Bactomin product monograph

BACTOMIN
Product Monograph
 Bactomin product monograph

CONTENTS

Executive Summary

Sultamicillin: what is the need?

Sultamicillin: Prodrug of ampicillin and sulbactam

Pharmacokinetics

Pharmacodynamics

Antimicrobial Spectrum

Clinical evidence of Sultamicillin

Dosage and Administration

Safety and Tolerability

Place of sultamicillin in therapy

Conclusion

References

Prescribing information
 Bactomin product monograph

Executive Summary

The discovery of the β-lactamase inhibitor sulbactam and its co-administration with ampicillin as

sultamicillin allowed the continued use of this antibiotic to treat infections caused by pathogens that

had developed resistance due to β-lactamase production, thus expanding the range of activity of

ampicillin alone.

Sultamicillin is a double ester in which ampicillin & the β-lactamase inhibitor, sulbactam are linked

via a methylene group. The combination of ampicillin plus sulbactam for parenteral use has previously

been shown to be clinically &bacteriologically effective in a variety of infections. Now the chemical

linkage of sulbactam & ampicillin has produced an orally effective compound, sultamicillin, with

antibacterial activity & clinical efficacy which are similar to those of the parenteral formulation.

Sultamicillin has a broad spectrum of antibacterial activity that includes Gram-positive and Gram-

negative aerobic and anaerobic bacteria. Sultamicillin is indicated as empirical therapy before the

identification of causative organisms, or for disease caused by single or several susceptible bacteria in

both adults and children with a broad range of community and hospital acquired infections. One of the

specific advantages of using sultamicillin combination when compared with other β-lactam/β-

lactamase combinations is the inherent activity of sulbactam against A. baumannii, thus, making the

drug a valuable option against multi-resistant isolates. Sultamicillin is not active against P.

aeruginosa and pathogens producing ESBLs and, therefore, is not recommended for infections due to

these organisms.

Numerous clinical trials and several meta-analyses have demonstrated sultamicillin to be as clinically

effective as relevant comparator antibiotics. The drug is effective for the treatment of URTIs and

LRTIs, intra-abdominal infections, UTIs, gynecological, diabetic foot and skin and soft tissue
 Bactomin product monograph

infections. Sultamicillin is generally well tolerated and its oral form, sultamicillin, provides effective

outpatient therapy against many commonly encountered infections.

Furthermore, the availability of oral sultamicillin also provides the option of oral follow-on therapy on

an outpatient basis after the initiation of treatment with i.v. formulation, thus, improving patients’

compliance. Sultamicillin has been recommended in nationwide guidelines as first-line therapy or in

combination with other antibacterials for various respiratory, intra-abdominal and skin and soft tissue

infections.

This monograph, dedicated to Sultamicillin, presents an up to date compilation of its characteristic

features & the comparative scientific data with conventional therapies for the management of various

infections.

Dr. Sanjaykumar Navale`;

M.B.B.S., M.D

Manager, Medical Services

Zuventus Healthcare Ltd.

 Bactomin product monograph

Sultamicillin: what is the need?

In the era of global emergence & spread of bacterial resistance and in the absence of development of

new effective antimicrobial agents, the correct use of the currently available antibiotics, in particular

the penicillins, is of great significance. After the introduction and the widespread use of β-lactam

antibiotics, many organisms initially susceptible to penicillins, developed resistance due to the ability

to produce β-lactamases enzymes that hydrolyze the β-lactam ring, and, therefore, to destroy the

antimicrobial activity of the antibiotics. [1] A highly effective and proven approach for tackling β-

lactamase-mediated resistance is the use of β-lactam/β-lactamase-inhibitor combinations. Such

combinations have gained great success and have proven to be among the most effective antibiotic

strategies. [2, 3]

Of the many β-lactamase inhibitors that have been evaluated, three inhibitors (sulbactam, tazobactam

and clavulanic acid) are currently in clinical use in various combinations, including ampicillin-

sulbactam, cefoperazone/sulbactam, piperacillin/tazobactam, amoxicillin/clavulanic acid and

ticarcillin/clavulanic acid [4].

Sulbactam is also available as a single agent in some countries. Ampicillin/sulbactam is a β-lactam/β-

lactamase-inhibitor combination that was first developed and marketed in US in 1987. Since then, our

knowledge on the effectiveness in the treatment of community and hospital-acquired infections comes

mainly from the use of its parenteral form applied in severe infections.

However, an interest for the oral administration of the combination has been developed for milder

cases in several clinical studies. The therapeutic efficacy of parenteral and oral formulations of

ampicillin-sulbactam has been demonstrated in a wide variety of infections, including upper and lower

respiratory tract infections, intra-abdominal infections, urinary tract infections, gynecological

infections, skin and soft tissue infections. [5-7]

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Sultamicillin: Prodrug of Sulbactam and Ampicillin

Fig: Structural formula of sultamicillin showing its relationship to sulbactam & ampicillin (Atia et al. 1983)

Chemical Name: [(2R)-3,3-dimethyl-4,4,7-trioxo-4λ6-thia-1-azabicyclo[3.2.0]heptane-2-

carbonyl]oxymethyl (2R)-{[(2S)2amino-2-phenyl-acetyl] amino}-3,3-di methyl-7-oxo-4-thia-1-

azabicyclo [3.2.0]heptane-2-carboxylate

Chemical formulation: C25H30N4O9S2

Sultamicillin is a mutual prodrug that was developed to overcome the poor oral absorption of

sulbactam. It is the tosylate salt of the double ester of ampicillin plus sulbactam. Sulbactam is a

semi-synthetic β-lactamase inhibitor which, when combined with certain antibacterials, extends

their activity against bacteria that are normally resistant due to production of inhibitable β-

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
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made it necessary to administer this combination parenterally. However, a double ester linkage of

sulbactam with ampicillin has been developed (fig.) to produce a prodrug, sultamicillin, which is

readily absorbed orally and hydrolyzed by enzymes in the intestinal wall, releasing ampicillin and

sulbactam in equimolar proportions. 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. [8, 9]

Pharmacokinetics

The pharmacokinetic profiles of ampicillin and sulbactam are similar and favor their co-

administration either orally or parenterally. Ampicillin has no effect on pharmacokinetics of

sulbactam and vice versa [11]. Both agents have similar time-to-peak plasma concentrations, no

interaction in between occur and both have similar profile of elimination half-time (∼ 1 h).

