ACTA FAC. MED. NAISS. 2003; 20 (2): 115-120

Review article

b– LACTAM ANTIBIOTICS

Jović Zorica¹, Cekić Snežana²

¹Department of pharmacology and toxicology Faculty of medicine Niš

²Department of physiology Faculty of medicine Niš

THE PENICILLINS

Although numerous antimicrobial agents have been produced since the first penicillin became available, penicillins are still widely used. Presently, some members of this group of antibiotics are the drugs of choice for a large number of infectious diseases.

Chemistry

The basic structure of penicillin consists of a thiazolidine ring connected to a b-lactam ring, to which a side chain is attached. Antibacterial activity show b-lactam and thiazolidine rings. The side chain determines many of the antibacterial and pharmacological characteristics of a particular type of a penicillin.

Between several natural penicillins, penicillin G (benzylpenicillin) has the greatest antimicrobial activity and is the only natural penicillin used clinically.

Besides natural penicillins semisynthetic penicillins are now obtained.

 Mechanism of action

The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), thus exposing the osmotically less stable membrane. Cell lysis can then occur, and these drugs are therefore bactericidal. The success of a penicillin antibiotic in causing cell death is related to its size, charge, and hydrophobicity. Penicillins are, of course, only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses.

Mechanisms of bacterial resistance to penicillins and cephalosporins

Various mechanisms of bacterial resistance to penicillins and cephalosporins are operative.

The microorganism may be resistant because of structural differences in the “penicillin binding proteins” that are the targets of these drugs.

Another mechanism of bacterial resistance to penicillins and cephalosporins involves the inability of the agent to penetrate  its site of action or by energy-dependent efflux system for pumping antibiotic out of the bacteria (Jacoby, 1994; Nikaido, 1998).

Some bacteria possess active efflux pumps that remove the antibiotic from its site of action before it can act. This is an important mechanism of b-lactam resistance in P. aeruginosa, E. coli and Neisseria gonorrhoeae.

The next mechanism of bacterial resistance is enzymatic degradation of b-lactam antibiotics. b- lactamases are capable of inactivating a certain number of these antibiotics. Individual penicillins and cephalosporins vary in their susceptibilities to these enzymes.

 Classification of the penicillins and summary of their pharmacological properties

Penicillins are classified according to their spectrum of antimicrobial activity:

·                   Penicillin G and its close congener  penicillin V are highly active against sensitive strains of gram-positive cocci. They are hydrolyzed by penicillinase.

·                   The penicillinase – resistant penicillins (methicillin, nafcillin, oxacillin, cloxacillin and dicloxacillin) have less potent antimicrobial activity against bacteria that are sensitive to penicillin G, but they are active against penicillinase-producing S. aureus and S. epidermidis that are not methicillin- resistant.

·                   Ampicillin, amoxicillin, bacompicillin and others make up a group of penicillins whose antimicrobial activity is extended and includes some gram-negative bacteria such as Haemophilus influenza, E. coli and Proteus mirabilis.This group is sensitive to penicillinases.

·                 Carbenicillin and ticaracillin have antimicrobial activity extended so as to include Pseudomonas, Enterobacter and Proteus species. These antibiotics are less potent against gram-positive cocci and Listeria compared to ampicillin.

·                 Mezlocillin, azlocillin and piperacillin are potent against pseudomonas, klebsiella and some other gram- negative microorganisms. Piperacillin has excellent activity against gram- positive cocci nad L. monocytogenes like ampicillin.

Table 1. Penicillins-Groups and classes

Table 2. Penicillins- classes, preparations, route of administration and dosage

*Mij = Milion international units, IV = intravenous, IM = intramuscular

PENICILLIN G AND PENICILLIN V

Penicillin G has great activity against a variety of species of gram- positive and gram- negative cocci, although many bacteria once sensitive to penicillin G are now resistant. Most streptococci (but not enterococci) are very susceptible to the drug. However, many species of Streptococcus viridans and S. pneumoniae become resistant to penicillin G. Penicillin- resistant pneumococci are especially common amongst pediatric population. Penicillin- resistant pneumococci are also resistant to the third- generation cephalosporines. More than 90% of strains of Staphylococci aureus are now resistant to penicillin G. Staphylococci epidermidis are resistant to this drug, too. Gonococci become resistant to penicillin G, but with rare exceptions meningococci are quite sensitive to penicillin G. Corynebacterium diphteriae and Bacilus anthracis are sensitive to penicillin G. Clostridium species with the exception of Bacteroides fragilis are very susceptible to this drug. Actinomyces Israeli, Bacteroides melaninogenicus, Pasteurela multocida and L. monocytogenes are inhibited by penicillin G. Leptospira species are moderately sensitive to penicillin G, but Treponema palidum is higly sensitive. Borrelia burgdorferi that causes Lyme disease is susceptible to penicillin G.

