections, the number of different
causative organisms isolated, the
varying dosage regimens (total daily
dosages of 750 to 2250mg for
treatment durations of 2 to 43 days)
and the coexistence of underlying
disease in many patients.
(Only 2 of the non-comparative
clinical trials were restricted to a
single type of infection. Pressler et al.
(1986) investigated the efficacy of
13
I C I
L L I
N
S
U
L T A M
oral sultamicillin 25 mg/kg
(maximum 750mg) 12-hourly for 14
days in 8 children with cystic fibrosis
and 10 children with other chronic
obstructive pulmonary disease
suffering from chronic obstructive
pulmonary disease suffering from
chronic or recurrent H. influenzae
infections. At the end of treatment
the original organism had been
eradicated in 65% of patients, but in
29% of patients other H. influenzae
biotypes were present. A follow-up 1
month later, 8 of 15 patients had
negative cultures). Davies et al.
(1984) studied a total of 30 adult
patients admitted to hospital with
acute purulent exacerbations of preexisting chronic bronchitis. Patients
received oral sultamicillin 750mg (16
patients) or 1000mg (14 patients)
twice daily for 10 days. An excellent
or good clinical response was noted
in 62.5 and 85.7% of patients,
respectively, at the end of treatment.
The major organisms isolated, either
singly or in combination, in 25 of 30
pretreatment sputum cultures were
H. influenzae, S. pneumoniae and
Branhamella catarrhalis. At the end
of treatment 8 patients still had
positive sputum cultures, but all ßlactamase-producing strains had
been eliminated.
and throat has been reported in
several small (n < 41) noncomparative clinical trials. The most
common infection was acute otitis
media,
followed
by
acute
exacerbations of chronic otitis
media, acute tonsillitis, acute and
chronic sinusitis and pharyngitis.
The most common infecting
organisms were S. aureus, S.
pneumoniae, other streptococci, H.
influenzae, Staphylococcus epidermidis, B. catarrhalis and P.
aeruginosa. Daily sultamicillin
dosages ranged from 750 to 2250mg,
with a paediatric total daily dosage
of 50 mg/kg; treatment duration
ranged from 3 to 21 days. The
percentage of patients having a good
to excellent clinical response with
sultamicillin ranged from 75 to
100%, (Kawakami et al. 1985; Onishi
et al. 1985; Sakamoto et al. 1985b).
3.2
Otorhinolaryngological
Infections
Two large double-blind studies
assessed the comparative efficacy of
thrice daily administration of
sultamicillin 375mg and cefaclor
250mg in adult patients with
otorhinolaryngological infections. In
3.2.1 Non-Comparative Results
The clinical efficacy of sultamicillin
in various infections of the ear, nose
The efficacy of sultamicillin has been
assessed in comparative clinical
trials of streptococcal pharyngitis
(Aronoff et al. 1984) and acute otitis
media (Khan et al. 1988; Sait et al.
1986) in children, and of tonsillitis
(Baba et al. 1985), pharyngitis and
peritonsillar abscesses (Federspil et
al. 1989) and acute otitis media
(Kawamura et al. 1985) in adults.
I C I
L L I
N
Ear, Nose and Throat
Infections
Sultamicillin has been found of
high efficacy in acute and
chronic cases of otitis media,
tonsillitis, sinusitis, and
pharyngitis. The most common
infecting organisms were
S.pneumoniae, H.influenzae,
B.catarrhalis, and Staph aureus.
both studies, patients groups were
no statistically different as to
demographic, clinical or bacteriological parameters, including the
incidence of ß-lactamase-producing
pathogens. In patients with lacunar
tonsillitis, baba et al. (1985) reported
clinical efficacy rates of 91.9% for
sultamicillin (91 of 99 patients) and
91.1% for cefaclor (82 of 90 patients),
with bacteriological eradication rates
of 98.9 and 97.7%, respectively.