Sultamicillin was initially developed to improve the oral absorption of the β-lactamase inhibitor

sulbactam. Initial work showed that sultamicillin was hydrolyzed within minutes, liberating the

active components [27]. 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 hydrolyzed by

enzymes in the intestinal wall. [28]

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Pharmacokinetic parameters (mean ± s. d.) for sultamicillin* in

healthy volunteers [10]
Parameter Ampicillin Sulbactam
Cmax (μg/ml) 9.1 ± 3.6 8.9 ± 3.4

tmax (h) 0.92 ± 0.30 0.96 ± 0.29

AUC (μg/(h ml)) 17.8 ± 0.2 16.7 1 ± 2.5

t1/2 (h) 0.96 ± 0.25 1.11 ± 0.69

Urinary recovery (% of dose) 59.4 ± 7.1 66.3 ± 6.7

*Oral sultamicillin (750 mg) equivalent to 440 mg ampicillin & 294 mg

sulbactam.

Absorption

 Either agent given alone has limited oral bioavailability, with the sulbactam oral absorption

being very poor [9]. This problem has been overcome with oral prodrug, sultamicillin [9,

11].

 Sultamicillin bioavailability is > 80%, leading to high serum concentrations of both agents.

 Although the ratio of ampicillin: sulbactam differs between parenteral and oral forms (2:1

versus 1:1), both formulations have similar efficacy as shown by comparable bioavailability

of ampicillin and sulbactam (administered as oral sultamicillin) when equivalent quantities

of the individual components are given intravenously [10, 11, 14].

 In studies in which sultamicillin (500 mg) was compared with ampicillin (500 mg) alone,

the peak serum concentrations of ampicillin were twice as great for the sultamicillin [10].

 Increased bioavailability of ampicillin is seen when co-administered with sulbactam

compared to amoxicillin plus clavulanic acid.

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 The effect of sulbactam in increasing the oral bioavailability of ampicillin is greater than

the effect of clavulanic acid on the oral bioavailability of amoxicillin. [15]

Distribution

 The protein binding of ampicillin and sulbactam in serum is similar-28%.

 High body tissue and fluid concentrations of sulbactam and ampicillin are obtained when

administered orally [12].

 Steady-state volumes of distribution have been shown at the level of 0.32 l/kg for ampicillin

and 0.34 l/kg for sulbactam [13].

 High tissue/fluid concentrations, which exceed the MICs of important bacterial pathogens,

have been demonstrated in CSF with sulbactam to increase ampicillin’s penetration,

particularly in the presence of inflamed meninges [14].

 Similarly, high concentrations have been seen in costal cartilage [17] and middle-ear fluid.

Sufficient penetration in peritoneal fluid, intestinal mucosa, prostatic and appendiceal

tissue, sputum & peritonsillar abscess pus has also been shown [15].

 The tissue/fluid concentrations attained were generally in excess of the MICs for common

pathogens associated with infections at these sites.

The high bioavailability of sultamicillin assures that these high tissue concentrations are

achievable with oral therapy. Furthermore, good tissue penetration of sultamicillin supports its

use in a twice-daily dosing regimen [9].

Metabolism and elimination

 Half-life’s of both agents are similar and approximately equal to 1 h.

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 Eliminated primary by urinary excretion: ∼ 65% of ampicillin & 46% of sulbactam from

sultamicillin excreted in the urine [15].

 Based on half-life, twice-a-day oral dosing schedule of sultamicillin is sufficient to achieve

high serum levels of ampicillin and sulbactam into the circulation [9].

 As the both agents are primarily eliminated by renal excretion, the t1/2 and serum

concentration in patients with renal impairment are increased [15]. As a result, the

frequency of dosing is reduced according to creatinine clearance in patients with renal

impairment (from three or four times daily to twice or once daily).

 Hemodialysis removes 30% of the given doses of ampicillin-sulbactam, and supplemental

doses are recommended after dialysis [13, 16].

 In women during pregnancy, a more frequent administration scheme (every 4 h) is more

appropriate due to a decreased elimination half-life [15].

Bile concentrations of both sulbactam and ampicillin were 2 to 3 mg/L. [29] Ampicillin

concentrations 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. [30] Transfer of sulbactam and ampicillin to

amniotic fluid and cord plasma has been demonstrated in 30 pregnant women [31; 32] and both

drugs have been detected in maternal milk samples from 5 patients.

Pharmacokinetics in special population

Pharmacokinetics in Pediatric Patients

 Age has no effect on the pharmacokinetics of ampicillin or sulbactam; pharmacokinetic

properties are comparable in children and adults. In children, and the results were also

independent of dose and gender [13].

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 Oral administration of a single dose of sultamicillin (42.5 mg/kg of sultamicillin equivalent

to 25 mg/kg ampicillin and 16.6 mg/kg sulbactam) resulted in greater peak serum

concentrations and AUC of ampicillin than those achieved with equivalent dose of

ampicillin alone in children (wt. 8.6 to 19.9 kg) [17].

 Additionally, in children with otitis media, higher middle ear concentrations of ampicillin,

administered as sultamicillin, were reported than after equivalent dose of ampicillin alone.

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 (750 mg) administered to 4 groups of 5 patients with varying

degrees of renal impairment produced similar results. [23] Additionally, in a clinical trial of

oral sultamicillin in 30 patients (age 62 yrs) with acute exacerbations of chronic bronchitis,

increases in mean AUCs and prolonged half-lives for both sulbactam and ampicillin were

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 [24]. Since

both sulbactam and ampicillin appear to be affected similarly in patients with impaired renal

function dosage alterations for sultamicillin may prove similar to those for ampicillin alone.

[23]

Hepatic Dysfunction

Little information is available on the use of sultamicillin in patients with hepatic dysfunction. In 2

patients with obstructive jaundice, 1 from cancer of the bile duct and the other from liver cirrhosis,
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who were administered single doses of sultamicillin 375mg, absorption and Biliary excretion of

ampicillin were slower than those of sulbactam, and urinary recovery in 12 hours was 44.4% and

35.7%, respectively [25].

