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Bacampicillin

Bacampicillin is a penicillin antibiotic and is a prodrug of ampicillin with improved oral bioavailability [1]. It is absorbed following oral administration. During absorption from the gastrointestinal tract, bacampicillin is hydrolyzed by esterases present in the intestinal wall. It is microbiologically active as ampicillin, and exerts a bactericidal action through the inhibition of the biosynthesis of cell wall mucopeptides. It is used to cure infection of upper and lower respiratory tract; skin and soft tissue; urinary tract and acute uncomplicated gonococcal urethritis.

Therapeutic use

For infections at the following sites: upper and lower respiratory tract; skin and soft tissue; urinary tract and acute uncomplicated gonococcal urethritis, when due to sensitive strains of the following organisms: Gram-positive: streptococci (including S. faecalis and S. pneumoniae) and nonpenicillinase-producing staphylococci; Gram-negative: H. influenzae, N. gonorrhoeae, E. coli, P. mirabilis, Salmonellae and Shigellae. Bacampicillin also has activity against certain spirochetes, including Treponema pallidum and Borrelia bugdorferi.

Dosage and Administration

Adult  (>25 kg):

Upper respiratory tract infections, Urinary tract infections, skin infections:

400 mg q12h; treat for a minimum of 48-72 hours after the patient becomes asymptomatic

Severe infections:

800 mg q12h; treat for a minimum of 48-72 hours after the patient becomes asymptomatic

Uncomplicated Gonorrhea

1.6 g once coadministered with 1g of probenecid

Pediatric:

Upper respiratory tract infections, Urinary tract infections, skin infections:

25 mg/kg/day in two divided doses q12h; treat for a minimum of 48-72 hours after the patient becomes asymptomatic

Severe infections:

50 mg/kg/day in two divided doses q12h; treat for a minimum of 48-72 hours after the patient becomes asymptomatic

Disease state based dosing:

Creatinine Clearance > 50 mL/min: dosing interval is every 6 hours

Creatinine Clearance10 to 50 mL/min: dosing interval is every 6 to 12 hours

Creatinine Clearance < 10 mL/min: dosing interval is every 12 to 24 hours

Hepatic failure: No dosing adjustment necessary
 

Toxicology

LD50 in mice (mg/kg): 8529 orally; 176 i.p.; 9475 s.c.; 184 i.v

Adverse effects

Bacampicillin use is associated with gastrointestinal disturbances, rash, and hypersensitivity reactions. Gastrointestinal effects include, nausea, vomiting, anorexia, diarrhea, and gastritis. Bacampicillin causes less diarrhea than ampicillin since it is better absorbed and has less of an effect on the intestinal flora. Clostridium difficile colitis can occur with bacampicillin therapy. Hypersensitivity reactions include, rash, angioedema, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, and serum sickness-like reactions. Anaphylaxis can also occur with bacampicillin therapy. Both unicarial and nonimmunologic maculopapular rashes are associated with aminopenicillins, with the incidence of rash being greatest in those with a viral disease. A very high incidence of rash is seen in patients with mononucleosis. Hematologic reactions to ampicillin include eosinophilia, hemolytic anemia, leukopenia, neutropenia, agranulocytosis, and thrombocytopenia. Rare cases of acute Bacampicillin interstitial nephritis have been reported with ampicillin.

Hematologic: anemia, thrombocytopenia, neutropenia, agranulocytosis

CNS: seizures

Renal: nephrotoxicity

Hepatic: transient increases in transaminases

Other: Jarisch-Herxheimer Reaction (fever, chills, sweating, tachycardia, hyperventilation, flushing, and myalgia)
 

Pharmacokinetic

In vivo the transformation into ampicillin is so rapid that no unchanged compound could be detected in the blood after oral administration of bacampicillin to rats, dogs, and humans. On oral administration to mice, rats, and dogs, bacampicillin was found to be better absorbed than ampicillin, giving higher and earlier peak blood levels of ampicillin. The bioavailability of bacampicillin in rats and dogs was three to four times higher than that of an equimolar amount of ampicillin.

Each mg of bacampicillin hydrochloride is equivalent to 623727 mg of ampicillin.

Hydrolysis. The formation of ampicillin as the microbiologically active product of hydrolysis of bacampicillin both in vitro and in vivo could be demonstrated. The compound was comparatively stable in synthetic gastric juice and in neutral buffer solution, but the hydrolysis to ampicillin was greatly enhanced by dilute human or rat serum (Table 1).

Table 1. Hydrolysis of bacampicillin and pivampicillin to ampicillin in various media (30 minutes, % of hydrolysis at 37C)*.

