Tetracyclines, chloramphenicol and miscellaneous antimicrobials

Dr. Suman Jain

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Tetracyclines, chloramphenicol and miscellaneous antimicrobials

TetracyclinesTetracyclines and chloramphenicol are termed broad spectrum antibiotics because

they are effective against a large no of organisms:– Atypical organisms (like Chlamydia spp, Legionella spp, Rickettsiae, Mycoplasma

pneumoniae)– Some atypical mycobacteria– Camplylobacter jejuni– Helicobacter pylori. – A variety of gram-positive, gram-negative organisms: vibrio cholerae, plague,

tularemia, brucellosis.– For protozoal infection- E. Histolytica, P.falciparum.– Effective against many anaerobes (doxycycline)

ClassificationOlder tetracyclines: 1. Short acting (half life 6 hours)-Tetracycline, chlortetracycline, oxytetracycline2. Intermediate acting- half life 16 hours- demeclocyclineNewer ones :3. Long acting – half life-18-24 hours- doxycycline and minocycline are more

lipophilic and most active. Tigecycline- newest, longest acting – half life-36 hours

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TetracyclinesMechanism of actionThese are bacteriostatic agents. They inhibit protein synthesis by actingon 30 S bacterial ribosome and preventing access of aminoacyl tRNA tothe acceptor (A) site of the mRNA-ribosome complex. This preventsaddition of amino acids to growing polypeptide chain.

At high concentrations, these also impair protein synthesis in mammalian cellshowever the host lacks active transport system.

Resistance to tetracyclinesCross-resistance between members of the group is observed except forminocycline.

Resistance is mediated by plasmids. This may be due to:• Decreased accumulation due to decreased influx or development of

energy dependent efflux pathway• Decreased access of tetracycline to the ribosome because of the

presence of ribosome protection proteins.• Enzymatic inactivation of tetracycline

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ADME of tetracyclinesAbsorption:• Doxycycline and minocycline- 100%. Food does not interfere with absorption of

doxycycline or minocycline.• Absorption is decreased by concurrent administration of dairy products (milk etc)

aluminum hydroxide, calcium, magnesium, and iron salts, and bismuth subsalicylate-due to chelation of divalent or trivalent cations.

Distribution• All tetracyclines concentrate in the liver and are exc. in intestine via bile.

Enterohepatic circulation occurs. • On I.V: appears in spinal fluid, They penetrate well in to other tissues and fluids- synovial

fluid and maxillary sinus. Minocycline reach concentrations in tears and saliva adequate to eradicate meningococcal carrier state. Minocycline is deposited in body fat.

• Are stored in RES of liver, spleen, bone marrow and in bone and the dentine and enamel of the unerupted teeth.

• Tetracyclines cross the placenta and enter fetal circulation and amniotic fluid. • Relatively high conc. found in breast milk.Metabolism• Minocycline and doxycycline are metabolized significantly in the liver.• Doxycycline is excreted in feces. Since it is completely metabolized, it is preferred to

treat extra renal infection in patients with renal failure. • Enzyme inducers decrease their half lives. ExcretionAll tetracyclines are excreted in urine and feces.i Urine- older ones mainly through kidney by GF.ii Feces – amount that is not absorbed and also which is secreted in bile and not reabsorbed.

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Adverse effects of tetracylinesI. Hypersensitivity reactions

– Cross sensitization among the various tetracycline is common.

II. Biological effects other than allergic or toxic.

– Superinfection with clostridium difficile. – Superinfection with the yeast and fungi-

vaginal, oral, pharyngeal or even systemic infection.

III. Toxic effect.5

Toxic effects of tetracyclinesi Gastrointestinal.

