Beta Lactam Antibiotics

Beta lactam antibiotics Dr. Suman Jain

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Beta lactam antibiotics Beta lactam antibiotics Classes These antibiotics have beta lactam ring. 1. Penicillins 2. Cephalosporins 3. Carbapenem (e.g. imipenem) 4. Monobactam (e.g. aztreonam) in addition β lactamase inhibitors (clavulanic acid, sulbactam )also have β lactam structure but are not antibacterial. 1. The Penicillins Chemistry These are derivative of 6 amino penicillanic acid. 6APA nucleus is essential for biological activity. Penicillin G (benzyl penicillin) is the only natural penicillin used clinically. Semisynthetic penicillins are prepared from penicillium chrysogenum. Unit of penicillin 1 international unit = 0.6μg of penicillin G sodium. 1 million units= 0.6 gm Semisynthetic penicillins are prescribed by weight.

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Penicillins Mechanism of action • They are bactericidal. They inhibit cell wall synthesis. • The peptidoglycan is composed of glycan chains which are linear strands of two alternating amino sugar (N acetylglucosamine and N acetylmuramic acid) that are crosslinked by peptide chains. • Penicillins bind to PBPs which catalyse transpeptidase reaction. The interaction between penicillin and PBP is covalent. • They inhibit transpeptidation (final stage in the synthesis of cell wall). • The lysis of bacteria that usually follow the use of beta lactam antibiotic is dependent on cell wall autolytic enzymes. Autolysins or murein hydrolases usually work in the process of cell division. Penicillins activate autolysins. 4

Penicillins: Mechanism of bacterial resistance

1. Structural differences in PBP due to mutation: e.g. Strep. Pneumoniae for penicillin G (called penicillin non-sensitive S. pneumoniae PNSP) Methicillin resistance in Staph. aureus. 2. Changes in porin structure- inability to penetrate, e.g E. coli, pseudomonas. 3. Production of beta lactamase (penicillinase) most important mechanism for development of resistance. e.g., Staph aureus, H. influenzae, bacteroids, enteric G-ve organisms (E. Coli, Pseudomonas). 4. Presence of efflux pump: gram negative organisms5 salmonella.

Abs oral administrati on

Resis.to Penicillinase

Useful antimicrobial spectrum

Comments

Name Benzyl penicillin G

Variable

No

High activity against gram positive bacteria, low activity against gram –ve bacteria, acid labile, destroyed by β lactamase.

Penicillin V

Good

No

Streptococcus species, Neisseria meningitidis, many anaerobes, spirochetes, actinomyces…

Staphylococci aureus

Antistaphylococcal penicillins: Isoxzolyl penicillins: Oxacillin Cloxacillin Dicloxacillin Flucloxacillin

Good

Yes

Highly protein bound >95%

Nafcillin

Variable

Yes

Similar to isoxazolyl penicillin; resistant to staph.β lactamase

Broad spectrum penicillins: Ampicillin

Good

No

Amoxicillin

Excellent

Antipseudomonal penicillins: i. Carboxypenicillins: Ticarcillin

Poor, not given orally

Ureidopenicillins: Extended spectrum penicillins: Piperacillin

Poor (not given orally)

No

No

Listeria monocytogenes, enterococci. Proteus mirabilis, Escherichia coli, salmonella, shigella, H. influenzae, and Helicobacter pylori.

Similar to penicillin G, destroyed by β lactamase but acid stable and more active against gram –ve bacteria

Above plus. Pseudomonas Enterobacter species, Proteus (indole positive)

Inferior to ampicillin, against gram positive cocci and L. monocytogenes

Pseudomonas species, Enterobacter species, mainly Klebsiella and bacteroids.

Resembles ticarcillin against gram –ve aerobes Piperacillin effective against gram positive cocci and monocytogenes (like ampicillin)

Similar to ampicillin but greater absorption, gives high blood concentrations, most effective of all β lactams for penicillin resistant strep pneumoniae.

