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Phenoxymethylpenicillin

Phenoxymethylpenicillin, commonly known as penicillin V, was introduced in 1953 [1] and is an orally active penicillin antibiotic. It is less active than benzylpenicillin (penicillin G) against Gram-negative bacteria [2-3]. Phenoxymethylpenicillin is more acid-stable than benzylpenicillin, which allows it to be given orally. It exerts a bactericidal action against penicillin-sensitive microorganisms during the stage of active multiplication. It acts by inhibiting the biosynthesis of cell-wall peptidoglycan. It is not active against b-lactamase-producing bacteria, which include many strains of staphylococci.

In table 1 is reported the antibacterial activity of phenoxymethylpenicillin against several bacterial pathogens.

Table 1. In vitro susceptibility (MIC, mg/ml) to phenoxymethylpenicillin.

Organism MIC (mg/ml)
0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.5 1 2 4 8 16 32 64 128 256 512
Gram-positives  
Enterococcus faecalis 0 0 0 0 0 0 0 0 0 4 16 7 0 0 0 0 0 0 0
Enterococcus faecium 0 0 0 0 0 0 0 0 0 2 3 4 1 0 0 0 4 2 0
Staphylococcus aureus 0 0 1 338 309 96 234 539 613 460 206 77 37 23 10 4 4 16 0
Staphylococcus coagulase negative 0 0 0 6 5 4 6 4 7 1 2 1 2 0 1 0 1 0 0
Staphylococcus saprophyticus 0 0 0 0 5 10 3 0 0 0 0 0 0 0 0 0 0 0 0
Streptococcus agalactiae 0 0 0 5 12 3 0 0 0 0 0 0 0 0 0 0 0 0 0
Streptococcus pneumoniae 0 41 327 594 103 24 20 27 30 16 16 3 0 0 0 0 0 0 0
Streptococcus pyogenes 0 0 40 73 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Streptococcus viridans 0 0 0 0 0 7 6 8 3 0 0 1 0 0 0 0 0 0 0
Clostridium difficile 0 0 0 0 0 0 0 0 0 17 159 165 45 6 5 0 1 3 0
Gram-negatives                                      
Haemophulus influenzae 0 0 0 0 0 2 0 9 39 129 294 124 46 44 23 10 5 53 0
Moraxella catarrhalis 0 0 0 2 1 6 17 29 13 34 52 20 41 38 5 0 0 1 0
Neisseria meningitidis 0 0 0 8 11 13 107 226 140 39 9 0 0 0 0 0 0 0 0
Pasteurella multocida 0 0 0 0 0 2 5 13 1 1 0 0 0 0 0 0 0 0 0

Therapeutic use

For the treatment of mild to moderately severe infections (e.g. dental infection, infections in the heart, middle ear infections, rheumatic fever, scarlet fever, skin infections, upper and lower respiratory tract infections) due to microorganisms.

Phenoxymethylpenicillin is usually used only for the treatment of mild to moderate infections, and not for severe or deep-seated infections since absorption can be unpredictable. Except for the treatment or prevention of infection with Streptococcus pyogenes (which is uniformly sensitive to penicillin), therapy should be guided by bacteriological studies (including sensitivity tests) and by clinical response. Patients treated initially with parenteral benzylpenicillin may continue oral treatment with phenoxymethylpenicillin once a satisfactory clinical response has been obtained.

For prophylaxis against rheumatic fever, phenoxymethylpenicillin given orally twice a day is used as an alternative to injections of benzathine penicillin given every two weeks.
 

Dosage and Administration

Pen V is available as 125-, 250- and 500-mg capsules or tablets, and as a pediatric syrup, 125 or 250 mg in 5 ml. These drugs are administered orally, with the usual dose for adults of 250500 mg administered every 6hours. The drugs should be given when fasting, preferably about 1 hour before meals. Higher doses may be used for the treatment of more serious infections.