• Dose dependent GI irritation :epigastric burning and distress, abdominal discomfort, nausea and vomiting

• Esophagitis and esophageal ulcer • Pancreatitis• Diarrhea –irritative effect – differentiate from pseudomembranous enterocolitis.

ii Photosensitivity• Mainly demeclocycline and doxycycline - sunburn. • It may also be associated with onycholysis and pigmentation of the nails.

iii Hepatic toxicity– With large oral or IV doses. Persons with preexisting liver disease and Pregnant

women are more susceptible- fatty infiltration of liver - may result in jaundice, azotemia, acidosis and irreversible shock.

iv Renal toxicity• May aggravate uremia in patients with renal disease by inhibiting protein synthesis.

Doxycycline is least nephrotoxic.• Nephrogenic diabetes insipidus may occur due to demeclocycline- used in the

treatment of chronic inappropriate secretion of ADH.• Fanconi syndrome – renal tubular acidosis- with use of outdated or degraded

tetracyclines- damage to proximal renal tubule- is reversible.

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Adverse effects. contdv Effect on calcified tissues.

• Long or short term therapy in children- brown discoloration of the teeth. Pigmentation of permanent dentition (ages of 2 months to 5 years). Dentine and enamel affected- increased caries. Pigmentation of milk teeth- from mid-pregnancy to 4-6 months postnatally.

• 40% decrease in bone growth- deposition in skeleton throughout gestation and childhood- reversible.

• Black bone disease- minocycline.

vi.Miscellaneous effects• Increased intracranial pressure and tense bulging of fontannel

(pseudotumor cerebri) in young infants.• Vestibular toxicity (dizziness, ataxia, nausea, vomiting) with

minocycline is seen more often in women.• Drug induced lupus- minocycline

PrecautionsShould not be used in pregnancy, lactation and in children, unless there is no other choice.

• Use with caution in patients with renal or hepatic disease• Don’t use expired preparations.

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Uses DOC:• Intracellular organism: chlamydiae (psittacosis, nonspecific urethritis (STD),

trachoma); rickettsia; mycoplasma, legionella.• Vibrio cholera.• In combination with aminoglycosides: plague, brucellosis, tularemia.• Spirochetal diseases: lyme disease, relapsing fever.

Secondary uses: • Exacerbation of chronic bronchitis• CAP• Treatment of acne.• Some nontuberculous mycobacterium infections.

Selective uses: • Tetracycline for eradication of H.pylori, • Doxycycline for lyme disease (1st choice) and prophylaxis of malaria• Minocycline for prophylaxis of meningococcmci and for carrier state.• Demeclocycline for chronic hyponatremia due to SIADH.• Tigecycline for skin infections and intraabdominal infections, multidrug

resistant nosocomial pathogens (MRSA, extended spectrum beta lactamaseproducing G-ve and acinetobacter sp).

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Tigecycline• It is glycylcycline.• Antimicrobial spectrum: spectrum very broad. • Effective against many tetracycline resistant organisms: Staph, MRSA,

vancomycin intermediate and vancomycin resistant strains, G+ve rods, enterobacteriaceae, multidrug resistant acinetobacter sp, anaerobes (G+ve, G-ve), atypical agents, ricketisiae, chlamydia, legionella, rapidly growing mycobacteria.

• Proteus and pseudomonas are intrinsically resistant.• Adm IV,intracellular penetration excellent, elimination biliary.

Adverse reactionsNausea, vomiting.

Uses• Multidrug resistant nosocomial pathogens (MRSA, extended spectrum

beta lactamase G –ve and acinetobacter sp.• Treatment of skin and intraabdominal infections. Not for UTI (not effective

conc in urine).9

ChloramphenicolIt contains a nitrobenzene moiety in its structure.

Mechanism of action• It is bacteriostatic. It may be bactericidal for certain microorganisms like

H.influenzae, N. meningitidis and S. pneumoniae.• It inhibits protein synthesis both in bacteria and in eukaryotic cells. It binds

reversibly to 50 S ribosomal subunit and prevents binding of amino acyl tRNA to 50 S ribosomal subunit. The interaction between peptidyl transferase and amino acid substrate cant occur and thus peptide bond formation is inhibited. Inhibits transpeptidation reaction.