While in this study neither overall
clinical nor bacteriological efficacy
differed to a statistically significant
extent between treatment groups, in
the subgroup of patients with severe
symptoms, excellent clinical efficacy
occurred in 11 of 14 sultamicillintreated patients (78.6%) versus only
2 of 8 cefaclor-treated patients
(25.0%) [p < 0.05]. There were no
statistically significant differences
between treatment groups in clinical
efficacy
against
ß-lactamaseproducing S. aureus (80% and 75%
14
S
U
L T A M
Urinary Tract Infections
Sultamicillin shows excellent
efficacy in upper urinary tract
and lower urinary tract
infections including acute
cystitis, acute or chronic
prostatitis and UTI acquired
post-surgically. The most
common pathogens isolated
were E.coli, Proteus spp,
Streptococcus faecalis, Staph
saphrophyticus and Serratia
spp.
for sultamicillin and cefaclor,
respectively) or against other ßlactamase-producing bacteria (73
and 70%, respectively). In patients
with
purulent
otitis
media,
Kawamura et al. (1985) reported an
excellent or good clinical response in
67.6% (75/111) of sultamicillintreated patients but only 52.3%
(58/111) of cefaclor-treated patients
(p < 0.05).
In another study, Sait et al. (1986)
compared
the
efficacy
of
sultamicillin administered twice
daily (n = 30) with that of
sultamicillin (n = 27) or amoxycillin
(n = 29) 3 times daily in 3 parallel
groups of children with acute otitis
media (dosages and duration of
therapy were not stated). Clinical
efficacy rates at the end of the study
were 92.8, 91.3 and 100%,
15
I C I
L L I
N
respectively, with both children
initially infected by ampicillinresistant H.influenzae being cured
by sultamicillin. However, at a 4week follow-up 41.7% of 24 children
who had taken amoxycillin had
recurrent otitis media with effusion
as opposed to 4.3% of 46 children
who had taken sultamicillin (p =
0.002). Total percentage relapses fo
the 3 groups were 18.5, 26.3 and
26.1%, respectively (no statistical
values were reported).
3.3 Urinary Tract Infections
3.3.1 Non-Comparative Results
The clinical efficacy of sultamicillin
has been reported in several noncomparative trials in patients with
acute uncomplicated cystitis and
complicated urinary tract infections
associated with underlying urinary
tract diseases.
A total of 274 patients with acute
uncomplicated cystitis were treated
with sultamicillin in total daily
dosages of 750 to 2250mg for 3 to 14
days in several clinical trials. Overall
clinical efficacy, defined as excellent
or moderate improvement in pain on
micturition, pyuria and bacteriuria,
occured in 80 to 100% of patients,
while
bacteriological
efficacy
(percentage of strains eradicated)
ranged from 66.7 to 100%. The most
common infecting bacteria were E.
coli and S. epidermidis. Although 3
ß-lactamase-producing strains of
E.coli were resistant to sultamicillin
S
U
L T A M
(MIC of 50 to 200 mg/L) in the study
of Suzuki et al. (1985b), clinical
improvement in the patients
harbouring these strains was
moderate to excellent. Kawada
(1989) noted that the eradication rate
of 84.2% for high ß-lactamaseproducing organisms, but this
difference was not statistically
significant.
381 patients with different types of
complicated urinary tract infections
were treated with sultamicillin in
various clinical studies. Total daily
dosages ranged from 750 to 2250mg
daily for 2 to 28 days. Overall clinical
efficacy ranged from 77% in a group
of geriatric patients (Nakauchi 1985)
to 89%, and bacteriological efficacy
(percentage of strains eradicated )
ranged from 66.7 to 93.8%. When
patients were subgrouped according
to
type
of
infection
(e.g.
postprostatectomy, upper urinary
tract or lower urinary tract), clinical
efficacy was widely variable among
studies. However, the presence of an
indwelling catheter resulted in
poorer clinical outcome in most
studies.
The
most
common
pathogens isolated were E. coli,
Streptococcus faecalis, Proteus
species,
P.
aeruginosa,
S.
epidermidis, Serratia marcescens
and K. pneumoniae. Bacteria which
produced high levels as opposed to
little or no ß-lactamase were more
susceptible to sultamicillin in 1
study (Mizuno et al. 1985) with
bacteriological eradication of 71.5%
I C I
L L I
N
of the high ß-lactamase-producing
strains of bacteria to be susceptible
to sultamicillin (MICs of 1.56 to 12.5
mg/L) with the exception of a strain
of Pseudomonas maltophilia (MIC
400 mg/L), in which case clinical
outcome was poor.
The division of a total daily dosage
of sultamicillin 1500mg into 2 equal
doses given 12-hourly or 3 equal
doses given 8-hourly, each for 7
days,
resulted
in
similar
bacteriological cure rates (87.5 and
89%, respectively) in 2 groups of 20
patients with infections due to
ampicillin-resistant organisms (Ball
et al. 1984).
