By Dr.Mohamed Abd Almoneim Attia B lactam antibiotics By Dr.Mohamed Abd Almoneim Attia

-lactam antibiotics   They share a -lactam ring in their molecular structure. They decrease bacteria cell wall synthesis. They include Penicillin Cephalosporins Monobactams Carbapenem

PENICILLINs  History   Antibacterial spectrum   *Gram-positive cocci, e.g. streptococci, pneumococci and staphylococci. *Gram-negative cocci: gonococci and meningococci. *Gram-positive bacilli: anthrax bacillus, C. diphtheria and clostridia. *Gram-negative bacilli: shigella, salmonella, etc. *Spirochetes: treponema pallidum. *Actinomyces.

Mechanism of action 1-Penicillins decrease bacterial cell wall synthesis by binding to cell receptors (penicillin binding proteins). After attachment, penicillin decreases activity of transpeptidation enzyme. Then transpeptidation reactions are blocked. 2-The next step involves activation of autolytic enzymes in the cell wall, and results in lysis of organism. Pharmacokinetics Absorption: Distribution: good throughout the body. They cross the placental barrier but none is teratogenic. Penetration into either bone or CSF is insufficient for therapy (only with inflammation of these sites). Excretion: Through the organic acid (tubular) secretory system of the kidney and by glomerular filtration. Propenecid inhibits the secretion of penicillins by competition and thus can increase blood levels. Naficillin and ureido penicillins are eliminated through the biliary route. Penicillins are excreted into breast milk and saliva.

*PREPARATIONS OF PENICILLINS  I. BENZYL PENICILLIN AND RELATED DRUGS:  Effectiveness -active against gram-negative and positive cocci, gram-positive bacilli and spirochetes. -It is sensitive to penicillinase enzyme.   Classification A. Injectable preparations: Short-acting preparation e.g. benzyl penicillin (penicillin-G): (6 hours) Its distribution is allover the body except CSF But it diffuses to CSF if meninges are inflamed (meningitis). Can be destroyed by B lactamase.

Long-acting preparations: To overcome the drawback of the short duration of action of benzyl penicillin, which necessitates its frequent parentral administration, long acting preparations of benzyl penicillin were prepared. These preparations are given only intramuscularly and never intravenously. The long acting penicillins include: 1-Procaine penicillin-G: 12-24 hours This is a combination of procaine and benzyl penicillin. It consists of 100.000 units of procaine penicillin + 100.000 units of benzyl penicillin. 2-Fortified procaine penicillin: 24 hours It consists of 300.000 units of procaine penicillin + 100.000 units of benzyl penicillin-Given once daily IM. 3-Benzathine penicillin: This preparation produces low blood levels lasting from few days to 4 weeks depending on the dose. It should not be used in acute infections because the blood levels are low. So it is used in chemoprophylaxis of rheumatic fever.

*Oral preparations: These penicillins are stable in acid medium and hence escape destruction in the gastric juice. They include: Phenoxymethyl penicillin (penicillin V). Phenethicillin.   II. PENICILLINASE RESISTANT PENICILLINS (-lactamase resistant penicilins and antistaphyllococcus penicillins) The only indication is infection by -lactamase producing staph. They have low activity against other gram-positive and inactive against gram-negative bacteria. They include: Methicillin. Cloxacillin, Dicloxacillin, Flucloxacillin. Nafcillin: It is more active than methicillin and cloxacillin.

III. Broad -SPECTRUM PENICILLINS A. AMINO PENICILLINS: Their spectrum like penicillin G plus gram negative bacteria e.g. H. influenza, Salmonella, Proteus, and Shigella. They are -lactamase susceptible They can be given orally (acid resistant) and by injection (IM and IV). They include: *Ampicillin It is concentrated in bile, so it is effective in gall bladder disease and typhoid carrier. But superinfection………………… *Pro-drugs of ampicillin: e.g. pivampicillin, talampicillin, and pacampicillin. These are esters of ampicillin which themselves are microbiologically inactive but after oral administration they are de-esterified in the gut mucosa or liver to release ampicillin to the systemic circulation. Advantages They are better absorbed from the gut than ampicillin itself, so gives higher levels in blood and tissues. Because they are inactive when present in the lumen of the gut, they have no effect on the gut flora and less G.I. upset (less superinfection).

*Amoxycillin: like ampicillin but differs in: 1-Better absorption from intestine, so it has higher plasma and tissue levels. 2-More active against Salmonella and Streptococcal fecalis (ampicillin more on shigella and H. influenza). 3-Can penetrate mucoid and purulant sputum, so it is useful in chronic bronchitis. 4-Less diarrhea as side effect. Clavulinic acid (hepatotoxic) has little antibacterial activity but inhibit the activity of -lactamase enzyme by competitive inhibition. This combined with amoxycillin (Augmentin) , this extends the spectrum of amoxycillin to include -lactamase producing organisms. Other -lactamase inhibitors include sulbactam, which can combine with ampicillin to extend its spectrum (Unasyn).

