Broad Spectrum Antibiotics – Tetracyclines and Chloramphenicol

Department of Pharmacology NEIGRIHMS, Shillong

Tetracycline - History

American Pharmaceutical Industry: In the 1940’s soil actinomycetes bacteria were systematically

screened for the elaboration of antimicrobial substances

Tetracyclines

• A class of antibiotics named for their nucleus of four (“tetra-”) hydrocarbon rings.

• All are obtained from soil actinomycetes.• 1948 first one – chlortetracycline (aureomycin) – S.

aureofaciens (Yellow coloured colony).– Oxytetracycline from S. rimosus (1950)– Tetracycline (1953)

• Only Penicillin and Streptomycin available – – Orally effective with wider spectrum of activity– Hence : BROAD SPECTRUM – gm+ve, gm-ve, actinomycetes,

rikettsiae and chlamydia

Streptomyces bacteria

Stretpomycesaureofaciens

Chlortetracycline

1948

C

O

NH

N

CH3CH3

OO OHOH

CH3OHCl

OH

OH

Streptomyces bacteria

Stretpomycesaureofaciens

Chlortetracycline

1948

New Class of Antibiotic

4 ringed hydronaphthacene nucleus

OO OHOHOH

C

O

NH

N

CH3CH3

OO OHOH

CH3OH

Chlortetracycline(1948)

Cl

OH

OH

C

O

NH

N

CH3CH3

OO OHOH

CH3OH

Tetracycline(1953)

OH

OH

Tetracyclines – common properties

• Nucleus of 4 rings• Bitter solids and weakly water soluble – HCl

salts are more soluble• Aqueous solutions are unstable• Same antimicrobial activity – only minor

differences• Newer ones – high lipid solubility and greater

potency

Tetracyclines - drugs

• Naturally occuring:– Tetracycline, cholrtetracycline, oxytetracycline

and demeclocycline

• Semisynthetic occurring:– Doxycycline, minocycline, lymecycline,

methacycline and rolitetracycline

Available drugs - characters

• Tetracycline, oxytetracycline, demeclocycline– Orally given, short acting– Incompletely absorbed from stomach (60-80%)– Primarily excreted through the kidneys

• Minocycline, doxycycline, tigecycline– Lipid soluble, parenteral possible, long acting– Completely absorbed from stomach (95-100%)– Excreted through liver

Tetracyclines – Antimicrobial spectrum

• Bacteriostatic drugs: originally all types of organisms except viruses and fungi – Both, gm+ve and gm-ve bacteria, Rickettsiae, Chlamydia, Mycoplasma, actinomycetes and some protozo

• Cocci: All +ve and –ve cocci– S. pneumoniae, gonococi, meningitidis are sensitive. Resistance developed

to s. aureus, pyrogens and enterococci• Bacilli (+ve): clostridia, listeria, anthracis etc, but not Mycobacteria• Gm-ve bacilli: Cholerae, Y. pestis, Helicobacter, Brucella etc. but H.

Influanzae become insensitive• Enterobacteriocae: resistant and not effective - pseudomonas,

klebsiella and salmonella• Enterococci: histolytica and plasmodia

Tetracyclines - Kinetics

• Older ones less absorbed – 60-80% but doxy and mino – completely (food interferes)

• Chelating property – milk, antacids and iron preparatons• Distribution: wide

– Concentrated in liver, spleen and bone & teeth – minocycline in fats– Good CSF penetration

• Excretion: Primarily in urine (dose adjustment in renal failure)– Doxycycline is exception (bile)

• Preparations: Oral capsules, ½ to 2 Hrs pre and post food– No IM: painful (oxy and tetra available)– Also cream, ointment and occular preparations

Adverse Effects GI disturbances: Due to Irritation• Mild nausea and diarrhoea to severe, possibly life-threatening

colitis and Oesophagitis etc. Superinfection: Disturbances in the normal flora (Diabetics)

– Candidiasis (oral and vaginal) – soreness and redness of mouth black hairy tounge and inflammatory lesions in vulva, vagina etc.

– Staphylococcal enteritis (S. aureus) – hospitalized patients – loss of appetite, abdominal discomfort and watery diarrhoea,

– Pseudomembranous colitis - C. difficile (profuse diarrhoea and fever) – Rare but dangerous

Difference of diarrhoea: Pus cell or RBCs (absent in irritation type)(Doxycycline and Minocycline – less likely to cause diarrhoea)

Adverse Effects – contd.

Liver damage: fatty infiltration – oxytetracycline safer; pregnancy – acute hepatic necrosis

Kidney damage: accumulates except doxycycline – enhance existing kidney disease FANCONY LIKE SYNDROME – outdated tetracycline (epitetracycline, anhydrotetracycline and

anhydroepitetracycline) – glycosuria, proteinuria and aminoacidria etc. Phototoxicity: Sunburn like - Skin rashes, mainly after topical application

Erythema, brown black discolouration of nails and loosening etc. Doxycycline and demeclycline - more

Teeth and Bones: Brown discolouration - Calcium tetracycline chelate (orthophosphate) Deciduous teeth – ill formed and prone to carries teeth Pregnancy and childhood - Temporary supression of one growth

Antianabolic effect: reduction in Protein synthesis Diabetes Insipidus: antagonizes ADH and urine conc. property Vestibular toxicity: Minocycline (ataxia, vertigo, nystagmus)