Several studies have shown that oral penicillin V is effective in streptococcal pharyngitis and bacterial upper respiratory tract infections if the total daily dose is administered in two divided doses instead of three or four divided doses [4-6]. Persistence of carriage is a definite concern after penicillin treatment. There is speculation that this can be due to tolerance or co-pathogenicity due to b-lactamase production by the commensal upper respiratory tract flora. More b-lactamase-stable agents, such as cephalosporins, probably offer an advantage if eradication is considered important.

Newborn infants and children

The pediatric syrup contains 125 or 250 mg in 5 ml. The Pen V dosage for children under five years is 125 mg four times a day, and for children over five years is the same as for adults, 250500 mg every 6-hours. In one study in children, 250 mg of Pen V given twice daily was found to be equally as effective as 250 mg given three times daily for the treatment of streptococcal pharyngitis [7].

Altered dosages

Dosage adjustments are rarely needed, unless substantial renal impairment is noted.

Toxicology

Phenoxymethylpenicillin is usually well tolerated but may occasionally cause transient nausea, vomiting, epigastric distress, diarrhea, and black hairy tongue. A previous hypersensitivity reaction to any penicillin is a contraindication.

Gastrointestinal side-effects

Transient disturbances, such as nausea and diarrhea, can follow administration of these drugs. Candidiasis may also occur. Pseudomembranous colitis developed in one 12-year-old girl following a 4-day course of oral phenoxymethylpenicillin [8-9].

Hypersensitivity reactions

These may occur in penicillin-sensitive patients. Phenoxypenicillins may be cross-allergenic with penicillin G and also with all other penicillins and include both anaphylaxis and serum sickness. Anaphylaxis is much less common with the oral phenoxypenicillins than with parenteral Pen G. In one patient, symptoms started 30 minutes after ingestion of 500 mg of penicillin V [10]. In another patient, generalized pruritus and flushing commenced within 3 minutes of ingestion of a tablet of penicillin V. This was followed by abdominal cramps, nausea, and vomiting; she received medical treatment 30 minutes after the dose when she was semiconscious, cyanosed with tachycardia and hypotension. She responded to standard resuscitative measures [11]. Serum sickness reactions are similar to those which occur after penicillin G.

Direct toxicity

Oral penicillins are of low toxicity, but massive doses, like those used with penicillin G, have not been administered to humans. Penicillin V is well tolerated in doses of up to 6 g/day.

Hemolytic anemia

One case of hemolytic anemia has been reported in a three-year-old boy who was treated with penicillin V in a dose of 125 mg every 6-hours [12]. This was an immune hemolytic anemia due to a penicillin antibody of the IgM class. Antibodies of the IgM class may also be implicated in hemolytic anemias following penicillin G administration in ordinary doses, but more commonly hemolytic anemia induced by penicillin G is a sequel to large doses and antibody of the IgG class is involved.

Jaundice

One adult patient developed liver damage as part of a severe hypersensitivity reaction to penicillin V [13].

Pharmacokinetic

Bioavailability 60%
Protein binding 80%
Metabolism Hepatic
Half-life 30-40 min (63min)
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd 35.4 l
Clearance 476.4 ml/min
Excretion Renal

Absorption

 

Distribution

Phenoxypenicillin, like penicillin G, diffuse readily into pleural, pericardial, ascitic, and synovial fluids and pass into the fetal circulation. There is very little penetration of phenoxypenicillin into the CSF if the meninges are uninflamed. Penicillin V penetrates poorly into maxillary sinus secretions [14]. In inflamed tonsillar tissue, the concentration is about 20% of the serum level at that time [15].

Excretion

About 2040% of a given dose can be recovered from urine during the first 6 hours. The drugs are mainly excreted unchanged, but small amounts of antibacterially active breakdown products are also present in the urine [16]. Renal tubular secretion of phenoxypenicillin can be partially blocked by probenecid. Only small amounts are excreted in the bile, mainly in the unchanged form.

Metabolism

 

Mechanism of Action

By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, penicillin V inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins.