• It also inhibits mitochondrial protein synthesis by acting on 70 S ribosome. Mammalian erythropoietic cells are particularly sensitive to the drug.

Antimicrobial spectrum (gram + and –ve orga. and anaerobes)i Broad spectrum (gram +ve and –ve and most anaerobes-including gram-positive

cocci and clostridium species and gram-negative rods including B. fragilis).ii. Susceptible organisms: H. influenzae, N. meningitidis, Salmonella typhi, Brucella

species, Bordetella pertussis.iii Strep. Pyogenes and Strep.pneumoniae- sensitive iv V. cholerae and Shigella are largely susceptible.v. Rickettsiae, Mycoplasma and Chlamydia.

Resistance to chloramphenicol• Due to plasmid encoded acetyl transferase, which acetylates (inactivates) the drug.

Acetylated drug fail to bind to bacterial ribosomes. • Decreased permeability of the microorganisms (E. Coli).

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Chloramphenicol

ADMEAbsorptioni Chloramphenicol is available orally in two forms: the inactive prodrug and

the active drug. Chloramphenicol palmitate (prodrug) is hydrolyzed in duodenum and then absorbed.

ii Chloramphenicol succinate is meant for IM or IV injection.

Distribution50% is protein bound. Distributed in body fluids- reaches therapeutic concentrations in cerebrospinal

fluid(60%). Also present in bile and milk. Crosses placental barrier and aqueous humor.

MetabolismIt is mainly metabolized in the liver by glucuronidation. Its T½ is 4 hours Enzyme inducers decrease its T ½.

ExcretionExcreted by GF and TS. 90% as metabolite and 10% in active form.

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Chloramphenicol: Adverse effects1. Hematological toxicity: :

i Idiosyncratic reaction (dose independent)- aplastic anemia: leukopenia, thrombocytopenia and aplasia of marrow. - genetic predisposition (1:30, 000). If aplasia is complete it is fatal and there is high risk of acute myeloblasticleukemia in those who recover.

ii A second dose related hematological effec: reversible suppression of bone marrow with conc > 25 μg/ml -characterized by anemia, leukopenia and thrombocytopenia. Stop drug if WBC count is <4000cu/mm

2. Hypersensitivity reactions- skin rashes, fever, angioedema may occur.

3. Toxic and irritable effects– Fatal chloramphenicol toxicity may occur in neonate especially in premature

babies. This illness called "gray baby syndrome" -due to failure of conjugation (lack of glucuronyl transferase in first 3-4 weeks of life, and decreased renal function)- appears when plasma concentration exceeds 100 μg/ml.

– Optic neuritis- symmetrical loss of ganglion cells from retina and atrophy of optic nerve. Peripheral neuritis may develop.

Drug interactions• Irreversible inhibition of hepatic microsomal enzymes of cytochrome P450 complex leads to

increased half-life of warfarin, phenytoin, tolbutamide, antiretroviral protease inhibitors and rifabutin.• Enzyme inducers (rifampin, phenobarbitone) shorten the T ½ of chloramphenicol.

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Chloramphenicol: Therapeutic usesShould never be used for minor infections, or infections which could be treated by other

drugs. 1 Typhoid fever: ciprofloxacin and ceftriaxone – effective- preferred for Drug

resistant organisms. 2. Bacterial meningitis: Third generation cephalosporins and quinolones are

the drugs of choice for the treatment of this disease. i H. influenzae meningitis: used with ampicillin .- 3rd generation cephalosporins

preferred. ii Meningitis due to N. meningitidis, Strep.pneumoniae in patients

allergic to penicillin. 3. Anaerobic infection- Brain abscess- used together with penicillin. Some prefer

metronidazole and penicillin. 4. Intraocular infection5. Topical use in conjunctivitis, and external ear infections .6. Second choice drug in:

a. Rickettsial infection: Tetracyclines are preferred, it may be used in:• Patients sensitized to tetracyclines• Patients with reduced renal function• In children, less than 8 years of age

b. Brucellosis: in patients where tetracyclines are contraindicated.