Other small groups of patients for
whom efficacy data is available from
non-comparative trials include those
with urinary tract infetions acquired
post-surgically (10 patients, overall
efficacy of 6%) [Nakayama et al.
1985; Suzuki et al. 1985a; Yamamoto
et al. 1985a] and those with nonsurgical acute or chronic prostatitis
(6 patients, overall efficacy 83%)
[Nakauchi 1985; Shimada et al. 1985;
Tominaga et al. 1985].
3.5 Skin and Soft Tissue Infections
3.5.1 Non-Comparative Results
The efficacy of sultamicillin
administered in total daily dosages
of 750 to 2250mg for 3 to 28 days has
been assessed in several noncomparative trials in patients with
various surgical skin and soft tissue
infections,
including
infected
16
S
U
L T A M
Skin & Soft tissue
Infections
Sultamicillin shows excellent
efficacy in various skin and soft
tissue infection like infected
atheromas, furuncles, abscesses,
carbuncles, cellulitis including
post surgical Skin and Soft
tissue infections.
atheromas, furuncles and abscesses
and in patients with similar types of
non-surgical skin infections. Clinical
efficacy rates ranged from 70.2 to
86.7% in surgical infections and from
75 to 100% in those of non-surgical
origin. Bacterial eradication in
surgical infections ranged from 63 to
80.6%
of
initially
infecting
organisms, including 1 patient each
infected with B. fragilis (Suzuki et al.
1985a) and Bacteroides species
(Sakai et al. 1985). In 1 of the above
studies, 78.9% of patients infected
with organism producing high levels
of ß-lactamase had a good to
excellent clinical response, as
opposed to 60% of patients infected
with low-ß-lactamase-producing
organisms and 73.7% of patients
with non-ß-lactamase-producing
organisms (Yura et al. 1985). Sakai et
al. (1985) found no relation between
clinical effect and total daily dosage.
3.5.2 Comparative Results
Adult diabetic patients with various
soft
tissue
infections
were
17
I C I
L L I
N
randomised to receive either
sulbactam plus ampicillin or
flucloxacillin
plus
ampicillin
parenterally for 3 to 18 days,
followed by oral sultamicillin (total
daily dosage 1.5g for 2 to 68 days) or
oral flucloxacillin plus ampicillin in
varying dosages for 4 to 47 days
(Chiodini et al. 1985). Seven of 12
patients in the sulbactam plus
ampicillin and sultamicillin group,
and 9 to 13 patients in the
flucloxacillin plus ampicillin group,
were cured. Both groups showed a
satisfactory response to therapy and
only 1 strain of E. coli was resistant
to sultamicillin. There were no
adverse effects of either treatment on
diabetic control.
A large
double-blind
study
compared the efficacy of 3 times
daily administration of sultamicillin
375mg and of bacampicillin 250mg
for 7 days to adult patients with
furuncle, furunculosis, carbuncle,
cellulitis or other skin and soft tissue
infections (Nohara et al. 1985).
Patient groups did not differ to a
statistically significant extent as to
demographic,
clinical
or
bacteriological
parameters,
including the incidence of ßlactamase-producing
pathogens.
The 2 drug treatments did not
statistically differ from each other:
excellent to good clinical response
occurred in 81 of 99 sultamicillin
treatment patients (81.8%) and 77 of
105 bacampicillin-treated patients
(74.3%),
while
bacteriological
S
U
L T A M
eradication rates were identical
(82%).
3.6 Obstetric and Gynaecological
Infections
The use of sultamicillin in the
treatment
of
obstetric
and
gynaecological infections in 4 noncomparative clinical trials resulted in
an overall good to excellent clinical
response in 49 of 50 patients studied
and a poor response in only 1 patient
with puerperal mastitis (Cho et al.
1985; Matsuda et al. 1985; Takase et
al. 1985; Yamamoto et al. 1985b).
Types
of
infection
included
endometriosis, adnexitis, vulval
infections,
puerperal
mastitis,
abscess, pelvic peritonitis and
cystitis or pyelonephritis associated
with cervical or ovarian cancer. The
infections were due to a variety of
organisms. The bacteriological
eradication rate was 82% overall. No
controlled trials of sultamicillin in
comparison with other drugs for the
treatment
of
obstetric
and
gynaecological infections have been
reported to date.
4. Drug Interactions
Probenecid delays the renal
secretion
of
sulbactam
and
ampicillin and prolongs the serum
half lives of both (section 2.3). This
interaction forms the basis for the
combined use of probenecid with
sultamicillin in the treatment of
gonorrhoea (section 3.4).