Geriatric Patients

Some pharmacokinetic values in elderly patients (age 81.6 yrs) administered a single dose of

sultamicillin 500 mg were altered slightly in comparison with values reported for younger patients.

[26] 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 hrs, respectively. This indicates that

enhanced absorption and delayed elimination of sultamicillin are likely to occur to some extent in

elderly patients.

PHARMACODYNAMICS

Sultamicillin is the tosylate salt of the double ester of ampicillin plus sulbactam in a 1:1 ratio. β-

lactamase inhibitor, in combination with a β-lactam antibacterial drug of known efficacy and

safety, is one approach to the problem of bacterial resistance. The best known of these inhibitors is

sulbactam, a semi-synthetic sulphone derivative of the penicillin nucleus. It is the progressive

competitive inhibitors of β-lactamase in that they compete with the β-lactam antibacterial drug for

the active site on the β-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 [22].

 The bacteriological efficacy of β-lactams agents, and as such of ampicillin-sulbactam, is

particularly dependent on the time (T) that free serum concentration of the drugs exceed the

MIC for the target pathogen (T > MIC) [18].

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 For ampicillin-sulbactam, a T > MIC of 30 – 40% of the dosing interval is required for

maximal bacteriological efficacy against respiratory pathogens, including Streptococcus

pneumoniae [19].

 Most β-lactams agents, including ampicillin, produce a short PAE when tested against

Gram-positive cocci [20].

 Specifically, sultamicillin produced prolonged PAE (about 3 days) for exposures of 50 –

100 μg/ml for > 2 h [21].

In vitro antimicrobial activity

 Good in vitro activity of ampicillin-sulbactam in a wide range of:

 Gram-positive bacteria: e.g., S. pneumoniae, Staphylococcus aureus,

Streptococcus enterococci.

 Gram-negative bacteria: Haemophilus influenza, Moraxella catarrhalis,

Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and

 Anaerobic Bacterial Pathogens: Bacteroides fragilis, Bacteroides spp. [5]

 The drug is not active against Pseudomonas aeruginosa [25].

 It should be noted that most β-lactamase inhibitors lack significant antimicrobial activity, except

for sulbactam which is active against Bacteroides fragilis, Neisseriae (meningitides and

gonorrhoeae) and Acinetobacter spp. [26-28].

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 In general, sulbactam is effective against β-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 β-lactamases from Bacteroides fragilis.

Table- I: In vitro activity of ampicillin plus sulbactam in a 2: 1 ratio (AM/SB) compared with that of

ampicillin (AM) and sulbactam (SB) individually against unselected clinical isolates and selected β-

lactamase-producing (β+) and resistant (R) bacteria. Data derived from studies assessing at least 10 strains

of each species and using inoculums of 104 to 106 colony-forming units [12]

a- MIC90 values given based on the ampicillin concentration

b- Resistant to benzylpenicillin or ampicillin, and mezlocillin, piperacillin or ticarcillin.
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c- Resistant to ampicillin.
d- Species Included Lactobacillus spp., Bifidobacterium spp., Eubacterium lentum and Actinomyces spp.

Table: Concentrations of sulbactam (S) and ampicillin (A) in various tissues and fluids after single-

dose administration of sultamicillin to patients. [33]

a A range of values is given for the patients studied unless otherwise noted.
b tmax sulbactam, Im. xampicillin.
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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.
References: 1 Aoki et al. (1985); 2 Cho et al. 1985); 3 Jones et al. (1985); 4 Mori et al. (1985); 5 Nasu et al. (1985); 6 Reilly
et al. (1963); 7 Sakai et al. (1965); 6 Sawada et at, (1985); 9 Takase et at, (1985); 10 Tomita et al. (1985); 11 .Voelker et al.
(1965); 12 Yamamoto et at. (1985a); 13 Yura at al. (1985).

Clinical Evidence of Sultamicillin

The therapeutic efficacy of sultamicillin has been demonstrated in a number of trials in patients with a

variety of infections. e.g.

 Respiratory Tract Infections,

 ENT infections,

 UTIs, gonorrhea,

 Skin and soft tissue infections,

 Obstetric and gynaecological infections,

 Osteomyelitis/septic arthritis, and

 Infections after ophthalmological and oral surgery.

Clinical efficacy from non-comparative studies

The overall clinical efficacy of sultamicillin was 89.8% in 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 trials was 86.8% of 2,947 strains. [34]

Clinical efficacy from comparative studies [34]

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Comparative studies including 2,159 patients treated with sultamicillin have assessed the therapeutic

efficacy of sultamicillin in comparison with other 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 gonorrhea, and

 89.4% for skin and soft tissue infections.

Clinical efficacy of sultamicillin in Respiratory Tract Infections

Non-comparative trials

 The clinical efficacy of sultamicillin in various infections of the lower respiratory tract has

been reported in several non-comparative clinical trials.

 The most common infections treated were varied pneumonia, acute and chronic bronchitis,

bronchiectasis, and diffuse pan-bronchiolitis, emphysema 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, at the end of treatment, ranged from 43 to 100%.

 The wide variation in response rate is not unexpected because of:

 The variety of infections,

 The number of different causative organisms isolated,

 The varying dosage regimens (total daily dosages of 750 to 2250 mg for treatment

durations of 2 to 43 days) and

 The co-existence of underlying disease in many patients.

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Comparative trial: Sultamicillin vs. Bacampicillin. [35]

 The efficacy of sultamicillin in the treatment of lower respiratory tract infections has been

compared with that of bacampicillin, in a multicentre, randomized, double-blind, placebo-

controlled trial.

 The diagnoses included pneumonia, chronic bronchitis; diffuse panbronchiolitis, lung abscess

and infections associated with bronchiectasis, emphysema, asthma, pulmonary fibrosis,

pneumonoconiosis and inactive tuberculosis.

 A total of 134 patients received sultamicillin 375mg 3 times daily for 14 days. A further 131

patients received bacampicillin 250mg 3 times daily.

 Sultamicillin was significantly more effective (82.8% vs. 69.8%) compared to bacampicillin

group (p = 0.03).

Otorhinolaryngological Infections

Non-comparative trials of sultamicillin [36, 37, 38]

The clinical efficacy of sultamicillin in various infections of the ear, nose and throat has been reported

in several small 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.

