Beta Lactamase Inhibitors, Vancomycin and Clindamycin

Beta-lactamase Inhibitors

Drugs having beta lactam molecules are not clinically given alone. There are 3 beta lactamase inhibitors:

1. Clavulanic acid
2. Sulbactam
3. Tazobactam

Mechanism of action

These drugs inhibit lactamse which degrades penicillin. They are more active against lactamases produced by bacteria. Those bacteria grouped into class A are more susceptible to inhibitory effects of these inhibitors. Such lactamases are produced by organisms like:

1. Salmonella
2. Shigella
3. H. influenza
4. Neisseria
5. E. coli
6. N. gonorrhea
7. K. pneumonia

Those grouped into class C are less susceptible.

These drugs have weak antibacterial activity so combined with penicillins to provide extended spectrum of activity. Such combinations are especially used for empirical therapy.

Vancomycin

Vancomycin is a cell wall inhibitor. It is produced by Streptococcus orientalis

Chemistry –tricyclic glycopeptide

Mechanism of Action – inhibits cell wall synthesis by binding D-ala-D-ala terminal, inhibiting transglycosylase.

Resistance

Resistance is produced when

1. D-alanine is replaced by D-lactate or D-serine
2. Metabolism is enhanced by bacteria.

Antibacterial activity

Against Gram positive organisms especially:

• Staphylococci
• Streptococci
• E. facium
• E. faecalis
• C. difficile 

Pharmacokinetics

Routinely given I/V, in dose of 1g 12 hourly. It is given in form of infusion over 1-2 hours.

Only indication oral administration is by pseudomembranous colitis– enterocolitis. Drug of choice is Metronidazole (flagyl). In resistant cases vancomycin is used.

PPB is 30%.

It is mainly excreted by glomerular filtration (more than 90%). Dose adjustment has to be done in renal impairment. 

Adverse effects

1. Hypersensitivity

• Skin rash
• Articaria
• Fever
• Chills

2. Local irritation at site of infusion

3. Phlebitis

4. Typical redman / red neck syndrome –when given rapidly I/V. direct toxic effects on most cells releasing histamine causing flushing, tachycardia and hypotension.
5. Ototoxicity
6. Nephrotoxicity

When combined with aminoglycosides, patient is closely monitored, as they also have similar effects.

Uses

1. Endocarditis
2. Pneumonia
3. Empyema
4. Meningitis
5. Osteomyelitis
6. Soft tissue abscess
7. Disseminated infections
8. MRSA
9. Pseudomembranous enterocolitis
10. Given orally to enhance spectrum of aminoglycosides

Clindamycin

Produced by Streptomyces lincolnensis

Chemistry – Cl substituted lincomycin

Mechanism of Action

Similar to macrolides. Inhibits protein synthesis by:

1. Interfering with formation of initiation complex
2. Inhibits aminoacyl translocation

Resistance

Resistance is produced by:

1.      Mutations –bring about change in receptor site for drug or production of proteins
2.      Methylase –alter receptor site for drug
3.      Enzymes produced by bacteria cause inactivation of drug
4.      Poor permeability in some bacteria of drug

Antibacterial activity

Gram positive and negative organisms including:

1.      Staphylococci
2.      Streptococci
3.      Bacterioides
4.      P.jiroveci 
5.      Toxoplasma

Pharmacokinetics

Can be given Orally, I/V, I/M. also available as gel form for topical use e.g. acne or vaginal infection.

Readily taken up by phagocytes in abscesses

In liver converted to active metabolites and excreted in urine and feces.

Adverse effects

1.      Abdominal pain
2.      Diarrhea
3.      Enterocolitis –pseudomembranous colitis appearing as super-infections. In severe form may be fatal, so drug is stopped and either metronidazole or vancomycin is used to treat colitis.
4.      Myelosuppression
5.      Impaired LFTs
6.      Local irritation in form of thrombophlebitis at site of injection
7.      Neuromuscular blocker

Clindamycin potentiates the effects of NM blockers as itself causes inhibition.

Uses

1.      Mainly used for treatment of anaerobic infections in different parts of body including:
a.      Abdomen
b.      genital tract
c.       Pelvic abscess or septic abortion
d.      Lung –like lung abscess or aspiration pneumonia
e.       Heart –valvular heart disease
2.      Dental treatment –prophylactically given
3.      Pneumonia caused by Pn. Jiroveci
4.      In patients of AIDS with primaquine
5.      Encephalitis caused by Toxoplasma along with pyrimethamine