The concurrent use of sultamicillin
I C I
L L I
N
Gynec & Obs Infections
Sultamicillin gives excellent
efficacy in obstetric and
gynaecological infections
including endometriosis,
adnexitis, vulva infections,
abscess, pelvic peritonitis,
cystitis and pyelonephritis
associated with cervical or
ovarian cancer.
with other antibacterial drugs
known to cause diarrhoea may
increase the severity of symptoms,
as found by Pressler et al. (1986) in 4
patients with severe diarrhoea
associated
with
concomitant
treatment with sultamicillin and
fusidic acid.
Concurrent
administration
of
allorpurinol and ampicillin increases
the incidence of rashes in patients
receiving both drugs compared to
that occuring with ampicillin alone.
It is not known whether this is due to
allopurinol or to the hyperuricaemia
present in these patients (Boston
Collaborative Drug Surveillance
Program 1972). This type of
interaction with sultamicillin and
allopurinol has not been reported.
5. Dosage and Administration
Sultamicillin is currently available in
tablet formulation containing 375mg
sultamicillin as the tosylate salt. The
18
S
U
L T A M
Dosage
The usual adults dose is
Sultamicillin 375 mg bid is
most cases and severe
infections 375 mg tid or
750 mg bid is advocated.
usual adult dosage is 375mg
administered orally 2 to 3 times
daily. Tablets should be taken
usually with an adequate amount of
water. A dosage adjustment may be
made depending on the patient's age
and/or symptoms.
Sultamicillin is contraindicated in
patients with a history of an allergic
reaction of any of the penicillins.
Sultamicillin is also contraindicated
in
patients
with
infectious
mononucleosis, due to a high
incidence of skin rash in response to
ampicillin in these patients; the latter
contraindication suggests caution in
the administration of sultamicillin to
patients with pharyngitis of
unidentified aetiology.
In patients with renal dysfunction
the elimination of both sulbactam
and ampicillin may be impaired,
resulting in increased serum
concentrations and prolonged halflives of both drugs (section 2.4.1).
The dosage of sultamicillin should
probably be decreased in accordance
with the usual practice for
ampicillin, and caution should be
exercised when administering the
drug to patients with severe renal
disease.
19
I C I
L L I
N
In patients who are malnourished or
debilitated, or are receiving
parenteral or enternal nutrition, the
manufacturer recommends that
caution should be exercised as
symptoms of vitamin K deficiency
(hypoprothrombinaemia
and/or
haemmorhagic tendency) may
appear (see section 4.2).
Dosage
The
usual
adults
dose
is
Sultamicillin 375 mg bid is most
cases and severe infections 375 mg
tid or 750 mg bid is advocated.
References
Allan JD, Moellering Jr RC,
Antimicrobial combinations in the
therapy of infections due to Gramnegative bacilli. American Journal of
Medicine 78 (Suppl. 2A): 65-75,
1985a
Allan JD, Moellering Jr RC,
Management of infections caused by
Gram-negative bacilli; the role of
antimicrobial
combinations,
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24
For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory
MUTUAL PRODRUG CONCEPT
FUNDAMENTALS AND APPLICATIONS
Indian J Pharm Sci 2006;68:286-294
PRODRUG CONCEPT
• Many drugs have various shortcomings.
For e.g. poor bioavailability (Ampicillin), incomplete absorption
(epinephrine), nonspecificity (antineoplastic agents).
• The chemical process that can overcome these drawbacks is called as
PRODRUG DESIGN.
• SULTAMICILLIN is one such Oral Mutual Prodrug which is completely
hydrolyzed into equimolar amounts of Ampicillin and Sulbactam.
BENEFITS
✓ The Mutual Prodrug effect of Sultamicillin results from its having a more
efficient oral absorption of Ampicillin (3.5 folds more) than plain Ampicillin.
✓ It provides the ß-lactamase inhibitor Sulbactam in the oral form.
TH E M
UT
✓ Enables a convenient BID dosing.
PRODRUG
L
A
U
TAB
THE SUPER POWER ß-LACTAM… ...SHIELDED WITH SULBACTAM
202, Ketan Apartment, 233, R.B. Mehta Marg, Ghatkopar (East), Mumbai 400 077
Abstract
few decades.
