Semisynthetic Penicillins

SEMISYNTHETIC PENICILLINS

Semisynthetic penicillins are produced by chemically combining specific side chains (in place of benzyl side chain of PnG) or by incorporating specific precursors in the mould cultures. Thus, procaine penicillin and benzathine penicillin are salts of PnG and not semisynthetic penicillins. The aim of producing semisynthetic penicillins has been to overcome the shortcomings of PnG, which are:

1.     Poor oral efficacy.

2.     Susceptibility to penicillinase.

3.     Narrow spectrum of activity.

4.     Hypersensitivity reactions (this has not been overcome in any preparation).

In addition, some βlactamase inhibitors have been developed which themselves are not antibacterial, but augment the activity of penicillins against βlactamase producing organisms.

Classification

1. Acid-Resistant  Alternative  To  Penicillin  G

Phenoxymethyl penicillin (Penicillin V).

2. Penicillinase-Resistant Penicillins

Methicillin, Cloxacillin.

3. Extended Spectrum Penicillins

·            Aminopenicillins: Ampicillin, Bacampicillin, Amoxicillin.

·            Carboxypenicillins: Carbenicillin, Ticarcillin.

·            Ureidopenicillins: Piperacillin, Mezlocillin.

β-Lactamase Inhibitors: Clavulanic acid Sulbactam, Tazobactam

ACIDRESISTANT ALTERNATIVE TO PENICILLIN-G

Phenoxymethyl Penicillin (Penicillin V)

It differs from PnG only in that it is acid stable. Oral absorption is better; peak blood level is reached in 1 hour and plasma t½ is 30–60 min.

The antibacterial spectrum of penicillin V is identical to PnG, but it is about 1/5 as active against Neisseria, other gram negative bacteria and anaerobes. It cannot be depended upon for more serious infections and is used only for streptococcal pharyngitis, sinusitis, otitis media, prophylaxis of rheumatic fever (when an oral drug has to be selected), less serious pneumococcal infections and trench mouth.

Dose: 250–500 mg, infants 60 mg, children 125–250 mg; given 6 hourly, (250 mg = 4 lac U). CRYSTAPENV, KAYPEN 125, 250 mg tab, 125 mg/5 ml dry syr—for reconstitution, PENIVORAL 65, 130 mg tab.

PENICILLINASE-RESISTANT PENICILLINS

These congeners have side chains that protect the βlactam ring from attack by staphylococcal penicillinase. However, this also partially protects the bacteria from the βlactam ring: non-penicillinase producing organisms are less sensitive to these drugs than to PnG. Their only indication is infections caused by penicillinase producing Staphylococci, for which they are the drugs of choice except in areas where methicillin resistant Staph. aureus (MRSA) has become prevalent. These drugs are not resistant to gram-negative βlactamases.

Methicillin

It is highly penicillinase resistant but not acid resistant—must be injected. It is also an inducer of penicillinase production.

MRSA have emerged in many areas. These are insensitive to all penicillinase-resistant penicillins and to other βlactams as well as to erythromycin, aminoglycosides, tetracyclines, etc. The MRSA have altered PBPs which do not bind penicillins. The drug of choice for these organisms is vancomycin/linezolid, but ciprofloxacin can also be used.

Haematuria, albuminuria and reversible interstitial nephritis are the specific adverse effects of methicillin. It has been replaced by cloxacillin.

Cloxacillin

It has an isoxazolyl side chain and is highly penicillinase as well as acid resistant. It is less active against PnG sensitive organisms: should not be used as its substitute. It is more active than methicillin against penicillinase producing Staph, but not against MRSA.

Cloxacillin is incompletely but dependably absorbed from oral route, especially if taken in empty stomach. It is > 90% plasma protein bound. Elimination occurs primarily by kidney, also partly by liver. Plasma t½ is about 1 hour.

Dose: 0.25–0.5 g orally every 6 hours; for severe infections 0.25–1 g may be injected i.m. or i.v.—higher blood levels are produced.

KLOX 0.25, 0.5 g cap, 125 mg/3 g dry syr, 0.25, 0.5 g inj; BIOCLOX, CLOCILIN 0.25, 0.5 g cap; 0.25, 0.5 g/vial inj.

Oxacillin, Dicloxacillin, Flucloxacillin (Floxacillin) are other isoxazolyl penicillins, similar to cloxacillin, but not marketed in India. Nafcillin is another parenteral penicillinase resistant penicillin.