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• MLS group :macrolides, lincosamines-clindamycin and streptogramins(quinupristin/dalfopristin).

• Linezolid• Glycopeptides- vancomycin, tiecoplanin• Other peptides: polymyxin B, bacitracin• Lipopeptide- daptomycin• Steroid: Fusidic acid.

Miscellaneous antibiotics

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Macrolide,azalide and ketolides

Examples:Macrolides: Erythromycin, clarithromycin,Azalides: azithromycin.Ketolide: telithromycin. • Macrolides have 14 membered lactone ring (erythromycin and

clarithromycin) or 15 membered lactone ring (azithromycin) with one or more deoxy sugars.

• Clarithromycin contains methyl group at position 6- differs from erythromycin.

• Azithromycin has methyl substituted nitrogen atom into the lactone ring.

• Telithromycin has ketone group at 3rd position.These structural modification improve acid stability and tissue penetration and broader antimicrobial activity

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ErythromycinBacteriostatic or bactericidal – depends on microorganism and

concentration of the drug.

Antimicrobial activity• Its antibacterial spectrum is similar to penicillin (effective against

both gram-positive (cocci -esp. Strep) and bacilli (C. diph, listeriamono, Clos perfringens), and spirochete- borrelia).

• Not so effective against Gram-ve aerobes like H. influenzae• Effective against Bordetella pertussis.• Also effective against atypical respiratory pathogens- M.

pneumoniae, L. pneumophila, Chlamydial infection.• Also effective against campylobacter jejuni.• Also effective against certain mycobacteria- kansasii.• Effective against anaerobes except B fragilis.

Mechanism of action• It inhibits protein synthesis by binding reversibly to 50 S ribosomal

subunit near peptidyl transpeptidase, inhibits aminoacyltranslocation step and formation of initiation complexes is blocked.

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ErythromycinResistance to macrolides results from: • Efflux of drug by an active pump mechanism (Staph, group A strep,

S. pneumoniae)• Induction of methylase enzyme leading to methylation of drug –

decreased drug binding (gram negative microorganisms)• Hydrolysis of erythromycin by esterases: Enterobacteriaceae).• Chromosomal mutations that alter a 50S ribosomal protein)- (G+ve)

decreased drug binding.

ADME• Erythromycin base: acid labile- destroyed in the stomach- given

as enteric coated tablet. Incomplete but adequate absorption from upper small intestine. Food delays absorption.

• Erythromycin esters (estolate, stearate)- less susceptible to acid and better absorbed, food does not affect their absorption.

• Concentrated in liver, and is excreted in active form in the bile. • It diffuses readily into intercellular fluids, prostatic fluid, ear

fluid, does not cross blood brain barrier. Crosses placenta and to breast milk

• It is demethylated (80-90%) in liver. The T ½ is 1.6 hours. 17

Erythromycin: therapeutic usesA. Erythromycin is preferred drug of choice in the following conditions:• Mycoplasma pneumoniae infection.• Legionnaires' disease-• Chlamydial infections.• Diphtheria• Pertussis• Campylobacter infections• For community acquired pneumonia.• Streptococcal infections -it is an alternative to penicillin in patients allergic to

penicillin. • Staphylococcal infection - in a patient allergic to penicillin or cephalosporins.

B. Following are the indications for erythromycin as an alternative to penicillin in patients allergic to this drug:

• Tetanus, syphilis, gonorrhea.• Prophylactic uses: recurrences of rheumatic fever. • For prevention of bacterial endocarditis following dental or respiratory tract

procedures.

C. Oral erythromycin, neomycin and kanamycin for preoperative preparation of colon 18

ErythromycinAdverse effects• GI toxicity: Epigastric distress, abdominal cramps, diarrhea –

-due to stimulation of motilin receptors.• Allergic reactions: fever, eosinophilia, and skin rashes.