A therapeutically significant drug may have limited
utilization in clinical practice because of various
shortcomings like poor organoleptic properties
(chloramphenicol), poor bioavailability (ampicillin),
short duration of action (pilocarpine), nonspecificity
(antineoplastic agents), incomplete absorption
(epinephrine),
poor
aqueous
solubility
(corticosteroids), high first-pass metabolism
(propranolol) or other adverse effects. There is a
great emphasis on research to discover methods
aimed at improving their therapeutic efficacy by
minimizing or eliminating these undesirable
properties. Sometimes, an adequate pharmaceutical
formulation can overcome these drawbacks, but
often the galenic formulation is inoperant and a
chemical modification of active molecule is
necessary to correct its pharmacokinetic
insufficiencies. This chemical formulation process,
whose objective is to convert an interesting active
molecule into a clinically acceptable drug, often
involves the so-called 'Prodrug design.' Mutual
prodrug is a type of carrier-linked prodrug, where
the carrier used is another biologically active drug
instead of some inert molecule. A mutual prodrug
consists of two pharmacologically active agents
coupled together so that each acts as a promoiety
for the other agent and vice versa. Mutual prodrug
design is really no different from the general drug
discovery process, in which a unique substance is
observed to have desirable pharmacological effects,
and studies of its properties lead to the design of
better drugs. It is a very fruitful area of research, and
its introduction in human therapy has given
successful results in improving the clinical and
therapeutic effectiveness of drugs suffering from
some undesirable properties that otherwise hinder
their clinical usefulness. The present article takes a
review of various applications of mutual prodrugs
and the developments in this field during the last
Classification of prodrugs
Wermuth, after surveying the literature, has
classified the prodrugs into two broad categories:
the carrier-linked prodrugs and bioprecursors. The
carrier-linked prodrug consists of the attachment of
a carrier group to the active drug to alter its
physicochemical properties and then subsequent
enzymatic or nonenzymatic mechanism to release
the active drug moiety. Thus, the carrier-linked
prodrugs are drugs with major drawbacks that are
linked through covalent linkage with specialised
nontoxic protective groups or carriers or promoieties
in a transient manner to alter or eliminate
undesirable properties in the parent molecule.
Depending upon the nature of carrier used, the
carrier-linked prodrug may further be classified
into:
1. Double prodrugs, pro-prodrugs or cascadelatentiated prodrugs, where a prodrug is further
derivatized in a fashion such that only enzymatic
conversion to prodrug is possible before the latter
can cleave to release the active drug.
2. Macromolecular prodrugs, where macromolecules like polysaccharides, dextrans,
cyclodextrins, proteins, peptides, and polymers
are used as carriers.
3. Site-specific prodrugs where a carrier acts as a
transporter of the active drug to a specific targeted
site.
4. Mutual prodrug, where the carrier used is another
biologically active drug instead of some inert
molecule. A mutual prodrug consists of two
pharmacologically active agents coupled together
so that each acts as a promoiety for the other agent
and vice versa. The carrier selected may have the
same biological action as that of the parent drug
and thus might give synergistic action, or the
MUTUAL PRODRUG CONCEPT
F U N DA M E N TA L S A N D A P P L I CAT I O N S
carrier may have some additional biological
action that is lacking in the parent drug, thus
ensuring some additional benefit. The carrier may
also be a drug that might help to target the parent
drug to a specific site or organ or cells or may
improve site specificity of a drug. The carrier drug
may be used to overcome some side effects of the
parent drugs as well.
Applications of mutual prodrug
approach
Reduction of gastrointestinal (GI) side
effects and ulcerogenicity of nonsteroidal
antiinflammatory drugs (NSAIDs):
Despite the intensive research that has been aimed at
the development of NSAIDs, their clinical
usefulness is still restricted by their GI side effects
like gastric irritation, ulceration, bleeding,
perforation and in some cases may develop into life
threatening conditions. GI lesions produced by
NSAIDs are generally attributed to either direct
and/or indirect mechanisms. The direct contact
effects result usually from local irritation produced
by free acidic group of NSAIDs and local inhibition
of prostaglandin synthesis in GIT. Indirect
mechanism is due to generalized systemic action
occurring after absorption and is demonstrated on
intravenous dosing. This problem has been solved
by derivatization of carboxylic function of NSAIDs
into ester and amide mutual prodrugs using amino
acids like L-tryptophan, L-histidine, L-glycine as
carriers that have marked antiinflammatory activity
of their own. Other analgesic, antiinflammatory
drugs like paracetamol and salicylamide have also
been used as carriers to synthesize mutual prodrugs
of NSAIDs, the examples of which are cited below.