Compound Phosphate buffer

(pH 7.4)

Phosphate buffer + 10% human serum Phosphate buffer + 10% rat serum synthetic gastric juice

(pH 1.2)

bacampicillin 3.20.7 54.45.8 95.07.4 0.240.02
bacampicillin A epimer 3.00.2 67.65.0 1006.7 0.270.05
bacampicillin B epimer 2.90.2 32.42.1 1065.0 0.280.03
pivampicillin 5.40.3 10.21.4 1015.8 0.240.04

* Mean of 10 observations plus standard error of the mean.

Human blood and plasma and canine plasma in vitro at 37C hydrolyzed bacampicillin approximately according to first-order kinetics, with half-lives of 5.2, 7.2, and 8.3 min, respectively (Figure 1).

Figure 1. In vitro hydrolysis at 37C of bacampicillin in heparinized human blood (0), human plasma (), and canine plasma (Δ).

 

Bioavailability 80-98%
Protein binding 17-20
Metabolism Rapidly hydrolyzed to ampicillin
Half-life 1.3 hrs
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd 27 l (0.28l/kg)
Clearance  
Excretion renal 73% (Approximately 6083% of an oral dose of bacampicillin is excreted in urine as unchanged ampicillin)

Absorption

The compound is stable in vitro at gastric pH and hydrolyzed slowly to ampicillin at neutral pH but very rapidly in the presence of biological fluids, e.g., tissue homogenates or serum. After oral administration to rats, bacampicillin was rapidly absorbed to give earlier and much higher peak levels of ampicillin compared to ampicillin itself (Figure 2). After equimolar (40 mmolIkg) doses of [35S]bacampicillin hydrochloride (20 mg/kg) and [35S]ampicillin (14 mg/kg), peak plasma levels were 8.1 and 1.8 mg/ml, respectively. From linear plots of concentration of biological activity versus time the areas under the curves indicated a 3.7 times larger bioavailability of bacampicillin than of ampicillin. The better bioavailability of bacampicillin was also indicated by the recovery of 35% of the radioactive dose in the urine, against only 16% after administration of ampicillin.

Figure 2. Plasma concentrations of total radioactivity and biological activity in rats after single oral, equimolar doses (40 mmol/kg) of [35S]bacampicillin hydrochloride (20 mg/kg, ο, ) and [35S]ampicillin (14 mg/kg, , ). Each point represents the mean value of five animals. Bars indicate the standard error of the mean. Filled symbols, Total radioactivity; open symbols, biological activity.

In three dogs receiving oral equimolar (40 mmol/kg) doses of [35S]bacampicillin (20 mg/kg) and [35S]ampicillin (14 mg/kg) in a crossover fashion, the former was more efficiently and consistently absorbed, giving higher peak levels (Table 2). From linear plots of biological activity versus time, it was estimated that the areas under curves for bacampicillin were about three times higher than those for ampicillin. In the case of bacampicillin, an average 55% of the radioactive dose given was recovered in the urine compared to 27% in the case of ampicillin.

Table 2. Plasma concentrations of ampicillin by microbiological assay after oral administration of equimolar (40 mmol/kg) amounts of bacampicillin hydrochloride (20 mg/kg) and ampicillin (14 mg/kg) to three dogs in a crossover experiment.

Dog n. Compound Plasma conc. (mg/ml)
5min 10min 20min 40min 1hr 1.5 hrs 2hrs 4hrs 8hrs
1 bacampicillin 0.13 1.0 2.5 4.0 2.8 2.5 1.3 0.71 0.13
  ampicillin 0.17 0.76 2.2 2.3 1.9 1.5 0.69 0.18 0.02
2 bacampicillin 0.11 0.89 4.2 6.8 6.6 4.7 3.4 0.60 0.10
  ampicillin 0.02 0.03 0.11 0.48 0.49 1.8 3.3 3.3 0.14
3 bacampicillin 0.02 0.09 0.65 5.4 3.9 2.6 2.5 0.70 0.13
  ampicillin 0.02 0.12 0.79 1.1 0.94 0.68 0.45 0.11 0.02

In rats as well as in dogs, the levels of radioactivity in plasma and urine were higher for both compounds than those of biological activity. This was due to biotransformation of ampicillin, leading mainly to antibacterially inactive penicilloate. The recovery of radioactivity was complete for both compounds. The amounts not accounted for in the urine were excreted with the feces.

Distribution

Since only ampicillin, not bacampicillin, could be found circulating in the blood after oral administration of the latter, the antibiotic being distributed in the body must be ampicillin. The penetration of it into organs and tissues after oral administration of bacampicillin and ampicillin was compared in two studies in rats receiving equimolar amounts (270 mmol/kg) of the two compounds. The peak blood levels obtained with this dose again appeared higher after bacampicillin than after ampicillin (Table 3; Figure 3). The results indicated a longer duration of the transudate than of the blood levels for both compounds, with a statistically significant difference (P < 0.05) in the case of bacampicillin 4 hrs after administration.