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listeria

ADME of Penicllin G Absorption Benzylpenicillin G- Only 1/3rd abs.from duodenum. Destroyed by gastric juice, Absorption better in achlorhydriac. Penicillin V- more stable in acidic medium and better absorbed orally. Benzylpenicillin G is administered IV. Penicillin G procaine, and Penicillin G benzathine (repository preparations- slowly release penicillin)- are adm.IM. Distribution Widely distributed 65% is reversibly protein bound. Therapeutic conc in most tissues except prostatic fluid. Penetration in CSF more if meninges are inflammed (normally 1% but in meningitis 5%adequate for susceptible organisms). Fever increases penetration. Excretion Through kidneys. 10% by GF and 90% by tubular secretion. Probenecid decreases excretion. T½ -30 minutes. Clearance low in neonates and infants and in renal failure. 7

Uses of Penicillin G Drug of choice (DOC) for: • N. meningitidis (meningococcal meningitis, septicemia). • Bacillus anthracis- anthrax • Clostridium perfringens (gas gangrene) • C. diphtheriae (diphtheria) • T. pallidum (syphilis) • Leptospira (leptospirosis) • Actinomyces israelii (actinomycosis). • Borrelia burgdorferi (lyme disease) in children. • Prophylactic uses of the penicillin: – Recurrences of rheumatic fever - 1.2 million units of benzathine penicillin G once a month. – Syphilis - prophylaxis for a contact with syphilis

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II.

The penicillinase resistant penicillinsantistaphylococcal penicillins.

Agents used for staphylococccal infection. No of isolates have developed resistance- MRS. Vancomycin is drug of choice for MRS. Resistance to methicillin is due to high molecular PBP which has very little affinity to beta lactam antibiotics. i.

Methicillin: may produce interstitial nephritis- no longer used.

ii.

Isoxazolyl penicillins - Dicloxacillin is the most active of all these. 30-80% absorption from GIT. Adverse reactions: with oxacillin- hepatitis. iii. Nafcillin. CSF concentration is adequate to treat Staph. meningitis. Adverse reactions: hepatitis, neutropenia Uses: Βeta-lactamase producing staph, also for penicillin susceptible strep

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3.

Aminopenicillins- broad spectrum penicillins

III. Aminopenicillins • Examples: ampicillin, amoxicillin and their congeners. • Destroyed by beta lactamase (produced by both gram-positive and negative organisms) Sensitive organisms are: • The Meningococci, Pneumococci, Gonococci and Listeria monocytogenes. • Gram –ve bacilli- H. influenzae, enterobacteriaceae (E. coli, Proteus mirabilis, salmonella and Shigella). • Gram –ve cocci- Moraxella. catarrhalis • Enterococci – synergism with aminoglycoside • Concurrent administration of a β lactamase inhibitor such as clavulanate or sulbactam markedly expands the spectrum of activity of these drugs. Resistant organisms- Enterobacter species, less active against B. fragilis

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Ampicillin and Amoxicillin

Ampicillin Well absorbed orally. Probenecid increases plasma conc. Appears in bile, undergoes enterohepatic circulation - excreted in feces and urine . T ½80 minutes. Given 4 times daily. Adverse reactions of ampicillin • Diarrhea. • Macular rash- in patients with AIDS, EB virus infection (infectious mononucleosis) or lymphatic leukemia, and also in patients with renal failure, or taking allopurinol. • Pseudomembranous enterocolitis (clostridium difficile diarrhea), secondary infection with candida

Amoxicillin • •

Antimicrobial spectrum identical to ampicillin with the exception that amoxicillin appears to be less effective than ampicillin for shigellosis. Plasma conc. are 2-2.5 times more and also lasts twice as long than ampicillin when given in the same dose, half life is same. This is because it is more rapidly and completely absorbed from the gastrointestinal tract than ampicillin. Because of its more complete absorption, the incidence of diarrhea is also less. It is given three 11 times daily.

Therapeutic indications broad spectrum (amino)penicillins

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Upper respiratory tract infection: Effective for sinusitis otitis media, acute exacerbation of chronic bronchitis and epiglotitis. Amoxicillin is more effective against Strep. pneumoniae.

2.

Urinary tract infections: Most uncomplicated UTIs.

3.

Meningitis: Acute bacterial meningitis in children caused by H. influenzae, Strep. pneumoniae or Neisseria meningitides. Ampicillinexcellent activity against L. monocytogenes- common in immunocompromised patients. of suspected bacterial meningitis.

4.

Salmonella infections:A fluoroquinolone or ceftriaxone - drug of choice, but co-trimoxazole or high doses of ampicillin also effective. For carrier without gall bladder disease - ampicillin, cotrimoxazole or ciprofloxacin are effective.

5.

Bacillary dysentery: Infection due to Shigella responds to ampicillin, but quinolones are preferred.

6.

Gonorrhea: If organisms are sensitive then use ampicillin or amoxicillin

7.