EXTENDED SPECTRUM PENICILLINS

These semisynthetic penicillins are active against a variety of gram-negative bacilli as well. They can be grouped according to their spectrum of activity.

1.  Aminopenicillins

This group, led by ampicillin, has an amino substitution in the side chain. Some are prodrugs and all have quite similar antibacterial spectra. None is resistant to penicillinase or to other βlactamases.

Ampicillin

It is active against all organisms sensitive to PnG; in addition, many gram-negative bacilli, e.g. H. influenzae, E. coli, Proteus, Salmonella and Shigella are inhibited. However, due to widespread use, many of these have developed resistance; usefulness of this antibiotic has decreased considerably.

Ampicillin is more active than PnG for Strep. viridans and enterococci; equally active for pneumococci, gonococci and meningococci (penicillin-resistant strains are resistant to ampicillin as well); but less active against other gram-positive cocci. Penicillinase producing Staph. are not affected, as are other gram-negative bacilli, such as Pseudomonas, Klebsiella, indole positive Proteus and anaerobes like Bacteroides fragilis.

Pharmacokinetics

Ampicillin is not degraded by gastric acid; oral absorption is incomplete but adequate. Food interferes with absorption. It is partly excreted in bile and reabsorbed—enterohepatic circulation occurs. However, primary channel of excretion is kidney, but tubular secretion is slower than for PnG; plasma t½ is 1 hr.

Dose: 0.5–2 g oral/i.m./i.v. depending on severity of infection, every 6 hours; children 25–50 mg/kg/day. AMPILIN, ROSCILLIN, BIOCILIN 250, 500 mg cap; 125, 250 mg/5 ml dry syr; 100 mg/ml pediatric drops; 250, 500 mg and 1.0 g per vial inj.

Uses

1. Urinary Tract Infections: Ampicillin has been the drug of choice for most acute infections, but resistance has increased and fluoroquinolones/ cotrimoxazole are now more commonly used for empirical therapy.

2. Respiratory Tract Infections: including bronchitis, sinusitis, otitis media, etc. are usually treated with ampicillin, but higher doses (50–80 mg/kg/day) are generally required now.

3. Meningitis: Ampicillin has been a first line drug, but a significant number of meningococci, pneumococci and H. influenzae are now resistant. It is usually combined with a third generation cephalosporin/chloramphenicol for empiricial therapy.

4. Gonorrhoea: It is one of the first line drugs for oral treatment of non-penicillinase producing gonococcal infections. A single dose of 3.5 g ampicillin + 1 g probenecid (ROSCIND, DYNACILPRB cap) is adequate and convenient for urethritis.

5. Typhoid Fever: Due to emergence of resistance it is now rarely used when other first line drugs cannot be given. It is less efficacious than ciprofloxacin in eradicating carrier state.

Salmonella diarrhoeas should usually not be treated with antimicrobials, including ampicillin.

6. Bacillary Dysentery: due to Shigella often responds to ampicillin, but many strains are now resistant; quinolones are preferred.

7. Cholecystitis: Ampicillin is a good drug because high concentrations are attained in bile.

8. Subacute bacterial endocarditis: Ampicillin 2g i.v. 6 hourly is used in place of PnG. Concurrent gentamicin is advocated.

9. Septicaemias and mixed infections: Injected ampicillin may be combined with gentamicin or one of the third generation cephalosporins.

Adverse Effects

Diarrhoea is frequent after oral administration. Ampicillin is incompletely absorbed—the unabsorbed drug irritates the lower intestines as well as causes marked alteration of bacterial flora.

It produces a high incidence (up to 10%) of rashes, especially in patients with AIDS, EB virus infections or lymphatic leukaemia. Concurrent administration of allopurinol also increases the incidence of rashes. Sometimes the rashes may not be allergic, but toxic in nature.

Patients with a history of immediate type of hypersensitivity to PnG should not be given ampicillin as well.

Interactions Hydrocortisone inactivates ampicillin if mixed in the i.v. solution.

By inhibiting colonic flora, it may interfere with deconjugation and enterohepatic cycling of oral contraceptives → failure of oral contraception.

Probenecid retards renal excretion of ampicillin.

Bacampicillin

It is an ester prodrug of ampicillin which is nearly completely absorbed from the g.i.t.; and is largely hydrolysed during absorption. Thus, higher plasma levels are attained. Tissue penetration is also claimed to be better. It does not markedly disturb intestinal ecology—incidence of diarrhoea is claimed to be lower.

Dose: 400–800 mg BD; PENGLOBE 200, 400 mg tab.