Other pharmacological effects

 


Medicinal Chemistry

CAS number:  87-08-1 EINECS:

Molecular Formula: C16H18N2O5S

Average mass:   350.39 Da

Monoisotopic mass: 350.093642386 Da

Systematic name: (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: [H][C@]12SC(C)(C)[C@@H](N1C(=O)[C@H]2NC(=O)COC1=CC=CC=C1)C(O)=O

Std. InChI: 1S/C16H18N2O5S/c1-16(2)12(15(21)22)18-13(20)11(14(18)24-16)17-10(19)8-23-9-6-4-3-5-7-9/h3-7,11-12,14H,8H2,1-2H3,(H,17,19)(H,21,22)/t11-,12+,14-/m1/s1

ACD/LogP: 1.880.25 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -1.10 ACD/LogD (pH 7.4): -1.85
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 7 #H bond donors: 2
#Freely Rotating Bonds: 5 Polar Surface Area: 121.24 2
Index of Refraction: 1.651 Molar Refractivity: 88.10.4 cm3
Molar Volume: 241.25.0 cm3 Polarizability: 34.90.5 10-24cm3
Surface Tension: 69.05.0 dyne/cm Density: 1.50.1 g/cm3
Flash Point: 365.931.5 C Enthalpy of Vaporization: 105.03.0 kJ/mol
Boiling Point: 681.455.0 C at 760 mmHg Vapour Pressure: 0.02.2 mmHg at 25C

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility:

logP:

pKa:
 

Stability:

 


1. Spitzy K.H. Wein Klin. Wschr. 65: 583, (1953).

2. Garrod, L. P. "Relative Antibacterial Activity of Three Penicillins". British Medical Journal 5172: 52729, (1960).

3. Garrod, L. P. "The Relative Antibacterial Activity of Four Penicillins". British Medical Journal 5214: 16956, (1960).

4. Gerber M.A., Markowitz M. "Management of streptococcal pharyngitis reconsidered". Pediatr. Infect. Dis. 4: 518, (1985).

5. Fyllingen G., Arnesen A.R., Biermann C. et al.. "Phenoxymethylpenicillin two or three times daily for tonsillitis with beta-haemolytic streptococci Group A: a blinded, randomized and controlled clinical sudy". Scand. J. Infect. Dis. 23: 553, (1991).

6. Fyllingen G., Arnesen A.R., Ronnevig J. "Phenoxymethylpenicillin two or three times daily in bacterial upper respiratory tract infections: a blinded, randomized and controlled clinical study". Scand. J. Infect. Dis. 23: 755, (1991).

7. Gerber M.A., Spadaccini L.J., Wright L.L. et al.. "Twice-daily penicillin in the treatment of streptococcal pharyngitis". Am. J. Dis. Child. 139: 1145, (1985).

8. Larson H.E., Parry J.V., Price A.B. et al.. "Undescribed toxin in pseudomembranous colitis". Br. Med. J. 1: 1246, (1977).

9. Barrison I.G., Kane S.P. "Penicillin-associated colitis". Lancet 2: 843, (1978).

10. Coates W.H. "Anaphylactic shock following the administration of oral penicillin". Med. J. Aust. 1: 967, (1963).

11. Simmonds J., Hodges S., Nicol F., Barnett D. "Anaphylaxis after oral penicillin". Br. Med. J. 2: 1404, (1978).

12. Bird G.W.G., McEvoy M.W., Wingham J. "Acute haemolytic anaemia due to IgM penicillin antibody in a 3-year-old child: a sequel to oral penicillin". J. Clin. Path. 28: 321, (1975).

13. Beeley L., Gourevitch A., Kendall M.J. "Jaundice after oral penicillin". Lancet 2: 1297, (1976).

14. Lundberg C., Malmborg A.S. "Concentration of penicillin V and tetracycline in maxillary sinus secretion after repeated doses". Scand. J. Infect. Dis. 5: 123, (1973).

15. Roos K., Grahn E., Ekedahl C., Holm S.E. "Pharmacokinetics of phenoxymethylpenicillin in tonsils". Scand. J. Infect. Dis. 18: 125, (1986).

16. Bond J.M., Lightbown J.W., Barber M., Waterworth P.M. "A comparison of four phenoxypenicillins". Br. Med. J. 2: 956, (1963).


 

 

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