 Clinical response with sultamicillin ranged from 75 to100%.

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Comparative trial: Sultamicillin vs. Cefaclor

 Two large double-blind studies assessed the comparative efficacy of thrice daily administration

of sultamicillin 375 mg and cefaclor 250 mg in adult patients with Otorhinolaryngological

infections.

 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. [39]

 Excellent clinical efficacy occurred in 11 of 14 sultamicillin-treated patients (78.6%) versus

only 2 of 8 cefaclor-treated patients (25.0%). [P < 0.05]

 In patients with purulent otitis media, Kawamura et al. (1985) reported an excellent or good

clinical response in 67.6% (75/111) of sultamicillin-treated patients but only 52.3% (58/111) of

cefaclor-treated patients (p < 0.05).[40]

Comparative trial: Sultamicillin vs. Amoxicillin

 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.

 Clinical efficacy rates at the end of the study were 92.8, 91.3 and 100%, respectively, with

both children initially infected by ampicillin-resistant H. influenzae being cured by

sultamicillin.

 However, at a 4-week 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).
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Urinary Tract Infections

Non-comparative trials of sultamicillin

The clinical efficacy of sultamicillin has been reported in several non- comparative trials in patients

with:

 Acute uncomplicated cystitis &

 Complicated UTIs associated with underlying urinary tract diseases.

 A total of 274 patients 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.

 Kawada (1989) noted that the eradication rate of 84.2% for high β-lactamase-producing

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%.

 The most common pathogens isolated were E. coli, Streptococcus faecalis, Proteus species, P.

aeruginosa, S. epidermidis, Serratia marcescens and K. pneumoniae. [41,42]

Skin and Soft Tissue Infections

Non-comparative trials of sultamicillin

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 The efficacy of sultamicillin administered in total daily dosages of 750 to 2250 mg for 3 to 28

days has been assessed in several non- comparative trials in patients with:

o Various Surgical Skin And Soft Tissue Infections,

o Including Infected Atheromas,

o Furuncles And Abscesses

 Efficacy rates ranged from 70.2 to 86.7% in surgical infections & from 75 to 100% in those of

non-surgical origin.

 Bacterial eradication in surgical infections ranged from 63 to 80.6% of initially infecting

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 β-

lactamase had a good to excellent clinical response, as opposed to 60% of patients infected

with low-β-lactamase-producing organisms and 73.7% of patients with non-β-lactamase-

producing organisms (Yura et al. 1985). Sakai et al. (1985) found no relation between clinical

effect and total daily dosage. [43, 44].

Comparative trials of sultamicillin vs. ampicillin, flucloxacillin

 Adult diabetic patients with various soft tissue infections were randomized to receive

sulbactam plus ampicillin, 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). [45]

 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 to sultamicillin. There were no

adverse effects of either treatment on diabetic control.

Sultamicillin vs. bacampicillin

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 A large double-blind study compared the efficacy of 3 times 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). [46]

 The clinical response occurred in 81 of 99 sultamicillin treatment patients (81.8%) and 77 of

105 bacampicillin-treated patients (74.3%).

Obstetric and Gynaecological Infections

Non-comparative trials of sultamicillin

Infections included

o Endometriosis,

o Adnexitis,

o Vulval infections,

o Puerperal mastitis, abscess,

o Pelvic peritonitis and

o Cystitis or pyelonephritis associated with cervical or ovarian cancer

 The use of sultamicillin in the treatment of obstetric and gynaecological infections in 4 non-

comparative 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 (47, 31, 32, 48).

 The bacteriological eradication rate was 82% overall.

Dosage and Administration

 The usual adult’s dose is Sultamicillin 375 mg bid is most cases and severe infections 375

mg t.i.d or 750 mg bid is advocated.

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 Since esophageal ulceration may occur if tablets lodge in the esophagus, tablets should be

taken with an adequate amount of water. A dosage adjustment may be made depending on the

patient's age and/ or symptoms, but no specific information is available on dosages for

paediatric patients.

 In patients with renal dysfunction the elimination of both sulbactam and ampicillin may be

impaired, resulting in increased serum concentrations and prolonged half-lives of both drugs.

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.

 In patients who are malnourished or debilitated, or are receiving parenteral or enteral nutrition,

the manufacturer recommends that caution should be exercised as symptoms of vitamin K

deficiency (hypo-prothrombinaemia and/or hemorrhagic tendency) may appear.

Safety and Tolerability

 Ampicillin-sulbactam or sultamicillin have been well tolerated in clinical trials both in adults

and children [6, 7].

 With regard to oral sultamicillin, a summary of data derived from 5947 patients with a variety

of community-acquired infections has provided evidence for a satisfactory tolerability profile

[7].

 Side effects were recorded in 17.9% of patients, with diarrhoea to be the most frequently

reported adverse reaction with an overall incidence of 10.4%.

 Other symptoms included soft stools (2.3%), loose stools (1.4%), nausea (1.1%) and rash

(0.9%). Discontinuation of treatment because of diarrhoea was observed in 2.8% of patients.

 Bactomin product monograph

 Clostridiun difficile or its toxin was not observed in the stools from patients with diarrhoea in

all patients.

 Ampicillin-sulbactam has been assigned to pregnancy category B by the FDA. Animal studies

have failed to reveal evidence of fetal harm. There are, however, no controlled data from

human pregnancy studies. Because animal reproduction studies are not always predictive of

human response, this drug should be used during pregnancy only if clearly indicated [49].

 Ampicillin is excreted into breast milk in low concentrations. Milk:plasma ratios have been

reported up to 0.2 [50]. Although adverse effects are apparently rare, three potential problems

exist for the nursing infant: modification of bowel flora, direct effects on the infant (e.g.,

allergic response or sensitization) and interference with the interpretation of culture results if a

fever workup is required.

Place of Sultamicillin in Therapy

 The oral use of sultamicillin is indicated in less severe infections such as acute exacerbations of

chronic bronchitis, acute or chronic sinusitis, otitis media, UTIs and cellulitis, or as a step-

down therapy for patients who have improved under parenteral therapy [51-54].