Other infections: Ampicillin plus aminoglycoside or one of the newer cephalosporins –to treat sepsis caused by gram-negative bacteria. Also for 12 subacute bacterial endocarditis- ampicillin + gentamicin.

IV. Antipseudomonal penicillins Carboxypenicillin: example: ticarcillin disodium • Active against pseudomonas aeruginosa and certain indole positive Proteus, enterobacter species resistant to ampicillin. Bacteroides fragilis is susceptible in high concentration. •

Currently preferred drug for Pseudomonas but is inferior to piperacillin for the treatment of serious pseudomonal infection.

•

Has synergistic activity with aminoglycosides.

•

Available in combination with clavulanic acid.

•

Be careful in patients with cardiac and renal function impairment- sodium load due to use of Na+ salts.

•

Therapeutic indications: Serious infections caused by gramnegative bacteria in patients with impaired immune system, aminoglycoside is usually added. 13

V.

Extended spectrum penicillins

Ureidopenicillins: Example: piperacillin. Active against Klebsiella in addition to the organisms inhibited by ticarcillin. Piperacillin • More active than ticarcillin for Pseudomonas aeruginosa. • Effective for Klebsiella, Enterobacteriaceae and bacteroides spp. • High biliary concentrations are achieved. • Available in combination with tazobactam. • Therapeutic uses • Serious infections caused by gram negative bacteriabacteremia, pneumonias, infections following burns, urinary tract infections due to organisms resistant to penicillin G and ampicillin give with aminoglycosides. 14 • For severe infections in neutropenic patients.

Untoward reactions to penicillins •

Hypersensitivity reactions: most common adverse reactions with penicillins. Penicillins are cross sensitizing and cross reacting. – Type I :Anaphylactic shock - most serious, urticaria, pruritus. – Type II: hemolytic anemia, neutropenia (nafcillin), thrombocytopenia. – Type III: Serum sickness (rare- urticaria, fever joint swelling, angioneurotic edema, pruritus, bronchospasm- 7-12 days after), interstitial nephritis (methicillin). – Type IV: contact dermatitis.

Cross allergenicity: Complete between penicillins, Can occur but rare between cephalosporins and penicillins, Can occur with carbapenems • • • • • •

Injection: Pain, and sterile inflammatory reaction, phlebitis or thrombophlebitis. Oral administration may cause nausea, vomiting and diarrhea- esp with ampicillin. Intrathecal injection of penicillin G – arachnoiditis, encephalopathy. Large doses in patients with renal insufficiency – convulsions. Injection of large doses of procaine penicillin G procaine –may produce procaine toxicity- dizziness, tinnitus, headache, hallucination and sometimes seizures. Jarisch Herxheimer reaction- in syphilitic patients 15

Βeta-lactamase inhibitors • Resemble β lactam molecules • Themselves are weak antibacterial substances. • They bind irreversibly to β lactamase and inhibit them ( suicide inhibitors)- are potent inhibitors of many but not all β lactamase and can protect hydrolyzable penicillins from inactivation by these enzymes. • Are particularly effective against plasmid encoded transferable element β lactamase such as staph, H. influenzae, bacteroids, N. gonococci, salmonella, shigella, E.coli, K.pneumoniae, pseudomoas.

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Beta lactamase inhibitors Examples 1. Clavulanic acid – Amoxicillin + clavulanic acid= Augmentin, or Co-amoxiclav- an oral preparation. Clavulanic acid may cause cholestatic jaundice. Used for refractory otitis media, sinusitis, bite wound infections. – Ticarcillin + clavulanic acid = timentin (parenteral)- used for mixed nosocomial infection along with an aminoglycoside. 2. Sulbactam – Sulbactam + ampicillin = unasyn (parenteral), used for mixed intra-abdominal and pelvic infections. Also used for CAP in combination with macrolide. 3. Tazobactam – Tazobactam+ piperacillin=zosyn (parenteral)- uses similar to timentin.

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2.