Table 3. Blood and transudate concentrations ofampicillin after oral administration ofequimolar amounts (270 mmol/kg) of bacampicillin hydrochloride (135 mg/kg) and sodium ampicillin (100 mg/kg) to rats with subcutaneous coil springs. Mean of four to six observations plus standard error of the mean.

Compound Concentration of ampicillin (mg/ml)
0.25 hrs 0.5 hrs 0.75 hrs 1 hr 1.5 hrs 2 hrs 3 hrs 4 hrs
Blood                
bacampicillin 33.8316.5 2.24.0 5.380.53 4.990.83 4.610.88 3.100.68 1.350.12 1.10.35
ampicillin 10.45.60 4.280.94 6.421.01 5.160.65 3.130.62 2.850.61 2.121.06 1.190.74
Trasudate                
bacampicillin 0.140.05 0.450.12 1.00.30 2.631.14 1.440.34 3.430.65 3.821.24 3.990.86
ampicillin ND 0.160.10 0.550.13 0.720.09 0.590.12 0.950.20 1.200.24 1.970.21

 

Figure 3. Blood and transudate concentrations of ampicillin after oral administration of equimolar amounts (270 mmol/kg) of bacampicillin hydrochloride (135 mg/kg, ο, ) and sodium ampicillin (100 mg/kg, , ) to ratg with subcutaneous coil springs.
Open symbols, Blood concentrations; filled symbols,
transudate concentrations.

Analysis of homogenates of kidney and liver showed three to four times higher levels of ampicillin after administration of bacampicillin than after ampicillin (Table 4). In the spleen bacampicillin gave slightly higher levels.

Table 4. Ampicillin concentrations in organ homogenates after oral administration of equimolar amounts (270 mmol/kg) of bacampicillin hydrochloride (135 mg/kg) and sodium ampicillin (100 mg/kg) to rats. Mean of four observations plus standard error of the mean.

Compound

Tissue

Concentration of ampicillin (mg/ml)
0.5 hrs 1 hr 1.5 hrs 2 hrs 3 hrs 4 hrs
bacampicillin kidney 31.13.7 35.28.2 35.79.4 43023.7 22.011.3 14.54.7
liver 27.83.3 26.12.2 25.93.3 14.92.4 7.91.3 3.90.4
spleen 1.70.3 1.10.1 1.60.3 1.00.1 0.50.1 0.30.1
ampicillin kidney 9.91.2 12.14.5 9.31.7 11.95.1 7.72.2 3.61.1
liver 7.30.9 7.01.0 5.70.6 5.00.3 4.30.6 2.10.3
spleen 1.20.6 1.30.7 0.40.1 0.30.1 0.30.03 0.40.3

Excretion

 

Metabolism

 

Mechanism of Action

During absorption from the gastrointestinal tract, bacampicillin is hydrolyzed by esterases present in the intestinal wall. It is microbiologically active as ampicillin, and exerts a bactericidal action through the inhibition of the biosynthesis of cell wall mucopeptides.

Antibacterial activity

Gram positive bacteria:  Streptococcus spp., Enterococcus, Listeria monocytogenes

Gram negative bacteria:  H. influenzae, E. coli, Proteus mirabilis, Salmonella spp., Shigella spp.

In vivo efficacy

On oral treatment of experimentally infected mice, bacampicillin was found to be more active than ampicillin. Orally administered bacampicillin showed good activity against experimental infections in mice caused by various Gram-positive and Gram-negative bacteria. When the compounds were given directly after the animals had been infected, bacampicillin was found to be as active as, or more active than, ampicillin against nine of the eleven organisms tested (Tables 5 and 6).

In one series of experiments with H. influenzae, the penicillins were, given 4 hrs after infection. It is likely that under such conditions the infection will be more severe as the bacteria are given time to establish themselves in the tissues of the animals. In accordance with this, much higher doses of the penicillins were needed to cure the animals of the infection (Table 6). However, it was also found that bacampicillin in this case was relatively more effective than ampicillin than when the animals were treated directly after the infection.

Table 5. Activity of bacampicillin hydrochloride and ampicillin against experimental infections in mice when administered orally immediately after infection.