 Ampicillin-sulbactam/sultamicillin has been recommended in nationwide guidelines as

monotherapy or in combination with other antibacterials for various respiratory, intra-

abdominal, skin and soft tissue infections, and sexually transmitted diseases [55-61].

 Therapeutic trials have demonstrated the clinical efficacy of sultamicillin in infections of the
respiratory tract, urinary tract, ear, nose and throat, skin and soft tissues, and in obstetric and

gynaecological infections and gonorrhea. Results of number of controlled trials suggest at least

equivalent therapeutic efficacy to several other antibacterial drugs.

 Bactomin product monograph

 Sultamicillin has an excellent tolerability profile, which is associated with a low rate of

treatment discontinuation. The incidence of diarrhoea has been high in some patient groups.

However, diarrhoea is usually not severe enough to necessitate discontinuation of treatment.

Accordingly, sultamicillin should be considered first choice options for the management of a

variety of pediatric infections.

Therefore, the use of sultamicillin extends the antibacterial efficacy of ampicillin, a drug of

proven efficacy and safety. It also offers the advantage of allowing treatment of a seriously ill

patient to commence with parenteral sulbactam plus ampicillin, and then continue with oral

sultamicillin as the condition improves, avoiding the potentially adverse clinical and financial

effects of prolonged parenteral therapy.

 Bactomin product monograph

Conclusions

Several studies and a number of meta-analyses demonstrated the usefulness of the combination of

Sultamicillin for a number of clinical indications. Its broad spectrum of activity against several β-

lactamase-producing pathogens, combined with a favorable safety and tolerability profile, makes this

antibacterial a first-line option for the empirical treatment of mild to moderate community acquired

infections. Due to the high prevalence of MRSA, pseudomonas and ESBL-producing bacteria in the

nosocomial setting, hospital acquired infections should not be treated with ampicillin-sulbactam

empirically and treatment should be adapted on the basis of pathogen identification. However, in the

era of increasing bacterial resistance, ampicillin-sulbactam preserves its critical place in worldwide

updated guidelines for the treatment of various infections including URTIs and LRTIs, sexually

transmitted infections, intra-abdominal and skin and soft-tissue infections.

 Bactomin product monograph

CLINICAL TRIAL SUMMARY

A. RESPIRATORY TRACT INFECTIONS
SN Author year Test drug Study Design Duration N Patients Conclusion
of the
treatment

1. Ferreira JB et Sultamicillin Open label, 10 days 102 Upper 1. No difference in two groups with respect
al. 2006. 375 mg BD randomizd, Respiratory to cure at the end of treatment. Number of
Vs multi-centiric, Tract Infections patients with diaarhea was significantly
Amoxyclav 500 higher in amoxycalv grouap as compared
mg TDS
to sultamicillin.
2. Sultamicillin is as safe and effective as
amoxyclav in the empiric treatment of
Upper Respiratory Tract Infections.[54]
2. Lopez EL, Sultamicillin Single arm, 7-14 days 467 Upper and lower 1. Clinical response rate was 97% and
Rivas NA. 25-5- open label respiratory tract bacteriological eradication in 99% of
1998. mg/kg/day infections evaluable cases.
2. Sultamicillin is an efficacious first line
drug in the treatment of pediatric
infections.[62]
3. Williams D, Ampicillin/sulb Open label. 75 Community 1. Overall treatment success rates were 97%
Perri M, Zervos actam Randomized (37 acquired for ampicillin/sulbactam group as
MJ. 1994. Vs Vs pneumonia compared to 81% for cefamandole group
Cefamandole 38) 2. Both agents are effective in community
acquired pneumonia but
ampicillin/sulbactam demonstrated
superior clinical efficacy.[63]
 Bactomin product monograph

B. URINARY TRACT INFECTIONS

SN Author year Test drug Study Design Duration N Patients Conclusion
of the
treatment

1. Schutz W. Sultamicillin Open label, 10 days 132 Uncomplicate Sultamicillin is as efficacious as amoxicillin-clavulanate ,
1996. 750 mg BD randomized (66 in d Urinary and is as well tolerated, it has the advantage of requiring
Vs Multi-centric each Tract only twice-daily dosing.[64]
Amoxycillin group) Infections
clavulanate 65
mg TDS
2. Naber KG, Sultamicillin Open label, 7 days 38 Urinary Tract 1. Sultamicillin eradicated bacteriuria during
Wittlenberger 375 mg BD randomized (19 in Infetions and 1-2 weeks after therapy in 63% of
R. 1989. Vs each sultamicilin patients as against 50% in
Trimethoprim/s group) trimethoprim-sulfomethoxazole group.
ulfamethoxazol
2. Sultamicillin is as effective and safe as
e (160 mg/800
mg) BD trimethoprim-sulfomethoxazole in the
treatment of Urinary Tract Infections.[65]
3. Kawada Y. Sultamicillin Randomized 5 days 224(113 Complicated 1. The overall bacteriological eradication was
1985. 1125 mg/day double blind Vs Urinary Tract 81.7% in sultamicillin group as compared to
Vs multicentric 111) Infections 61.5% in cefadroxil group.
Cefadroxil 750 2. Inspite of the side effects recorded
mg/day
sultamicillin is very useful agent in the
treatment of complicated Urinary tract
Infections.[66]
 Bactomin product monograph

C. ENT INFECTIONS
SN Author year Test drug Study Design Duration N Patients Conclusion
of the
study

1. Topuz B et al. Sultamicillin Randomized 10 days 108 Acute sinusitis 1. Sultamicillin had similar clinical success
2002 375 mg BD (66 Vs rate as compared to amoxicillin.
Vs 42) 2. Side effects were significantly lower in
Amoxycillin sultamicillin as compared to amoxicillin.[67]
500 mg TDS
2. Federspil P et Sultamicillin Open label, 10 days 135 Tonsillitis, 1. 100% clinical cure in sultamicilin group as
al. 1989 500 mg BD randomized, Pharyngitis, against 95.2% in amoxicillin group and
Vs Multi centric Peritonsillar 83% bacteriological eradication in
Amoxycillin abscess sultamicillin group as against 68% in
500 mg TDS
amoxicillin group.
2. Sultamicillin is an useful agent in the
treatment of pharyngitis and tonsillitis.[68]
3. Alvart R. 1992. Sultamicillin Open label, Sultamicil 110 Acute ENT 1. 100% clinical cure in sultamicillin group as
750mg OD or Randomized lin 8.1 +/- (55 infections compared to 94.5% in cefuroxime group.
1500 mg OD 1.5 days Vs 55) 2. Sultamicillin is as safe and effective as
Vs Vs cefuroxime in the treatment of acute ENT
Cefuroxime 500 Cefuroxi
infections.[69]
mg OD or me
1000 mg OD 7.9 +/- 1.6
days,
4. Rodriguez WJ. Sultamicillin Open label, 10 days 86 Acute ottis Sultamicillin was comparable to amoxycillin in the
1990. 500 mg/day Randomized media in treatment of acute otitis media.[70]
Vs children
Amoxycillin
250 mg/day