Toxicity/Contraindications of Tetracyclines

• Because drug is deposited in tooth dentine and enamel, brown bands form

• Do not give to children or pregnant/nursing women

(bone growth, deformities, stature)• Misc. side effects

– Thrombophlebitis– Various WBC dystrophies– Increased intracranial pressure in

neonates– Hypersensitivity reactions(superinfections)

Tetracyclines - uses

1. Empirical therapy2. Rickettsial infections: Rocky Mountain Spotted Fever, All

forms of typhus and Q fever (Coxiella burnetii)3. Venereal diseases:• Chlamydial urethritis/endocervicitis: Doxycycline• Lymphogranuloma venereum (Chlamydia trachomatis)• Granulloma inguinale (Klebsiella granulomatis)

4. Atypical pneumonia: due to mycoplasma5. Cholera6. Plague 7. Brucellocis: D 200+ R600/day X 6 weeks

Tetracyclines – other uses

Second choice drugs: To penicillins for tetanus,anthrax,actinomycosis and listerias To ceftriaxone/amoxy/azithro for gonorrhoea To penicillins for syphilis (allergic to pens) To pens for leptospirosis (doxy 100 mg BD 7 days) To azithromycin for chlamydia pneumonia To ceftriaxone and azithromycin for chancroid To streptomycin for tularemia

Other uses: UTI, Chloroquine Resistant falciparum adjuvant to quinine, Amoebiasis, Community aquired pneumonia, Acne vulgaris and COPD

Tetracyclines - Precautions

• Pregnancy, lactation and children• Renal and hepatic insufficiency• Expiry Date• With diuretics

• Intrathecal injection

Tetracyclines - MOA

Inhibition of Bacterial Protein Synthesis

Tetracycline Resistance

Efflux pump 30S Ribosome Enzymatic Degradation

Proteins in the cytoplasmchemically degrade

Tetracyclines

RarePlasmid encodes a gene

that produces a membrane based protein thatactively pumps out

tetracyclines

RibosomalProtectionProteins(RPP’s)

Mutation

Cross resistance*Not Minocycline

Chloramphenicol

Streptomyces venezuelae

Chloramphenicol(streptomyces venezuelae)

• A natural product (contains a nitrobenzene moiety)

• Now all are synthetic products

• Yellowish white crystalline solid

• Stable aqueous solution• Nitrobenzene –

antibacterial activity

Chloramphenicol - MOA

• Binds to 50S ribosomal subunit

• Prevents peptide bonds from forming and blocking proteins synthesis

• Bacteriostatic - Effective against a wide variety of organisms

• Mainly like tetracycline - +ve, -ve, Rikettsiae and mycoplasma

• Generally used as drug of last resort for life-threatening infections

Chloramphenicol – Differences with Tetracycline

• Highly effective against S. typhi (RESISTANT NOW)

• More effective against H. influenzae, B. pertissis, N. menigitidis

• Less active against gm+ve cocci and spirochaetes

• Not effective against – chlamydia, entamoeba and plasmodia

Resistance - chloramphenicol

• High incidence of Resistance due to indiscriminate use in the past – developing countries

• Resistant strains of S. typhi developed due to transfer of R plasmid.

• R Plasmid mediated-formation of acetyl- transferases that inactivate the drug

• Acetyl – chloramphenicol does not bind to ribosomes• Other mechnisms – • Decreased permeability (passive and facilitated diffusion)• Lowered affinity of ribosomes to chloramphenicol

Pharmacokinetics

• Given orally or parenterally• Wide distribution, including CSF• Present in bile, milk, and placental fluid• Conjugated in liver (glucoronic acid)• Cirrhotics & neonates have low conjugating ability• Little is excreted unchanged in urine• T1/2 = 3-5 hrs• Available as capsules 250 mg – 500 mg (maximum dose

28 gm in a course of less than 2 weeks)• Also as inj. 0.25, 0.5 and 1 g per vial• Eye drops 0.4% and ear drops

Adverse effects

• Irritative effects – Nausea, vomiting, diarrhoea and pain in injection• Bone marrow depression: Notorious causes aplastic anaemia,

agrannulocytosis, thrombocytopenia1. Non dose related (idiosyncratic): genetic basis and unpredictable – long term

leukaemias2. Dose and duration related – predictable, reversible

• Hypersensitive effects – Rashes, fever, glossitis and angioedema• Gray Baby Syndrome: (2-9 days after dose of 100mg/kg)

– Within 24 hours, baby starts to vomit, stops eating, rapid and irregular respiration, abdominal distension, periods of cyanosis, and pooping loose green stool

– Baby then turns ashen gray and becomes flaccid and hypothermic– Also can occur in adults who are cirrhotics– Death in 40% of cases (CVS collapse)– Due to Inability to metabolised & excrete chloramphenicol

Chloramphenicol - Uses

1. Enteric fever: Mainstay in the past (Resistance)2. Pyogenic meningitis as 2nd line to 3rd generation

cefalosporins – child and allergics– Meningcoccal meningitis and H. influenzae

3. Anaerobic infections – Bact. Fragilis4. Intraocular infections – Endophthalmitis5. Second choice: Brucellosis, UTI, rickettsial

infections, conjunctivitis, external ear infections

Chloramphenicol - Precautions

• Minor infections and undefined etiology• Infections treatable by other AMAs• Avoid repeated courses• Should not use more than 2-3 gms per day, use

for less than 2 weeks and total dose should not exceed 28 gms.

• Regular peripheral blood smear – reticulocyte count

• No combination with other antimicrobials

Remember Adverse Effects and Indications!

Thank you