Cephalosporins and cephamycins

These are 7 amino cephalosporanic acid derivatives. In cephamycin there is methoxy group at 7th position in beta lactam ring. Cefoxitin and Cefotetan are cephamycins. Mechanism of action • Like penicillin, these are bactericidal drugs. They all inhibit cell wall synthesis in the susceptible organisms. • These are more stable than penicillins for many bacterial beta lactamase – hence they have broad spectrum. • These are not good for enterococci, E. faecium, MRSA, listeria monocytogenes. Mechanisms of bacterial resistance to cephalosporins • Beta lactamase that can hydrolyze the beta lactam ring. Most prevalent mechanism of resistance is destruction of cephaloporins by beta lactamases. • Decreased permeability • Alteration in penicillin binding proteins (PBPs). 18

General features ADME A. Some (cephalexin, cephradine, cefaclor and cefuroxime axetil and cefixime are absorbed after oral administration. Others can be administered either IM or IV. D Cefuroxime (2nd gen), cefotaxime, ceftriaxone and ceftizoxime (3rd gene) penetrate into cerebrospinal fluid and are useful in meningitis. All cephalosporins cross placenta. Cefoperazone is found in high concentration in bile. ME Excreted through kidney, dosage should be adjusted in patients with renal insufficiency, probenecid slows tubular secretion of most. Cefoperazone- exc. predominantly in bile. Some are deacetylated, metabolites also possess antimicrobial 19 activity and are excreted in urine.

Classification: By generation is based on general features of antimicrobial activity

1st generation Oral: cephalexin Injection: Cefazolin IV Spectrum: • Good for gram +ve cocci (strep, staph, pneum) not for enterococci, not for MRSA. • Good for gram –ve organisms like E. coli, Kleb, proteus mirabilis but poor for others (pseudo, proteus indole +ve, enterobacter,serratia, citrobacter and acinetobacter). • Anaerobic cocci (peptococcus, peptostreptococcus) but not for B. fragilis. Uses: Oral • UTI • Minor staph. lesion • Minor polymicrobial infections (strep, staph) e.g cellulites , skin and soft tissue abscess. • Strep pharyngitis. • Not for serious infections- not for empirical treatment of otitis media or sinusitis. Parenteral Cefazolin • DOC for surgical prophylaxis- single injection just before surgery (procedure where skin flora are likely pathogen. For colorectal surgery 2nd generation cefoxitin is preferred for prophylaxis. 20

2nd generation (More for gram –ve and less for gram +) Oral: Cefaclor, Cefuroxime axetil Parenteral • Cefuroxime- Crosses BBB. • Cefoxitin, cefotetan (anaerobic organisms) Spectrum: • Gram –ve organisms, Klebsiella (resistant to 1st generation), H. influenzae (including β lactamase producers). • Not against serratia, enterococci, pseudo. • Cefoxitin, cefotetan- cephamycin- effective against anaerobes (B. fragilis). Uses: Oral: • Beta lactamase producing H. influenzae, M. Catarrhalis producing upper respiratory tract (sinusitis, otitis) and lower respiratory tract infections. • Alternative for UTI Parenteral: • Cefoxitin: - for prophylaxis in GIT surgery, diabetic foot, mixed anaerobic infections- peritonitis, diverticulitis 21 • Cefuroxime-CAP (community acquired pneumonia)

3rd generation More for gram –ve, effective for serratia, citrobacter, destroyed by beta lactamase from enterobacter. Oral- cefixime Parenteral- ceftriaxone, cefotaxime, ceftazidime, cefoperazone, ceftizoxime ( for B.fragilis ). • Cefoperazone and ceftazidime are good for pseudomonas. • Except for oral and cefoperazone all achieve conc. in CNS for –ve rods except pseudomonas. • Ceftriaxone has long half life- 8 hours, may be given once daily. • Cefoperazone and ceftriaxone are excreted in bile, others are excreted in urine by GF and TS.

Clinical uses Oral - Cefixime- respiratory tract infection , urinary tract infection. Parenteral: • DOC for serious infections (nosocomial infections (entero, kleb, serratia, etc)- resistant to penicillin, ampicillin, aminoglycoside and 1st generation cephalosporins. • Gonorrhoea- ceftriaxone or cefixime is the present day DOC (single adm). • Meningitis – Ceftriaxone and cefotaxime are DOC for meningitis due to pneumo, meningo, H. influenzae and enteric gram –ve rods. – Ceftazidime with aminoglycoside- used for pseudomonal meningitis. – For penicillin resistant strains of pneumococci- may add rifampin or vancomycin. • Empirical therapy of sepsis of unknown cause–use with aminoglycoside. • Typhoid- cefoperazone, ceftriaxone. • Lyme’s disease • Ceftazidime alone for pseudomonas infection in neutropenic patients. 22 • CAP

4th generation cephalosporins Cefepime • More resistant to hydrolysis by beta lactamases (produced by enterobacter, and also organisms which destroy 3rd generation cephalosporins). • Active against pseudo, enterobacteriaceae, Staph. aureus, Strep. pneumoniae, H. influenzae, Neisseria. • Good for penicillin resistant Strep. and is useful for enterobacter. • Penetrates BBB, excreted in urine, half life is 2 hours. Uses • Nosocomial infection with organisms producing extended spectrum beta lactamase, such as enterobacter, citrobacter, serratia)- susceptible 23

Adverse effects 1.