5. Biolcati AH. Sultamicillin 50 Open label, 11 days 60 Acute ottis 1. Sultamicillin was as efficacious as cefaclor
1992. mg/kg/day randomized (30 in media in in the treatment of acute ottitis media in
Vs each children children.
Cefaclor group) 2. Adverse events were reported in 33% of
40 mg/kg/day
sultamicillin group as against 33% in
cefaclor group implying better tolerability
of sultamicillin[71]
6. Chan KH et al. Sultamicillin 50 -Randomized, -10 days 144 Acute ottis Sultamicillin may be an alternative for the treatment of
mg/kg/day double blind (96 media in acute otitis media due to persistent or recurrent ottitis
 Bactomin product monograph

SN Author year Test drug Study Design Duration N Patients Conclusion

of the
study

Vs Vs children medis.[72]
Amoxycillin 48)
clavulanate

D. SKIN AND SOFT TISSUE INFECTIONS

SN Author year Test drug Study Duratio N Patients Conclusion
Design n of the
treatme
nt

1. Goldfarb J et al. Sultamicillin was Double- 7 days 52 Superficial skin 1. 16 of 21 in the sultamicillin group and
administered as 250 mg twice blind, and soft tissue 13 of 21 in the cloxacillin group were
daily to children under 5 randomized infections in cured.
years, 500 mg twice daily to children 2. One child in the sultamicillin group
those over 5 years, and 750
andtwo in the cloxacillin group failed
mg twice daily to those over
20 therapy.
kg. 3. Sultamicillin therapy appeared to be
Cloxacillin was given as 50 at least equivalent to standard oral
mg/kg per day to children therapy for the
under 20 kg and 250 mg four treatment of superficial skin and soft
times daily > 20 kg.. tissue infections[73]

E. OBSTETRIC AND GYNECOLOGICAL INFECTIONS

SN Author year Test drug Study Duratio N Patients Conclusion

Design n of the
treatme
nt

1. Cho N et Sultamicillin was Non 26 cases of OBGY 1. 100% clinical efficacy and 88.9%
al.1985. administered as 1125 mg per comparativ OBGY infections microbiological efficacy
day e infections and UTI 2. Sultamicillin is both safe and
and 14 cases effective in the treatment of obstetric
of UTI
and gynecological infections.[74]
 Bactomin product monograph

F. MISCELLANEOUS
SN Author year Test drug Study Duratio N Patients Conclusion
Design n of the
treatme
nt

1. Mirbagheri Group A:Triple therapy Three 10 days 360 H.pylori positive Ampicillin sulbactam based quadruple
SA,Hasibi M, (Omeprazole 20 mg BD, arm, (120 in patients with regimen yeilde highest eradication rates
Abouzari M, Amoxycillin randomi each dyspepsia as compared to amoxicillin based
Rashidi A. 1000 mg BD, Clarithromycin 500 zed group) quadruple regimen and standard triple
2006. mg BD) therapy. Hence it is a suitable first line
Vs alternative to be used in regions with
Group B: Quadruple therapy amoxicillin-resistant H pylori strains.[75]
(Omeprazole 20 mg BD,
Amoxycillin
1000 mg BD, Colloidal bismuth
subcitrate 240 mg BD and
metronidazole500 mg BD)
AND
Group C: Quadruple therapy
(Omeprazole 20 mg BD,
Sultamicilin 375 mg
i.e ampicillin 225 plus sulbactam
150 mg BD, Colloidal bismuth
subcitrate 240 mg BD and
metronidazole500 mg BD)

2. Goker K, Sultamicillin Vs Open 5 days 100 Patients with Sultamicillin, Ofloxacin, Clindamycin are
Guvener O. Ofloxacin label, (25 in surgical removal of equiefficacious in decreasing the risk of
1992. Vs randomi each impacted postoperative infection and
Clindamycin zd group) mandibular third bacteraemia.[76]
Vs molars
Placebo
3. Aronoff SC et Ampicillin (50 mg/kg per dose) Open 21 days 9 Skeletal infections The regimen of parenteral
al. 1986. and sulbactam (12.5 mg/kg per label for septic in children sulbactam/ampicillin and oral
dose) parenterally at 6-hr intervals arthritis sultamicillin used sequentially is effective
for 6-11 days days followed by and 30 and safe for the treatment of skeletal
sultamicillin 25 mg/kg dose every days for infections in children. This significantly
6 hours. osteomye reduces the duration of hospitalization in
litis such patients.[77]
4. Chang ST, Sequential treatment with Open- Parentera 140 Various medical and 1. Overall 98% of 114 evaluable
 Bactomin product monograph

SN Author year Test drug Study Duratio N Patients Conclusion

Design n of the
treatme
nt

Chung HY, Pai parenteral sulbactam/ampicillin label l therapy surgical infections: patients achieved clinical cure
SD, Lee JH. and oral sultamicillin for 7-14 Intraabdominal (42 while 86% achieved
1989. days cases), respiratory microbiological eradication.
tract (52 cases), skin 2. Cured or improved patients in
and soft tissue (29
each diagnostic group were
cases), urinary tract
(16 cases), and 97% for
miscellaneous intraabdominalinfections,
infections (14 cases) 100% for respiratory
tract infections, 100% for
skin and soft tissue infections,
100% for urinary tract
infection, and 91% for other
types of infections.
3. Sultamicillin following
parenteral ampicillin-
sulbactam is very safe and
effective in various
complicated medical and
surgical infections.[51]
 Bactomin product monograph

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 Bactomin product monograph

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field.Chemotherapy. 1985; 33(2): 714-29.
75. Mirbagheri SA, Hasibi M, Abouzari M, Rashidi A. Triple, standard quadruple and ampicillin-sulbactam-based
quadruple therapies for H. pylori eradication: a comparative three-armed randomized clinical trial. World J
Gastroenterol. 2006 ;12(30):4888-91.
76. Göker K, Güvener O. Antibacterial effects of ofloxacin, clindamycin and sultamicillin on surgical removal of
impacted third molars. J Marmara Univ Dent Fac. 1992 ;1(3):237-49
77. Aronoff SC et al. Efficacy and safety of sequential treatment with parenteral sulbactam/ampicillin and oral
sultamicillin for skeletal infections in children. Rev Infect Dis. 1986 ;8 Suppl 5:S639-43.