Cholestatic hepatitis may occur with estolate ester . • Mild elevation of serum aspartate aminotransferase activity• Transient auditory impairment on large IV doses • Cardiac arrhythmias including QT interval prolongation

with ventricular tachycardia with large IV doses in patients with underlying cardiac disease or with drugs like class I and III antiarrhythmic drugs, cisapride, terfenadine, etc

Drug interactions• Inhibition of cytochrome P450 related metabolism of drugs

and potentiation of their effects; e.g., theophylline, cyclosporin, carbamazepine, warfarin, etc.

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Clarithromycin- C6 methyl erythromycinThis chemical change improves acid stability and oral absorption. Advantage of clarithromycin over erythromycin:Better tolerability- less GI upset.Twice daily administration- half life longerTissue penetration better.

Antimicrobial spectrumSimilar to erythromycin except that it is more active against mycobacterial avium complex.It also has activity against M. leprae and toxoplasma gondii, H. pylori

ADME- abs well from GIT. Has active metabolite 14- hydroxyclarithromycin. Hepatic metabolism is saturable. Penetratemost tissues well- tissue conc equal or more than serum.30% exc unchanged in urine, adjust dose in renal function (cr clearance is <30 ml/min). Prolonged half life- twice daily.

Adverse effects:Similar to erythromycin, but gastric tolerance is better. Pseudomembranous enterocolitis has been reported. Safety in pregnancy and lactation is unknown.Drug interactions are similar to erythromycin.

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Clarithromycin.Therapeutic uses: Similar to erythromycin. In addition following :

• It is the first line therapy for prophylaxis and treatment of disseminated infection caused by M. avium- intracellularein AIDS patients and for the treatment of pulmonary disease in nonHIV- infected patients.

• With minocycline - lepromatous leprosy.

• In combination regimens for eradication of H. pylori infection..

• With pyrimethamine for toxoplasmosis encephalitis and diarrhea due to cryptosporidium in patients with AIDS.

• For upper and lower respiratory tract infection (mild and severe): sinusitis, otitis media, atypical pneumonia

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AzithromycinAdvantages over erythromycin:

– Extended spectrum– Improved pharmacokinetics- acid stable, rapid oral abs, marked tissue

distribution. (tissue conc 10-100 times blood conc), intracellular penetration, conc. in macrophages and fibroblasts and slow release from there responsible for post antibiotic effect, has long half life, given once daily.

– Shorter duration of therapy.– Better GI tolerability– Less drug interactions- does not inhibit CYP 450 enzymes

Antimicrobial spectrumSpectrum and uses- similar to clarithromycin: active against MAC, T. gondiiSlightly less active than clarithromycin and erythromycin against Strep and Staph butslightly more active against H. influenzae.Highly active against chlamidia, legionella, mycoplasma, and better activityagainst Neisseria spp,Campylobacter Spp M. catarrhalis,

ADME:Acid stable, abs. rapidly from GIT, food affects abs. Distributes widely except in CSF. It has extensive tissue distribution, conc 10-100 times higher than serum conc.Gradually released from tissues, elimination half life 3 days. Metabolized and

excreted mainly in bile. 22

Azithromycin

Adverse effectsMild GI upset, headache, and dizziness. No inhibition of cytochrome P450 enzymes- 15 membered ring- no

many drug interactions.

Therapeutic usesIt is used only for adults.• Legionnaire’s disease.• Chlamydial infections- pulmonary and genital infections. A

single dose of azithromycin is as effective as 7 day treatment with doxycycline for genital infection.

• PID• Upper and lower respiratory tract infection- pharyngitis, tonsillitis,

sinusitis, otitis media, pneumonias, acute exacerbations of chronic bronchitis.

• For CAP: 5 days treatment.• Useful for Mycobacterium avium-intracellulare infection• Diarrhoea due to Cryptosporidium• For eradication of H. pylori.