Infecting organism Challenge (LD50)a CD50 (mg/kg)b
bacampicillin ampicillin
Diplococcus pneumoniae type II 8.1 <0.6 0.8
12.0 0.9 1.4
23.0 0.6 1.1
32.0 3.6 3.0
38.6 6.1 6.5
40.0 8.1 3.5
Listeria monocytogenes 24.0 13.7 14.0
28.0 12.2 13.5
48.0 16.7 19.0
Staphylococcus aureus Smith 3.3x104 0.6 0.8
  >105 <0.6 1.0
  >106 1.3 0.8
Streptococcus faecalis 4.3 48.8 58.0
4.3 44.8 52.0
5.5 17.1 46.5
Streptococcus pyogenes 143.0 <0.1 0.5
647.0 0.4 0.8
>105 1.2 3.6
>105 4.6 11.0
Escherichia coli 2.6 3.0 10.0
2.8 9.5 2.0
3.2 12.9 35.5
Klebsiella pneumoniae 26.0 12.9 35.5
60.0 6.5 10.5
100.0 4.9 9.0
Pasteurella multocida 7.9x104 13.5 9.5
>105 12.5 21.0
>105 23.6 11.5
Proteus mirabilis 226 8.5 9.5
270 4.0 12.5
316 5.2 13.5
Proteus vulgaris 1.1 214 105
1.4 170 125
2.8 214 315

a LD50. The dose of bacteria required to kill 50% of the mice.
b CD50. Median curative dose.

Table 6. Activity of bacampicillin hydrochloride and ampicillin against experimental H.influenzae infections in mice when administered immediately or 4 hrs after infection.

Challenge (LD50)a

CD50 (mg/kg)b

administered immediately after infection administered 4 hrs after infection
bacampicillin ampicillin bacampicillin ampicillin
38.3 3.0 3.5    
631 3.0 3.0    
3100 4.5 4.5    
26300     56 95
2000     25 125
266     12.5 17.5
1000     24.0 113
310     19.5 105

a LD50. The dose of bacteria required to kill 50% of the mice.
b CD50. Median curative dose.

 

Other pharmacological effects

 


Medicinal Chemistry

CAS number:  50972-17-3 EINECS:

Molecular Formula:  C21H27N3O7S

Average mass: 465.519989 Da

Monoisotopic mass:  465.156982 Da

Systematic name: 1-[(Ethoxycarbonyl)oxy]ethyl (2S,5R,6R)-6-{[(2R)-2-amino-2-phenylacetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

SMILES: C1([C@@H](NC(=O)[C@@H](c2ccccc2)N)[C@H]2SC([C@@H](N12)C(O[C@@H](C)OC(OCC)=O)=O)(C)C)=O

Std. InChI: 1S/C21H27N3O7S/c1-5-29-20(28)31-11(2)30-19(27)15-21(3,4)32-18-14(17(26)24(15)18)23-16(25)13(22)12-9-7-6-8-10-12/h6-11,13-15,18H,5,22H2,1-4H3,(H,23,25)/t11?,13-,14?,15+,18-/m1/s1

ACD/LogP: 2.090.90 # of Rule of 5 Violations: 1
ACD/LogD (pH 5.5): 0.86 ACD/LogD (pH 7.4): 2.01
ACD/BCF (pH 5.5): 1.36 ACD/BCF (pH 7.4): 18.85
ACD/KOC (pH 5.5): 19.44 ACD/KOC (pH 7.4): 270.38
#H bond acceptors: 10 #H bond donors: 3
#Freely Rotating Bonds: 11 Polar Surface Area: 162.56 2
Index of Refraction: 1.607 Molar Refractivity: 116.90.4 cm3
Molar Volume: 338.35.0 cm3 Polarizability: 46.30.5 10-24cm3
Surface Tension: 62.25.0 dyne/cm Density: 1.40.1 g/cm3
Flash Point: 364.131.5 C Enthalpy of Vaporization: 99.63.0 kJ/mol
Boiling Point: 678.455.0 C at 760 mmHg Vapour Pressure: 0.02.1 mmHg at 25C

Major Impurities:

Appearance: White crystals from acetone-petr ether

Melting point: 171-176C

Optical rotation: [a]D20 +161.5

Solubility: soluble in water and in dichloromethane, freely soluble in alcohol and in chloroform, and very slightly soluble in ether.

logP:

pKa: 6.8

pH: The pH of a 2% aqueous solution is between 3.0 and 4.5

Stability:

PRODUCTION

If manufactured by a process that may leave residues of dimethylaniline in the substance and/or by a process using starting materials or intermediates which contain residues of dimethylaniline, it complies with the following test : N,N-Dimethylaniline (2.4.26, Method A). Not more than 20 ppm.

 


1. Bodin N.O., Ekstrm B., Forsgren U. et al."Bacampicillin: a New Orally Well-Absorbed Derivative of Ampicillin". Antimicrob. Agents Chemother. 8 (5): 51825, (1975).

 

 

 

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