For the use of a Registered Medical Practitioner of Hospital or Laboratory only

PRESCRIBING INFORMATION
BACTOMIN

COMPOSITION:
BACTOMIN 375 mg Film-Coated Tablet: Each tablet contains 375 mg sultamicillin (as tosylate)
which is the equivalent of 147 mg sulbactam and 220 mg ampicillin.
BACTOMIN 750 mg Film-Coated Tablet: Each tablet contains 750 mg sultamicillin (as tosylate)
which is the equivalent of 294 mg sulbactam and 440 mg ampicillin.

DESCRIPTION
 Bactomin product monograph

Sultamicillin is a double ester in which ampicillin and the beta-lactamase inhibitor sulbactam are
linked via a methylene group.

Figure: Structure of Sultamicillin

 Chemical name: oxymethylpenicillinate sulphone ester of ampicillin

 Molecular weight: 594.7.

CLINICAL PHARMACOLOGY
Pharmacodynamics
Biochemical studies with cell-free bacterial systems have shown sulbactam to be an irreversible
inhibitor of most important beta-lactamases that occur in penicillin-resistant
organisms. While sulbactam antibacterial activity is mainly limited to Neisseriacea, the potential
for sulbactam sodium in preventing the destruction of penicillins and cephalosporins by resistant
organisms was confirmed in whole organism studies using resistant strains, in which sulbactam
sodium exhibited marked synergistic effects with penicillins and cephalosporins. Since sulbactam
also binds to some penicillin-binding proteins, some sensitive strains are rendered more
susceptible to the combination than to the beta-lactam antibiotic alone.
The bactericidal component of this product is ampicillin which, like benzyl penicillin, acts against
sensitive organisms during the stage of active multiplication by the inhibition of biosynthesis of
cell wall mucopeptide.

Pharmacokinetics
Following oral administration in humans, sultamicillin is hydrolysed during absorption to provide
sulbactam and ampicillin in a 1:1 molar ratio in the systemic circulation. The bioavailability of an
oral dose is 80% of an equal intravenous dose of sulbactam and ampicillin. Administration
 Bactomin product monograph

following food does not affect the systemic bioavailability of sultamicillin. Peak serum levels of
ampicillin following administration of sultamicillin are approximately twice those of an equal
dose of oral ampicillin. Elimination half-lives are approximately 0.75 and 1 hour for sulbactam
and ampicillin respectively in healthy volunteers, with 50-75% of each agent being excreted in the
urine unchanged. Elimination half-lives are increased in the elderly and in patients with renal
dysfunction. Probenecid decreases the renal tubular secretion of both ampicillin and sulbactam.
Concurrent use of probenecid with sultamicillin results in increased and prolonged blood levels of
ampicillin and sulbactam.
MICROBIOLOGY
Sultamicillin is effective against a wide range of gram-positive and gram-negative bacteria
including: Staphylococcus aureus and S. epidermidis (including penicillin-resistant and some
methicillin resistant strains); Streptococcus pneumoniae, Streptococcus faecalis and other
Streptococcus species; Haemophilus influenzae and H. parainfluenzae (both beta-lactamase
positive and negative strains); Moraxella catarrhalis; anaerobes including Bacteroides fragilis
and related species; Escherichia coli; Klebsiella species; Proteus species (both indole-positive
and indole-negative); Enterobacter species; Morganella morganii; Citrobacter species; Neisseria
meningitidis and Neisseria gonorrhoeae.

INDICATIONS:
Sultamicillin is indicated for infections caused by susceptible micro-organisms. Typical
indications are:
 Upper respiratory tract infections including sinusitis, otitis media and tonsillitis
 Lower respiratory tract infections including bacterial pneumonias and bronchitis
 Urinary tract infections and pyelonephritis
 Skin and soft tissue infections
 Intra-abdominal infections and
 Gonococcal infections.
 Sultamicillin may also be indicated in patients requiring sulbactam/ampicillin therapy
following initial treatment with sulbactam/ampicillin IM/IV.

DOSAGE & ADMINISTRATION

 Bactomin product monograph

The recommended dose of sultamicillin in adults (including elderly patients) is 375-750 mg orally
twice daily.
In both adults and children treatment is usually continued until 48 hours after pyrexia and other
abnormal signs have resolved. Treatment is normally given for 5-14 days but the treatment period may
be extended if necessary.
In the treatment of uncomplicated gonorrhea, sultamicillin can be given as a single oral dose of 2.25
grams (six 375 mg tablets). Concomitant probenecid 1.0 gram should be administered in order to
prolong plasma concentrations of sulbactam and ampicillin.
Cases of gonorrhea with a suspected lesion of syphilis should have dark field examinations before
receiving sultamicillin and monthly serological tests for a minimum of four months.
It is recommended that there be at least 10 days treatment for any infection caused by hemolytic
streptococci to prevent the occurrence of acute rheumatic fever or glomerulonephritis.
Use in Children and Infants
For children weighing less than 30 kg the dosage of sultamicillin for most infections is 25-50
mg/kg/day orally in 2 divided doses depending on the severity of the infection and the physician's
judgment.
For children weighing 30 kg or more the usual adult dose should be given.
Use in Patients with Renal Impairment
In patients with severe impairment of renal function (creatinine clearance 30 ml/min), the elimination
kinetics of sulbactam and ampicillin are similarly affected and hence the plasma ratio of one to the
other will remain constant. The dose of sultamicillin in such patients should be administered less
frequently in accordance with usual practice for ampicillin.
CONTRAINDICATIONS
BACTOMIN is contraindicated in patients with known hypersensitivity to any of its ingredients or
with a history of an allergic reaction to any of the penicillins.