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Ketolides:Telithromycin• Telithromycin is a ketolide - 14 membered ring having a ketone substitute at 3rd position for

cladinose sugar. • Binds to two domains of 50S ribosome- much more tightly than macrolides if one is

methylated, the other still is occupied by ketolide.Antimicroobial spectrum• Effective against gram +ve cocci (Strep pyogenes, Strep pneumoniae, (macrolide

resistant),Staph aureus.• Active against H. influenzae, M. catarrhalis, legionella spp. Chlamydiae spp (atypical

pathogens), H. pylori, N. gonorrhoeae, B. fragilis, T. gondii and nontubercularmycobacteria.

• Many macrolide resistant strains are susceptible to ketolides (less efflux)ADMETissue and intracellular penetration good. Conc in alveolar macrophages exceeds plasma

conc.Metabolized in liver and is eliminated in bile and urine. Administered once daily.Uses:• RTI:

– CAP– Acute exacerbations of chronic bronchitis, acute maxillary sinusitis.– Group A β hemolytic streptococcal pharyngitis or tonsillitis.

Adverse effects:• GI upsets .• Drug drug interactions - less than macrolides.• Avoid in patient with prolonged QTc interval, hypokalemia and patients taking class IA

or III antiarrhythmics.• Rare cases of hepatitis and liver failure. 24

LincosaminesTwo drugs belonging to this group are lincomycin and clindamycin.I Clindamycin It is 7-deoxy, 7-chloro derivative of lincomyin. It is more

active, causes fewer unwanted effects hence preferred over lincomyin.

Mechanism of actionLike erythromycin and chloramphenicol it inhibits protein synthesis by

binding to 50 s ribosomes- not used with chloramphenicol, erythromycin which bind at the same site.

Antibacterial activityGram-positive cocci (like strep, staph, and pnuemo) but not enterococciand G-ve orga.Bacteroids spp and other anaerobes (both G+ve and –ve) -susceptible.Clostridium difficile is resistant.Also effective against actinomyces israelii, nocardia asteroids, toxoplasmagondii, pneumocystis carinii and chloroquine resistant P. falciparum & P.vivax.

ADMEOral absorption- good. Widely distributed in many fluids and tissues

including bone; accumulates in leukocytes, alveolar macrophages and in abscess. Does not cross BBB, crosses placental barrier. Mainly metabolised in liver. Half life is 2.5 h. 25

Clindamycin: Therapeutic uses• Anaerobic infection (of abdomen and pelvis- abscess) caused by bacteroides,

particularly B. fragilis and other anaerobes found in mixed infections- used in combination with aminoglycosides and cephalosporin.

• Effective in aspiration pneumonia, postobstructive pneumonia, lung abscess-alternative to penicillin.

• Clindamycin with pyrimethamine- toxoplasma gondii encephalitis in patients with AIDS.

• Chloroquine resistant P. falciparum malaria along with other drugs.

• With primaquine for pneumocystis jiroveci pneumonia in AIDS patients.

• Prophylaxis of endocarditis in persons with valvular lesion for dental extraction.

• For serious infections due to aerobic gram positive cocci (staphylococcal osteomyelitis- MRSA).

• In acne vulgaris both orally and topically (solution, gel, lotion).• Diabetic foot and decubitus ulcer 26

Adverse effects: Clindamycin

1. Antibiotic associated colitis:– incidence of diarrhea is 2-20%, average around 8%; – is due to pseudomembranous colitis caused by toxin from

C. difficile.– is characterized by diarrhea, abdominal pain, fever, mucus

and blood in stools. Proctoscopic examination reveals white to yellow plaques on the mucosa of the colon. This syndrome could be lethal.

– Its treatment consists of –stopping the drug immediately and giving metronidazole orally or IV. Other drugs are vancomycin(not because of development of resistance for enterococci), bacitracin orally . Don't give opiates as they prolong and worsen the condition.

2. Skin rashes

3. Other reactions –uncommon:• Impaired liver functions: reversible increase in SGOT and SGPT• Neutropenia, thrombocytopenia

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StreptograminsQuinupristin/dalfopristin:• Used as a combination of the two in a ratio of 30:70• Rapidly bactericidal for most except E. faecium for which it is static.