Therapeutic uses

Penicillin G is the drug of choice for the management of infections caused by sensitive strains of S. pneumoniae:

 Pneumococcal infections

·                 Pneumococcal pneumonia- therapy should be continued for 7 to 10 days, including 3 to 5 days after the patient’s temperature has returned to normal.

·                 Pneumococcal meningitis- the recommended therapy is from 20 to 24 million units of penicillin G daily by constant intravenous infusion or divided into boluses given every 2 to 3 hours. The usual duration of therapy is 14 days.

 Streptococcal infections

·                 Streptococcal pharyngitis (including scarlet fever)- recommended therapy is penicillin V, 500mg every 6 hours for 10 days or administration of penicillin G in doses of 600000 units intramuscularly.

·                 Streptococcal pneumonia, arthritis, meningitis and endocarditis- While uncommon these conditions should be treated with penicillin G when they are caused by S. pyogenes; 12 to 20 million units intravenously for 2-4 weeks.

·                 Infections caused by other Streptococci- The viridans streptococci are the most common cause of infectious endocarditis. Penicillin- sensitive group of viridans streptococci can be treated with 1,2 million units of procaine penicillin G, given 4 times a day for 2 weeks, or with daily doses of 12  to 20 million units of intravenous penicillin G for 2 weeks.

Enterococcal endocarditis is treated  by a combination of 20 million units of penicillin G or 12 g of ampicillin given daily intravenously with an aminoglycoside for 6 weeks.

Infections with anaerobes- Many anaerobic infections are caused by a mixture  of microorganisms. The majority is sensitive to penicillin G with the exception of B. fragilis group. Pulmonary and periodontal infections usually respond to penicillin G.

Staphylococcal infections- The vast majority of staphylococcal infections are caused by species of staphylococci that are resistant to penicillin G due to production of penicillinase.

Meningococcal infections- Penicillin G is the drug of choice for meningococcal disease. The infection is treated by high doses of this drug intravenously administered.

Gonococcal infections- Gonococci become very resistant to penicillin G and penicillins are no longer the therapy of choice.

Syphilis- Penicillin G is highly effective against Treponema palidum. Primary, secondary and latent syphilis of less than a year’s duration may be treated with penicillin G procain (2,4 units per day intramuscularly) plus probenecid (1,0 g per day orally) for 10 days or  with 1 to 3 weekly intramuscular doses of 2,4 million units of penicillin G benzathin (3 doses in patients with HIV).

Actinomycosis- Penicillin G is the drug of choice for the treatment of all forms of actinomycosis.

Dyphtheria-  In spite of the fact that specific antitoxin is the only effective treatment for dyphteria, penicillin G eliminates the carrier state (2 to 3 million units per day in divided doses for 10 to 12 days).

Anthrax- Penicillin G is the drug of choice for the treatment of all forms of anthrax. The dose is 12 to 20 million units per day.

Clostridial infections-Penicillin G is the drug of choice for gas gangrene. The dose is 12 to 20 million units per day, given parenterally.

  Fusospirochetal infections- Gingivostomatitis caused by Leptotrichia buccalis and spirochetes are readily eliminated by penicillin G.

Rat-bite fever- Penicillin G is the drug of choice, but due to possible complications this drug is recommended in very high doses that range from 12 to 15 million units per day given parenterally for 3 to 4 weeks.

Listeria infections- Penicillin G or ampicillin in combination with gentamycin are the best therapy for this type of infection. Recommended doses are 15 to 20 million units parenterally applicated  per day.

Lyme disease- Tetracycline is the drug of choice, but amoxicillin is effective , too, given orally in doses of 500mg for 21 day.

Prophylactic uses of penicillin

For this purpose, penicillins are highly effective in some situations. Penicillins are recommended for prophylaxis of streptococcal infection in individuals exposed to streptococcus pyogenes. Penicillin benzathine G is the best choice when given once a month intramuscularly in a single injection of 1,2 million units.

Penicillin G benzathine is given as a single intramuscular injection of 1,2 million units once a month to stop the incidence of recurrence of rheumatic fever in susceptible individuals.