Benorylate (1) is a mutual prodrug of aspirin and
paracetamol, linked through ester linkage, which
claims to have decreased gastric irritancy with
synergistic analgesic action. Glycine methyl ester
conjugate of ketoprofen (2), histidine methyl ester
conjugate of diclofenac (3), and various conjugates
of flurbiprofen with amino acid like L-tryptophan
(4a), L-histidine (4b), phenylalanine (4c) and alanine
(4d) as mutual prodrugs were reported to have less
ulcerogenicity with better antiinflammatory /
MUTUAL PRODRUG CONCEPT
F U N DA M E N TA L S A N D A P P L I CAT I O N S
analgesic action than their parent drugs. Mutual
prodrugs of ibuprofen with paracetamol (5) and
salicylamide (6) have been reported with better
lipophilicity and reduced gastric irritancy than the
parent drug[16]. Naproxen-propyphenazone mutual
prodrugs (7) were synthesised with an aim to
improve therapeutic index through prevention of GI
irritation and bleeding. Esterification of naproxen
with different alkyl esters and thioesters led to
prodrugs with retained antiinflammatory activity
but exhibited greatly reduced GI erosive properties
and analgesic potency, but esterification with ethyl
piperazine showed that analgesic activity was
preserved whereas antiinflammatory activity was
generally reduced. Propyphenazone, a nonacidic
pyrazole with good analgesic and antipyretic
activity, was coupled with naproxen to achieve
many advantages related to the synergistic analgesic
effect
with
reduced
gastric
irritation.
Propyphenazone is converted to its active
metabolite, 3-hydroxy methyl propyphenazone,
which actually gives the analgesic effect. Coupling
of these two compounds as a hybrid drug or
through a spacer as a mutual prodrug resulted in
potent analgesic/antiinflammatory compound with
reduced adverse local effects related to NSAID.
SULTAMICILLIN
ampicillin are achieved that are approximately 3.5-
Sultamicillin is an example of a mutual prodrug
oral ampicillin. Equimolar concentrations of
with synergistic action. In the design of sultamicillin,
sulbactam are also provided with both ampicillin
the irreversible ß-lactamase inhibitor sulbactam has
and sulbactum, being widely distributed among
been combined chemically via ester linkage with
various
ampicillin. This design is based on the rationale that
pharmacokinetic parameters of the two components
as sulbactam, a ß-Lactamase inhibitor with very
are similar, both being eliminated primarily by renal
limited antibacterial activity in a physical mixture
excretion. Although the elimination half-lives of
with ampicillin, clearly enhances the activity of the
ampicillin and sulbactam are each approximately 1
latter
ß-Lactamase-producing
h, the high serum concentration achieved, coupled
bacteria, both in vitro and in vivo, the same
with their synergistic activity permit twice-daily
phenomenon might hold true when these two drugs
dosing. One more important advantage presented
are linked chemically. Upon oral administration,
by sultamicillin is that even though most ß-
sultamicillin is completely hydrolyzed to equimolar
Lactamase-resistant antimicrobials must be given
proportions of sulbactam and ampicillin, thereby
parenterally, sultamicillin is given by mouth. It has
acting as an efficient mutual prodrug. The mutual
been found to be effective against respiratory tract
prodrug effect produced by sultamicillin results
infection otorhinolaryngological, urinary tract
from its having a more efficient oral absorption than
infection, skin and soft tissue infection and obstetric
Site-specific drug delivery
the single agent does. Peak serum concentrations of
and gynecological infection.
A drug, after its absorption into systemic circulation,
gets distributed to target site as well as non-targeted
tissues. The distribution of drug to non-targeted
tissues may lead to undesirable toxic effects in those
tissues and insufficient concentration in the target
site to evoke any therapeutic response. If the target
site has a longer distribution time, the drug may get
eliminated without reaching such a site; and even if
the drug reaches the targeted area in sufficient
concentrations, it may have such a low penetration
power that it may not penetrate the target cells at all.
Targeting the drug to its site of action through
prodrug concept has been utilized to overcome these
problems.
Sulfasalazine is the classic example of colon-specific
mutual prodrug of 5-aminosalicylic acid (5-ASA)
and sulfapyridine, used in the treatment of
ulcerative colitis.
against
certain
fold those obtained with an equivalent amount of
body
fluids
and
tissues.
The