B. ANTIPSEUDOMONAL PENICILLINS: They are broad-spectrum, but should only be used for pseudmonas infection and ampicillin resistant proteus. Also they have activity against anaerobic gram negative bacteria e.g. Bacteroids fragilis (a common pathogen in intra-abdominal sepsis) They are -lactamase susceptible. They have synergistic effect when they are used with aminoglycosides. *Examples: Carbencillin, Ticarcillin , Azlocillin, Mezlocillin, and Piperacillin   IV. AMIDINOPENICILLINS Mecillinam Pivmecillinam

2-Staphylococcal infections of skin, mucous membrane and bone. Therapeutic uses of penicillins A. Treatment of infection: Penicillins may be used in the treatment of:   1-Streptococcal infections, e.g. wound sepsis, puerperal fever acute throat infections, subacute bacterial endocarditis,.. etc. 2-Staphylococcal infections of skin, mucous membrane and bone. 3-Pneumococcal infections e.g. pneumonia and empyema. 4-Syphilis and gonorrhoea. 5-Meningococcal infections. 6-Typhoid and paratyphoid fevers: ampicillin and amoxycillin. 7-Pseudomonas infection. 8-Other uses: *Actinomycosis, Anthrax and H. influenza infections. *Diphtheria, tetanus and gas gangrene (Penicillin may be used together with the specific antitoxins). *Peptic ulcer…………………………..

B-Prophylaxis: Penicillins may be used prophylactically in the following conditions:  1-To prevent recurrence of rheumatic fever. 2-To prevent gonorrhoeal ophthalmia in neonates: 3-To prevent subacute bacterial endocarditis due to bacteraemia resulting from operative procedures such as dental extraction, tonsillectomy…etc. in patients with congenital or acquired valvular disease or immunocompromised patient.

Adverse effects penicillins are among the most widely used and least toxic antibiotics available.   1-Hypersensitivity (10% of patients): hypersensitivity reactions are common with prolonged course, history of other allergic disease and with procaine penicillin. Allergy generally occurs to all forms of penicillins at once. Allergy is not due to penicillin itself but to degradation product common to all penicillin. Types:  *Early (Type I reaction-anaphylactic): A severe fall in blood pressure occurs, with bronchoconstriction, angioedema (including larynx) and sometimes death due to loss of fluid from the intravascular compartment. Anaphylactic shock usually occurs suddenly, in less than an hour after the drug has been given orally, but within minutes if it has been given IV. *Delayed (Type III reaction, serum sickness): it occurs after 2-12 days in the form of fever, malaise, arthralgia, skin rash and angioedema.

Prevention:  *Never give penicillin if there is history of penicillin allergy. *Test for hypersensitivity Treatment: ECAA  Epinephrine = antihistamine (e.g. chlorpheniramine)corticosteroids and aminophylline. 2-Neurotoxicity: Convulsions, coma, and death has followed intrathecal injections of penicillin. It occurs after high doses and in renal failure.   3-Glossitis, stomatitis and superinfection: Superinfection by Candida albicans, notably with ampicillin. Diarrhea is frequently observed in patients receiving ampicillin and on occasion with amoxicillin.

4-Cation toxicity: Large doses of the sodium or potassium salt of penicillin-G in patients with renal insufficiency can result in excessive blood levels of these cations.   5-Procaine penicillin: It produces mental changes, convulsion, pulmonary infarction (due to accidental IV administration). 6-Herxheimer reaction in late syphilis: 7-Masking of infection (syphilis and gonorrhea): 8-Other Adverse effects: Both carbenicillin and ticarcillin may interfere with platelet aggregation and; occasionally, cause bleeding problems.

Interactions 1-Penicillins with bacteriostatic drugs (e.g. tetracycline, chloroamphenicol, erythromycin): since penicillin act by inhibiting cell wall synthesis, but drugs which decreases protein synthesis, interfere with the action of penicillin. 2-All antipseudomonal penicillins impair the antibacterial action of gentamicin when the 2 drugs are mixed together in vitro. This inactivation is likely to occur in patients with severe renal impairment. 3-e.g. combined use of penicillin and an aminoglycoside antibiotic (such as gentamicin) on the enterococcus. In this example, inhibition of cell wall synthesis by penicillin permits better penetration of the cell wall by the aminoglycoside and more effective inhibition of protein synthesis than either drug alone.  