Surgical procedures in patients with valvular heart disease need prophylaxis with antibiotics. It is proved that a person who has had teeth removed has a transient bacteriemia. That emphasizes the potential importance of chemoprophylaxis for those who have congenital or acquired valvular heart disease of any type.

THE PENICILLINASE-RESISTANT PENICILLINS

These penicillins are less effective against bacteria that are usually sensitive to penicillin G, but they are effective against resistant staphylococci. Methicillin was the first obtained penicillin of this group, but it is rarely used now because:

-         methicillin is a drug for parental application only;

-         a vast majority of staphylococci become resistant to this drug;

-         methicillin becomes nephrotoxic and myelotoxic and thereby it is removed from therapy;

Isoxazolyl penicillins like oxacillin, cloxacillin, dicloxacillin and naphcillin are now available. All are relatively stable in an acidic medium and are adequately absorbed after oral administration. These penicillins were considered as the drugs of choice for most staphylococcal diseases, but increasing development of resistant staphylococci strains removed them from therapy. So, these penicillins are not registered in our country. Nowdays, the recommended antibiotics for staphylococci diseases are amoxicillin with clavulanic acid, cephalosporins (cephalotin), vancomycin, fusidinic acid and teicoplanin.

AMINOPENICILLINS: AMPICILLIN, AMOXICILLIN AND THEIR CONGENERS

These are the first penicillins of extended spectrum of actions. The spectrum is extended to gram- negative bacteria such as E. coli, Clebsillae, Proteus mirabilis, H. influenza, Salmonela, Shigella and Heliobacter pylori. The sensitivity of gram-positive bacteria is identical as against natural penicillins, while the most species of staphylococci are resistant. Ampicillin is stable in acid and is well asorbed after oral administration. This drug can be given parenterally, too. The adjustment of the dose of ampicillin is required in the presence of renal disfunction. Amoxicllin is chemically and pharmacologically similar to ampicillin. This drug is stable in acid and can be given orally, too. It has better absorption than ampicillin, and achieves two times higher concentration in blood compared to ampicillin. The antimicrobial spectrum of this drug is similar to ampicillin with the exception that amoxicillin appears to be less effective for shigellosis than ampicillin.

Ampicillin was frequently used in practice, so many bacteria such as E. coli and H. influenza have become resistant. Nowdays, ampicillin is used for treatment of sinusitis, otitis media, acute exacerbations of   chronic bronchitis and epiglottitis caused by sensitive strains of S. pyogenes and S. pneumoniae. Ampicillin- resistant H. influenza may be a great problem. The addition of b- lactamse inhibitor ( amoxicillin- clavulanate or ampicillin- sulbactam) extends the spectrum to b- lactamase- producing H. influenza ana Enterobacteriaceae.

Ampicillin can be used for the treatment of urinary infections caused by Enterobacteriaceae and E. coli, but the resistance of these bacteria is increasingly common. Amoxicillin is the antibiotic for enterococcal urinary tract infections. Ampicillin has high activity against L. monocitogenes, the cause of meningitis in immunocompromised persons. Thus, a combination of ampicillin and vancomycin plus a third- generation cephalosporin is a rational regime for the empiric treatment of suspected bacterial meningitis. The typhoid carrier state has been eliminated successfully in patients without gall bladder disease with ampicillin, trimethropin- sulfamethoxazole or ciprofloxacin. The dose for gram- positive bacteria infections are 0,5- 1g orally, every 6 hours and for gram- negative infections are 0,75- 2g every 2 to 4 hours. Amoxicillin is indicated for prophylaxis of endocarditis in patients who have high risk before the extraction. The dose is 3g, one hour before extraction in local anesthesia or 1g intravenously in general anesthesia; after intervention amoxicillin is applied every 6 hours in dose of 500mg. For other infections doses of amoxicillin for adults are 250- 500 mg every 8 hours; for small children 20- 40 mg/kg divided in three single doses or 125-250 mg every 8 hours. In serious respiratory infections, the doses of this drug are 3 g every 12 hours.

ANTIPSEUDOMONAL PENICILLINS: THE CARBOXYPENICILLINS AND UREIDOPENICILLINS

Pseudomonas aeruginosa is a bacteria highly resistant against various antibiotics. It is the cause of serious and possibly fatal intrahospital infections. Thus, antipseudomonal penicillins are the drug of choice for the treatment of such infections, especially azlocillin, mezlocillin and piperacillin in combination with an aminoglycoside.