Hypersensitivity reactions: – – –

Type I: less frequent, cross reactive with penicillin (5-10%). Patient with a H/O anaphylaxis to penicillins should not receive cephalosporins Type II: thrombocytopenia, hemolytic anemia, neutropenia, interstitial nephritis or abnormal liver functions- reversible. Type III: serum sickness- cefaclor.

2.

Nephrotoxicity with cephalothin.

3.

GIT disturbances.

4.

Biliary pseudolithiasis (ceftriaxone)

5.

Hypoprothombinemia, bleeding tendency (responds to vitamin K), disulfiram like reaction with alcohol- cefoperazone, cefotetan.

6.

Superinfection with 2nd and 3rd generation – fungi and staph.

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3.

Carbapenem derivatives

Parenteral β lactam antibiotics, β lactamase resistant. Have broadest spectrum of activity. Examples: imipenem, meropenem, ertapenem

i. Imipenem with cilastatin Marketed as primaxin containing equal amount of imipenem and cilastatin (an inhibitor of renal dipeptidase (dehydropeptidase) which hydrolyses imipenem to a nephrotoxic metabolite. Mechanism of action: It binds to penicillin binding proteins and disrupts bacterial cell wall synthesis and causes death of susceptible microorganisms. It is very resistant to hydrolysis by most beta lactamases. Antimicrobial activity • Broad spectrum of activity- effective against –ve and + aerobic and anaerobic microorganisms, e.g., streptococci ( including penicillin resistant S pneumoniae), enterococci , Enterobacteriaceae, Pseudomonas, Acinetobacter, anaerobes including B. fragilis. • It is not effective against Enterococcus faecium, MRSA and Clostridium. difficile 25

Carbapenem derivatives. Imipenem contd ADME Not absorbed orally, given IV, penetrates body tissues and fluids, including CSF. T ½ of 1 hour. 70% excreted in urine – reduce dose in renal insufficiency. Therapeutic uses: • Organisms resistant to other drugs: for UTI, lower RTI, nosocomial pneumonia, intraabdominal and pelvic infection, septicemia, skin, soft tissue, bone and joint infection • Penicillin resistant pneumococci • DOC for mixed infections caused by cephalosporin-resistant nosocomial organisms such as Citrobacter and Enterobacter spp. Adverse reactions of carbapenems: • Nausea, vomiting and diarrhea, skin rashes. • Reaction at infusion sites • Seizures with high concentration in patients with CNS disease or renal insufficiency. Seizures are less with meropenem and ertapenem. • Hypersensitivity reactions may occur- cross sensitivity with penicillin exists. 26

Carbapenem derivatives contd ii.

Meropenem

•

• •

Does not require co administration of cilastatin, as it is not sensitive to renal dehydropeptidase. Effective against imipenem resistant Pseudomonas aeruginosa. It crosses BBB - used in meningitis. Uses similar to imipenem- IV every 6 hrs. Incidence of seizures is less than that with imipenem. No nausea

iii.

Ertapenem

• •

Less active than other two. Not degraded by dehydropeptidase. Half life is longer -4 hours- given once or twice daily. Can be given by IM route. Uses: CAP, intraabdominal sepsis. 27

4.

Monobactam: aztreonam

Aztreonam

•

Monocyclic beta lactam-active against –ve rods including pseudomonas and serratia.

Mechanism of action: It interacts with PBP (PBP target 3 site is preferred) and induces formation of long filamentous bacteria. Antibacterial activity • Resembles that of an aminoglycoside- highly effective against β lactamase producing G-ve rods :enterobacteriacea, Kleb, pseudo, serratia. H. influenzae; • G-ve cocci (N. meningitidis, N. gonorrhae) • Gram-positive bacteria and anaerobic organisms are resistant. ADME Adm.IM or IV, exc.unchanged in urine, T ½ is inc. in renal failure. Adverse reactions • Patients allergic to beta lactam antibiotics don't show cross hypersensitivity. • Nausea, diarrhea, urticaria, rash, hepatitis (increase in transaminases), and blood disorders (thrombocytopenia, neutropenia) may occur. Therapeutic uses • Used as an alternative to aminoglycosides, in septicemia, or complicated UTI

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