Antibacterial spectrum:• G+ve cocci including MDR strains of Strep, penicillin resistant Strep. pneumoniae, MRSA

and E. faecium (but not faecalis).

Mechanism of actionBoth are protein synthesis inhibitors that bind to 50S ribosomal subunit- inhibit polypeptide

chain elongation.

ADME:Given by IV infusion- run over 1 hour. Metabolised in liver by conjugation and 80% of drug is excreted in bile. Half life 1hour.

Uses:• Infections caused by Staph or vancomycin resistant strains of E. faecium but not

faecalis- intrinsically resistant due to efflux mechanism.

Adverse reactions:• Infusion related events: pain • Arthralgia-myalgia syndromeDrug interaction:• Inhibitor of CPY3A4 enzyme- increased levels of certain drugs like diazpam, warfarin,

protease inhibitors.28

Linezolidsynthetic antimicrobial - oxazolidinone derivative.Antibacterial activity. • G+ve organisms including Staph, Strep, enterococci, G+ve anaerobic cocci and G+ve rods

such as corynebacteria and Listeria monocytogenes.• Primarily bacteriostatic, except for Strep for which it is bactericidal• Active against mycobacterium tuberculosis.Mechanism of action-: It inhibits protein synthesis by preventing formation of ribosome complex

that initiates protein synthesis. Its unique binding site located on 23 S ribosomal RNA of the 50S subunit. There is no cross resistance with other drug classes. .

ADE. It is well absorbed after oral administration (bioavailability 100%), food does not affect its absorption. The half life is approximately 4-6 hours. It is metabolized in liver by conjugation. Half life 4-6 hours.

Therapeutic uses• Vancomycin-resistant E. faecium infections• Nososcomal penumonia• CAP• Skin infections-Complicated or uncomplicated .• It should be reserved for treatment of infections caused by multidrug resistant gram +ve

bacteria.Adverse reactions. • Hematologic- mild and reversible.

– thrombocytopenia- serious adverse effect– neutropenia

• It is a weak, nonspecific MAOI.• Minor side effects like GI complaints, headache, rash.

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Glycopeptidesi. Examples: Vancomycin and tiecoplanin

VancomycinAntibacterial activity• Gram-positive cocci : especially MRSA and also for Staph. epidermidis, Strep.

pyogenes, Strep. Pneumoniae (PNSP), Strep. viridans.• Entero. faecium and faecalis- synergistic action with aminoglycosides.• Corynebacterium, Actinomyces, and Clostridium difficile.

Mechanism of action• It inhibits the late stage of peptidoglycan synthesis (synthesis of cell wall). The

cell wall is weakened and cell is susceptible to lysis. The cell membrane is also damaged. It is bactericidal.

ADME• Poor absorption after oral adm. Given IV. • Crosses CSF if meninges are inflammed.• Up to 90% is excreted by glomerular filtration. Dosage adjustment is required in

renal failure. • Its half-life is 6 hours.

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Vancomycin

Therapeutic usesOnly to treat serious infections particularly:• Infection due to MRSA- pneumonia, empyema, endocarditis, osteomyelitis and

soft tissue abscesses and in severe Staph. infection in patients allergic to penicillin and cephalosporins.

• Disseminated staphylococcal infection or localized infection of a shunt.• Enterococcal endocarditis in patients allergic to penicillin, given with

aminoglycosides• To treat meningitis due to penicillin resistant Strep. pneumoniae- used with

ceftriaxone/cefotaxime/rifampin .• Orally - antibiotic associated colitis due to Clostridium difficile and

Staphylococcus aureus.

Adverse effects• Phlebitis and pain at site of injection. Chills, fever. • A shock like state (red neck or red man syndrome, due to flushing) may

develop during rapid IV infusion, due to release of histamine. • Ototoxicity – worsened by aminoglycosides and high ceiling diuretics • Nephrotoxicity- don’t use with other nephrotoxic drugs.• Reversible neutropenia with long term use.• Hypersensitivity reactions.