Carbenicillin was the first penicillin with activity against P. aeriguinosa and some Proteus strains that are resistant to ampicillin. Carbenicillin may cause serious adverse reactions in addition to those that are common for other penicillins: congestive heart failure as a result of excessive content of Na+; hypokalemia may occur because of obligatory excretion of cation with a large amount of nonreabsorbable anion presented in distal renal tubule and bleeding.

Ticarcillin is similar to carbenicillin, but is two to four times more active against P.aeruginosa. Ticarcillin is inferior to piperacillin and mezlocillin against P. aeruginosa.

Mezlocillin is more active against Klebsiella than is carbenicillin; activity against P. aeruginosa is similar (or higher) than of ticarcillin. The usual dose of mezlocillin for an adult person is 6 to 18 g per day, divided into four to six portions given intravenously.

Piperacillin is effective against P. aeruginosa, Enterobacteriaceae (non-b-lactamase-producing), and many Bacteroides species. In combination with tazobactam (b-lactamase inhibitor) it has the broadest antibacterial spectrum of penicillins.

These penicillins are important agents for the treatment of patients with serious infections caused  by gram-negative bacteria, especially in imunocompromised patients with acquired infections in the hospital.

The combination of antipseudomonal  penicillins and aminoglycoside achieves synergistic effect and prevents the occurance of resistant bacteria and is recommende for serious gram-negative infections. The drugs must be given separately, not in the same syringe.

 Untoward reactions to Penicillins

Penicillins are among the safest drugs, and blood levels are not monitored, although adverse reactions do occur.

·                 Hypersensitivity: this is the most important adverse effect of the penicillins. Penicilloic acid is the major antigenic determinant of penicillin hypersensitivity.

·                 Diarrhoea: this effect occurs to a greater extent with those agents that are incompletely absorbed (ampicillin) and have an extended antibacterial spectrum.

·                 Nephritis: all penicillins, but particularly meticillin, have the potential to cause acute interstitial nephritis.

·                 Neurotoxicity: seizures may appear with very high blood levels of penicillins because they can iritate neuronal tissue.

·                 Platelet dysfunction: carbenicillin and ticarcillin and to some extent penicillin G may decrease aggregation.

·                 Cation toxicity: penicillins are generally administered as the sodium and potassium salt. Sodium excess may result in hypokalemia.
 

Literature:

1.      Berrios, X., del Campo, E., Guzman, B., and Bisno, A.L. Discontinuing rheumatic fever   prophylaxis in selected adolescents and young adults. A prospective study. Ann. Intern. Med., 1993, 118:401-406

2.      Bryson, H.M., and Brogden, R. N. Piperacilin/tazobactam. A review of its antibacterial activity, pharmacokinetic proporties and therapeutic potencial. Drugs, 1994, 47:506-535.

3.      Chambers HF, Sande M.A. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9. edition, Mc Graw Hill, New York 1996: 1029-225.

4.      Daniel KP, Krop LC. Piperacillin-tazobactam: a new b-lactamase-b-lactamase inhibitor combination. Pharmacotherapy 1996; 16: 149-62.

5.      Donowitz, G. R., and Mendell, G. L. Beta-Lactam antibiotics. N. Engl. J. Med.. 1988, 318:419-426, 490-500.

6.      Fass, R.J., Copelan, E.A., Brandt, J.T., Moeschberger, M.L., and Ashton, J.J. Platelet-mediated bleeding caused by broad-spectrum penicillins. J. Infect. Dis., 1987, 155:1242-1248.

7.      Kažić T. Gotovi lekovi-Priučnik za farmakoterapiju, 7. izdanje, integra, Beograd 1999.

8.      Nikaido, H. Antibiotic resistance caused by gram-negative multigrug efflux pumps. Clin. Infect. Dis., 1998, 27(suppl. I): S32-S41.

9.      Phillips, I., Wise, R., and Leigh, D.A. Cetotetan: a new cephamycin. J. Antimicrob. Chemother., 1983, 11 (suppl.):1-239.

10.    Spratt, B. G., Resistance to antibiotics madiated by taret alterations. Science,1994, 264:388-393.

11.    Tomasz, A. Multiple-antibiotic-resistant pathogenic bacteria. A report on the Rockefeller University Workshop. N. Engl. J. Med.., 1994, 3301247-1251.

12.    Varagić V, Milošević M. Farmakologija, 14.izdanje, ElitMedica, Beograd 1998.

13.    Yogev, R., Melick, C., and Kabat, W.J. In vitro and in vivo synergism between amoxicillin and clavulanic acid against ampicillin-resistant Haemophilus influenzae type b. Antimicrob. Agents Chemother., 1981, 19:993-996.