CEPHALOSPORINS They are bactericidal antibiotics CEPHALOSPORINS They are bactericidal antibiotics. They share the following properties with penicillins: They have a -lactam ring. They are bactericidal. They inhibit bacterial cell wall synthesis. Pharmacokinetics Cefoperazone and to less extent ceftriaxone (third generation) are primarily excreted in bile and its serum level is not greatly influenced by renal failure. Cefotaxime on other hand is excreted mainly by kidney, so dose adjustment is needed in renal insufficiency. Antibacterial spectrum They are divided into 1st, 2nd, 3rd, and 4th generations. In general, the activity against gram-positive bacteria decreases from first to third generation while activity against gram-negative organisms increases.

I. FIRST GENERATION CEPHALOSPORINS   They are active against aerobic gram-positive cocci and some aerobic gram-negative bacilli. They do not cross the meninges and are therefore not used in treatment of meningitis. They are -lactamase sensitive : There is partial cross allergenicity between them and penicillins. Examples of this class include: *For parenteral administration: Cephalothin , and Cephradine. *For oral administration: Cephalexin, Cephradine and Cefadroxil .

II. SECOND GENERATION CEPHALOSPORINS They have extended spectrum including few anaerobes and gram-negative bacilli especially Proteus, Enterobacter and H. influenza. They are relatively resistant to -lactamases. Examples of this class include: For parenteral administration: Cefuroxime . For oral administration: Cefuroxime and cefaclor.

THIRD GENERATION CEPHALOSPORINS -They cover gram negative organisms including Pseudomonas and anaerobic microorganisms with diminished gram positive activity. -Highly resistant to -lactamase. -Penetrate blood brain barrier and attain high concentrations in CSF, therefore they are used in gram-negative bacterial meningitis except cefoperazone. Examples of this group include: For parenteral administration: Cefotaxime , Ceftazidine . Cefoperazone , Ceftriaxone IV. FOURTH GENERATION CEPHALOSPORINS Like 3rd generation but more resistant to B lactamases Highly active against Haemophilus, Pseudomonas, and anaerobes. For parenteral administration: Cefepime

Therapeutic uses of cephalosporins 1-Severe undiagnosed sepsis especially in immunosuppressed patient. 2-Treatment of infection of respiratory tract, urinary tract, skin, soft tissue, bones and joints due to susceptible organisms. 3-Gram-negative bacterial meningitis may be treated by cefotaxime (third generation) and Ceftriaxone that reach the C.N.S. 4-Biliary infection: 3rd generation (cefoperazone or ceftriaxone). 5-Gonorrhoea due to penicillin-resistant Gonococci. It is treated by single IM injection of ceftriaxone. 6-Pseudomonal infection .

Adverse effects 1-Allergic reactions, such as rash, urticaria, fever, serum sickness, hemolytic anemia, and eosinophilia. Because of the similarities in structure between the cephalosporins and penicillins, it is not surprising that patients, who are hypersensitive to penicillin occasionally exhibit similar sensitivity when treated with a cephalosporin (cross resistance). Therefore, it is important to inquire about both penicillin and cephalosporin hypersensitivity, especially the immediate variety, before administering any of these agents.   2-Nephrotoxicity is potentiated by the simultaneous use of diuretics (e.g. thiazide) or nephrotoxic agents such as aminoglycosides. It is less with oral preparations. 3-Superinfections with Pseudomonas, Klebsiella, Enterobacter, E. coli, Proteus, Serratia and Candida have been reported leading to diarrhea. 4-Hypoprothrombinemea, thrombocytopenia and/or platelet dysfunction are new adverse effects of selected extended-spectrum cephalosporins . 5-A disulfiram-like reaction has also been noted with some of these agents, such as cefoperazone if it is given with alcohol because they block the second step in alcohol oxidation which results in the accumulation of acetaldehyde.

*MONOBACTAMS e.g. Aztreonam It is monocyclic -lactams (monobactams). -A synthetic derivative, aztreonam, is effective against gram negative and poorly active against gram positive cocci and anaerobic bacteria. -Aztreonam is stable to most -lactamases. It has a low potential to produce hypersensitivity reactions, even in patients with known -lactam allergy.

*CARBAPENEMS e.g. Imipenem and meropenem It is resistant to -lactamase enzyme. The ease of penetration (due to its low molecular weight) and resistance to -lactamase imparts a broad-spectrum of antimicrobial activity against most aerobic and anaerobic bacteria (Gram-positive and gram-negative) with the exception of occasional Pseudomonas strains. If imipenem is given alone it is inactivated by dihydropeptidase enzyme in kidney, therefore it is combined with cilastatin (Tienam) to inhibit renal dihydropeptidase enzyme. Meropenem: The other drug of this group which is currently available. It does not undergo metabolism by renal dihydropeptidase enzyme. Adverse effects Allergy Blood disorders. Neurotoxic in high doses . G.I.T: nausea, vomiting, etc.

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