USE IN SPECIAL POPULATIONS

Pregnancy
Animal reproduction studies have revealed no evidence of impaired fertility or harm to the fetus due to
sultamicillin. Sulbactam crosses the placental barrier. However, safety for use in human pregnancy has not
 Bactomin product monograph

been established. Therefore, sultamicillin should be used during pregnancy only if the potential benefits
outweigh the potential risk.
Lactation
The use of sultamicillin during lactation is not recommended. Low concentrations of ampicillin and
sulbactam are excreted in the milk. This should be considered as the neonate may be exposed, particularly
since renal function is not fully developed in neonates.

WARNING AND PRECAUTIONS

 Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in
patients on penicillin therapy including sultamicillin. These reactions are more apt to occur in
individuals with a history of penicillin hypersensitivity and/or hypersensitivity reactions to
multiple allergens. Before therapy with penicillin, careful inquiry should be made concerning
previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an
allergic reaction occurs, the drug should be discontinued and the appropriate therapy instituted.
 Serious anaphylactic reactions require immediate emergency treatment with adrenaline.
oxygen, intravenous steroids, and airway management, including intubation, should be
administered as indicated.
 As with any antibiotic preparation, constant observation for signs of overgrowth of
nonsusceptible organisms, including fungi, is essential. Should superinfection occur, the drug
should be discontinued and/or appropriate therapy instituted.
 Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including sultamicillin, and may range in severity from mild diarrhea to
fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over
two months after the administration of antibacterial agents.
 Since infectious mononucleosis is viral in origin, ampicillin should not be used in the
treatment. A high percentage of patients with mononucleosis who receive ampicillin develop a
skin rash.
 It is advisable to check periodically for organ system dysfunction during prolonged therapy;
this includes renal, hepatic and hematopoietic systems.
 Bactomin product monograph

 The principal route of excretion of sulbactam and ampicillin following oral administration of
sultamicillin is via the urine. Because renal function is not fully developed in neonates, this
should be considered when using sultamicillin in neonates.
 Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicine

DRUG INTERACTIONS
1. Allopurinol: The concurrent administration of allopurinol and ampicillin increases
substantially the incidence of rashes in patients receiving both drugs as compared to patients
receiving ampicillin alone.
2. Anticoagulants: Penicillins can produce alterations in platelet aggregation and coagulation
tests. These effects may be additive with anticoagulants.
3. Bacteriostatic drugs (chloramphenicol, erythromycin, sulfonamides and tetracyclines):
Bacteriostatic drugs may interfere with the bactericidal effect of penicillins; it is best to avoid
concurrent therapy.
4. Estrogen-containing oral contraceptives: There have been case reports of reduced oral
contraceptive effectiveness in women taking ampicillin, resulting in unplanned pregnancy.
Although the association is weak, patients should be given the option to use an alternate or
additional method of contraception while taking ampicillin.
5. Methotrexate: Concurrent use with penicillins has resulted in decreased clearance of
methotrexate and a corresponding increase in methotrexate toxicity. Patients should be closely
monitored. Leucovorin dosages may need to be increased and administered for longer periods
of time.
6. Probenecid: Probenecid decreases renal tubular secretion of ampicillin and sulbactam when
used concurrently; this effect results in increased and prolonged serum concentrations,
prolonged elimination half-life, and increased risk of toxicity.
7. Laboratory Test Interactions: False positive glycosuria may be observed in urinalysis using
Benedict reagent, Fehling reagent, and Clinitest. Following administration of ampicillin to
pregnant women, a transient decrease in plasma concentration of total conjugated estriol,
estriol-glucuronide, conjugated estrone and estradiol has been noted. This effect may also
occur with sulbactam sodium/ampicillin sodium IM/IV.
 Bactomin product monograph

ADVERSE EFFECTS
Sultamicillin is generally well tolerated. The majority of the side effects observed were of mild or
moderate severity and were normally tolerated with continued treatment.
Infections and Infestations: Pseudomembranous colitis.
Immune System Disorders: Anaphylactic Shock, Anaphylactic reaction, Hypersensitivity
Nervous System Disorders: Dizziness, Somnolence, Sedation, Headache.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea.
Gastrointestinal Disorders: Enterocolitis, Melaena, Diarrhoea, Vomiting, Abdominal pain Dyspepsia,
Nausea.
Skin and Subcutaneous Tissue Disorders: Angioedema,urticaria, dermatitis, Rash, Pruritus.
General Disorders and Administration Site Conditions: Fatigue, Malaise.

Adverse reactions associated with use of ampicillin alone may be observed with sultamicillin. Adverse
reactions associated with the use of ampicillin and/or sulbactam/ampicillin IM/IV include:
Blood and Lymphatic System Disorders: agranulocytosis, hemolytic anaemia, thrombocytopenic
purpura, thrombocytopenia, leukopenia, Neutropenia, eosinophilia, anaemia.
Nervous System Disorders: Convulsion.
Gastrointestinal Disorders: Glossitis, Stomatitis, Tongue discolouration.
Hepatobiliary Disorders: Cholestasis, Cholestasis hepatic, Bilirubinaemia, Hepatic function abnormal,
Jaundice.
Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome,
Erythema multiforme, Dermatitis exfoliative.
Renal and Urinary Disorders: Tubulointerstitial nephritis.
Investigations: Platelet aggregation abnormal, Alanine aminotransferase increased, Aspartate
aminotransferase increased.

OVERDOSAGE
Limited information is available on the acute toxicity of ampicillin sodium and sulbactam sodium in
humans. Overdosage of the drug would be expected to produce manifestations that are principally
extensions of the adverse reactions reported with the drug. The fact that high CSF concentrations of -
 Bactomin product monograph

lactam antibiotics may cause neurologic effects, including seizures, should be considered. Because
ampicillin and sulbactam are both removed from the circulation by hemodialysis, these procedures
may enhance elimination of the drug from the body if overdosage occurs in patients with impaired
renal function
.

PRESENTATION
Verify presentation

STORAGE
To be filled by R & D