Talampicillin, Pivampicillin, Hetacillin are other prodrugs of ampicillin.

Note: A fixed dose combination of ampicillin + cloxacillin (AMPILOX and others) containing 250 mg of each per cap or per vial for injection is vigorously promoted for postoperative, skin and soft tissue, respiratory, urinary and other infections. This combination is not synergistic since cloxacillin is not active against gram-negative bacteria, while ampicillin is not active against staphylococci. Since mixed staphylococcal and gram-negative bacillary infections are uncommon, for any given infection, one of the components is useless but adds to the cost and adverse effects. Since the amount of the drug which is actually going to act in any individual patient is halved (when the combination is used), efficacy is reduced and chances of selecting resistant strains are increased. Both drugs are ineffective against MRSA. Blind therapy with this combination is irrational and harmful.

Amoxicillin

·     It is a close congener of ampicillin (but not a prodrug); similar to it in all respects except:

·   Oral absorption is better; food does not interfere with absorption; higher and more sustained blood levels are produced.

·       Incidence of diarrhoea is lower.

It is less active against Shigella and H. influenzae. Many physicians now prefer it over ampicillin for bronchitis, urinary infections, SABE and gonorrhoea.

Dose: 0.25–1 g TDS oral/i.m.; AMOXYLIN, NOVAMOX, SYNAMOX 250, 500 mg cap, 125 mg/5 ml dry syr. AMOXIL, MOX 250, 500 mg caps; 125 mg/5 ml dry syr; 250, 500 mg/vial inj. MOXYLONG: Amoxicillin 250 mg + probenecid 500 mg tab (also 500 mg + 500 mg DS tab).

2.  Carboxypenicillins

Carbenicillin

The special feature of this penicillin congener is its activity against Pseudomonas aeruginosa and indole positive Proteus which are not inhibited by PnG or aminopenicillins. It is less active against Salmonella, E. coli and Enterobacter, while Klebsiella and gram-positive cocci are unaffected by it. Pseudomonas strains less sensitive to carbenicillin have developed in some areas, especially when inadequate doses have been used.

Carbenicillin is neither penicillinase-resistant nor acid resistant. It is inactive orally and is excreted rapidly in urine (t½ 1 hr). It is used as sodium salt in a dose of 1–2 g i.m. or 1–5 g i.v. every 4–6 hours. At the higher doses, enough Na may be administered to cause fluid retention and CHF in patients with borderline renal or cardiac function.

High doses have also caused bleeding by interferring with platelet function. This appears to result from perturbation of agonist receptors on platelet surface.

PYOPEN, CARBELIN 1 g, 5 g, per vial inj.

The indications for carbenicillin are—serious infections caused by Pseudomonas or Proteus, e.g. burns, urinary tract infection, septicaemia, but piperacillin is now preferred. It may be used together with gentamicin, but the two should not be mixed in the same syringe.

Ticarcillin

It is more potent than carbenicillin against Pseudomonas, but other properties are similar to it.

3.  Ureidopenicillins

Piperacillin

This antipseudomonal penicillin is about 8 times more active than carbenicillin. It has good activity against Klebsiella and is used mainly in neutropenic/immunocompromised patients having serious gram-negative infections, and in burns. Elimination t½ is 1 hr. Concurrent use of gentamicin or tobramycin is advised.

Dose: 100–150 mg/kg/day in 3 divided doses (max 16 g/ day) i.m. or i.v. The i.v. route is preferred when > 2 g is to be injected.

PIPRAPEN 1 g, 2 g vials; PIPRACIL 2 g, 4 g vials for inj; contains 2 mEq Na+ per g.

Mezlocillin

It has activity similar to ticarcillin against Pseudomonas and inhibits Klebsiella as well. It is given parenterally primarily for infections caused by enteric bacilli.

BETA-LACTAMASE INHIBITORS

βlactamases are a family of enzymes produced by many gram-positive and gram-negative bacteria that inactivate β lactam antibiotics by opening the βlactam ring. Different βlactamases differ in their substrate affinities. Three inhibitors of this enzyme clavulanic acid, sulbactam and tazobactam are available for clinical use.

Clavulanic Acid

Obtained from Streptomyces clavuligerus, it has a βlactam ring but no antibacterial activity of its own. It inhibits a wide variety (class II to class V) of βlactamases (but not class I cephalosporinase) produced by both gram-positive and gram-negative bacteria.