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TeicoplaninMechanism of action- similar to vancomycin.Antibacterial spectrum: similar to vancomycin.

ADME• Can be administered IM. • Its half-life is 50 hours.- adm. once daily. In renal insufficiency adjust dose.

Therapeutic uses• Osteomyelitis, endocarditis caused by MRStaph and M. susceptible Staph., Strep., and

Enterococci- similar to vancomycin.• One of the most effective agent against enterococci (combined with aminoglycoside).

Adverse reactions• Skin rash.• Hypersensitivity reactions- drug fever and neutropenia have also been reported.• Ototoxicity

Differences between vancomycin and teicoplanin are:• Vancomycin- more active against Staph. while teicoplanin- more active for enterococci• Tolerability and safety of teicoplanin are superior to vancomycin.• Teicoplanin can be given IM.• No red neck syndrome has been reported with the use of teicoplanin.

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Daptomycin• Cyclic lipopeptide• Bactericidal• Antimicrobial spectrum- similar to vancomycin, but is active against

vancomycin resistant enterococci and vancomycin intermediate and resistant S. aureus.

• Mechanism of action: Depolarises cell membrane and causes potassium efflux and rapid cell death.

• Kineitcs: adm IV. Exc through kidney.

Uses:• Effective alternative to vancomycin.

– Treatment of skin and soft tissue infections.– Treatment of endocarditis

Adverse effects• Myopathy, monitor creatinephosphokinase• Pulmonary surfactant antagonises its action – don’t use to treat

pneumonia.33

Fosfomycin• Is bacterial cell wall synthesis inhibitor.

• Inhibits enzyme enolpyruvate transferase- inhibits formation of UDO-N-acetylglucosamine.

• Active against both G+ve and G-ve organisms.

• Bactericidal conc.obtained in urine against most urinary pathogens.

• Synergism seen with beta lactam antibiotics, aminoglycosides or fluroquinolones.

• Adm: oral/parenteral.

• Uses: single dose for uncomplicated lower urinary tract infections in women.

• Safe during pregnancy. 34

Polymyxins

• These are cationic detergent, basic polypeptides.• Polymyxin B and polymyxin E obtained from bacteria.Because of nephrotoxicity

associated with parenteral administration of these drugs, they are now rarely used,except topically.

Mechanism of action• These are bactericidal, surface acting amphipathic agents. They bind with

phospholipids of cell membrane and disrupt its structure and increase permeability.

Antibacterial activity: gram-negative bacteria like E.coli, Salmonella, Enterobacter, Pseudomonas, Klebsiella, Pasteurella, Bordetella and shigella.

ADMENot absorbed orally or topically.

Adverse reactions• On parenteral administration, nephrotoxic and neurotoxic, hence not used. • On topical administration, hypersensitization is uncommon. • On oral administration- nausea, vomiting and diarrhea may occur. Therapeutic usesTopical use:• Infections of skin, mucous membranes, eye (corneal ulcer due to pseudomonas)

and ear (external otitis-due to pseudomonas)• For diarrhea- caused by susceptible organisms in infants and children.• Aerosol administration:as an adjuvant in patients with pseudomonas pneumonia.

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BacitracinCyclic polypetide, obtained from baccteria. .Mechanism of action• Inhibits bacterial cell wall synthesis.

Antibacterial activity• Gram-positive organisms (cocci and bacilli)

ADME- used for topical application. Parenterally the drug is highly nephrotoxic.

Adverse effects• Hypersensitivity reactions from topical use.• Nephrotoxicity on parenteral use- not used.

Therapeutic uses• Dermatological application- used topically either alone or along with other

antibiotics like neomycin or polymyxin for open infections: infected eczema, infected dermal ulcers.

• Ophthalmic applications: suppurative conjunctivitis. Infected corneal ulcer.• Eradication of Staph from nares.• Orally- for antibiotic associated colitis. 36