Clavulanic acid is a ‘progressive’ inhibitor : binding with βlactamase is reversible initially, but becomes covalent later—inhibition increasing with time. Called a ‘suicide’ inhibitor, it gets inactivated after binding to the enzyme. It permeates the outer layers of the cell wall of gram-negative bacteria and inhibits the periplasmically located βlactamase.

Pharmacokinetics

Clavulanic acid has rapid oral absorption and a bioavailability of 60%; can also be injected. Its elimination t½ of 1 hr and tissue distribution matches amoxicillin with which it is used (called coamoxiclav). However, it is eliminated mainly by glomerular filtration and its excretion is not affected by probenecid. Also, it is largely hydrolysed and decarboxylated before excretion, while amoxicillin is primarily excreted unchanged by tubular secretion.

Uses

Addition of clavulanic acid reestablishes the activity of amoxicillin against β lactamase producing resistant Staph. aureus (but not MRSA that have altered PBPs), H. influenzae, N. gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella and Shigella . Bact. fragilis and Branhamella catarrhalis are not responsive to amoxicillin alone, but are inhibited by the combination. Amoxicillin sensitive strains are not affected by the addition of clavulanic acid. Coamoxiclav is indicated for:

·    Skin and soft tissue infections, intraabdominal and gynaecological sepsis, urinary, biliary and respiratory tract infections: especially when empiric antibiotic therapy is to be given for hospital acquired infections.

·    Gonorrhoea (including PPNG) single dose amoxicillin 3 g + clavulanic acid 0.5 g + probenecid 1 g is highly curative.

AUGMENTIN, ENHANCIN, AMONATE: Amoxicillin 250 mg + clavulanic acid 125 mg tab; also 500 mg + 125 mg tab; 125 mg + 31.5 mg per 5 ml dry syr; CLAVAM 250 + 125 mg tab, 500 + 125 mg tab, 875 + 125 mg tab, 125 mg + 32 mg per 5 ml dry syr, 1–2 tab TDS.

Also AUGMENTIN, CLAVAM: Amoxicillin 1 g + clavulanic acid 0.2 g vial and 0.5 g + 0.1 g vial; inject 1 vial deep i.m. or i.v. 6–8 hourly for severe infections.

It is more expensive than amoxicillin alone.

Adverse Effects are the same as for amoxicillin alone; g.i. tolerance is poorer—especially in children. Other side effects are Candida stomatitis/vaginitis and rashes. Some cases of hepatic injury have been reported with the combination.

Sulbactam

It is a semisynthetic βlactamase inhibitor, related chemically as well as in activity to clavulanic acid. It is also a progressive inhibitor, highly active against class II to V but poorly active against class I βlactamase. On weight basis, it is 2–3 times less potent than clavulanic acid for most types of the enzyme, but the same level of inhibition can be obtained at the higher concentrations achieved clinically. Sulbactam does not induce chromosomal βlactamases, while clavulanic acid can induce some of them.

Oral absorption of sulbactam is inconsistent. Therefore, it is preferably given parenterally. It has been combined with ampicillin for use against

βlactamase producing resistant strains. Absorption of its complex salt with ampicillin— sultamicillin tosylate is better, which is given orally. Indications are:

·     PPNG gonorrhoea; sulbactam per se inhibits gonorrhoeae.

·    Mixed aerobic-anaerobic infections, intraabdominal, gynaecological, surgical and skin/ soft tissue infections, especially those acquired in the hospital.

SULBACIN, AMPITUM: Ampicillin 1 g + sulbactam 0.5 g per vial inj; 1–2 vial deep i.m. or i.v. injection 6–8 hourly. Sultamicillin tosylate: BETAMPORAL, SULBACIN 375 mg tab.

Pain at site of injection, thrombophlebitis of injected vein, rash and diarrhoea are the main adverse effects.

Tazobactam is another βlactamase inhibitor similar to sulbactam. Its pharmacokinetics matches with piperacillin with which it has been combined for use in severe infections like peritonitis, pelvic/urinary/respiratory infections caused by β lactamase producing bacilli. However, the combination is not active against piperacillin-resistant Pseudomonas, because tazobactam (like clavulanic acid and sulbactam) does not inhibit inducible chromosomal βlactamase produced by Enterobacteriaceae. It is also of no help against Pseudomonas that develop resistance by losing permeability to piperacillin.

Dose: 0.5 combined with piperacillin 4 g injected i.v. over 30 min 8 hourly.

PYBACTUM, TAZACT, TAZOBID, ZOSYN 4 g + 0.5 g vial for inj.