ANTIBIOTICS

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ANTIBIOTICS

• Agents (may be given iv/po/im) used to treat or occasionally prevent infection ( known as Prophylaxis), also known as antimicrobials (includes antibacterial agents, antifungal agents, anti-parasitic agents)

• NB: Samples from site of infection to be sent to laboratory for identification and antibiotic susceptibility profile- means appropriate antibiotic may be selected

CONTENTS OF LECTURE

• Basis of Antimicrobial Action• Site of Action• Examples of Antibiotic Class, Site of

Activity, Spectrum of Activity, Toxicity, Resistance to Antibiotic

• Antibiotic Policy, Audit, Surveillance• Brief Outline of Antifungal/Antiviral

Therapy

ANTIBIOTICS

• Biologically produced by filamentous fungi and bacteria of the actinomycete family.

• The key to their mode of Action is Selective Toxicity: the ability to inhibit bacteria or other microorganisms, without affecting the host adversely- balance of toxicities

• Action: may be narrow spectrum or broad spectrum

CHOICE OF ANTIBIOTIC• Antibiotics should only be used if indicated• Inappropriate use may be detrimental to the

patient e.g.non-treatment of infection, change of normal flora, development of pseudomembranous colitis

And detrimental to the wider community encouraging the development of Resistance

The House of Lords select committee( Path to Least Resistance) and SARI Report ( A Strategy for the Control of Antimicrobial Resistance in Ireland )

Get Smart campaign in the U.S

CHOICE OF ANTIBIOTIC

IS DETERMINED BY:Bacteria causing infection in that particular

patient, VERY IMPORTANT to SEND SAMPLES FROM INFECTION SITES of patient to Microbiology for gram stain and culture and sensitivity profiles

Spectrum of ActivityHOST FACTORS:

Pharmacokinetics/PharmacodynamicsPresence of Resistance

Four things

SARI REPORT APRIL 2001 RECOMMENDED STRATEGIES

• Recommended Infrastructure

• Surveillance of Antimicrobial Resistance

• National Reference Laboratories

• Monitoring Supply and Use of Antimicrobials

• Development of Guidance for Appropriate Use of Antibiotics

• Education in relation to appropriate use of Antibiotics

• Development of Principles in relation to Infection Control

• Future Research in the Area

Better Prescribing

Complications Appropriate

ANTIBIOTICS

May be:

• Bacteriostatic – inhibits growth of Bacteria, so acts by preventing bacteria from multiplying and then hosts defences deal with the small number of bacteria left

• Bactericidial – kills Bacteria, so eliminates bacteria

HOW TO KILL A CELL

• Damage to CELL WALL or inhibition of it`s synthesis

• Damage to cell membrane

• Alteration of cell proteins and/or nucleic acids

• Enzyme Inhibition

• Inhibition of nucleic acid /protein

FOUR MAIN TARGETS OF ANTIBIOTICS IN BACTERIA

• Cell Wall Synthesis

• Protein Synthesis

• Nucleic Acid Synthesis

• Cell Membrane Function

EXAMPLES OF ANTIBIOTICS WORKING AT TARGET SITES

• Cell Wall Synthesis: B-Lactams e.g. Penicillins, Cephalosporins and Glycopeptides e.g. Vancomycin

• Protein Synthesis: Aminoglycosides, Erythromycin,Tetracyclines, Chloramphenicol, Fusidic Acid

• Nucleic Acid Synthesis: Quinolones, Rifampicin

• Cell Membrane Function: Polymyxin, Amphotericin

3 MECHANISMS OF RESISTANCE

• Alteration in Target Site: target enzyme altered so that it has a lowered affinity for the antibacterial (or additional target enzyme may be synthesized)

• Altered Uptake: so decreasing amount of drug reaches the target, may do this by altering entry into the cell or pumping drug out i.e Efflux Mechanism

MECHANISMS OF RESISTANCE

• Production of enzymes which modify or destroy the antibacterial agent (drug inactivation) –very important e.g. B-lactamases, aminogylcoside modifying enzymes

• ALL TYPES OF RESISTANCE MAY BE CHROMOSOMAL OR PLASMID OR TRANSPOSON MEDIATED

For each Antibiotic consider

• Mechanism of Action

• Spectrum of Activity

• Toxicity

• Resistance

Cell Wall Synthesis Inhibitors

CELL WALL SYNTHESIS INHIBITOR ANTIBIOTICS

B-Lactam antibiotics• Structure: large family of compounds all

containing the B-Lactam ring. The different members are distinguished by the structure of the ring attached to the B-Lactam ring.

• Examples: Penicillins, there is a five member ring attached to the B-Lactam ring, in Cephalosporins a six member ring .

Blactam ring

Mechanism of Action

• Peptidoglycan: a vital component of the cell wall, unique to bacteria.

• B-Lactam antibiotics inhibit cell wall synthesis by binding enzymes called Penicillin Binding Proteins which are responsible for the final stages of peptidogylcan (cell wall) crosslinking or formation, subunits acculmulate in the cell Cell Lysis or Death

Spectrum of Activity

• Benzylpenicillin: mainly active against Gram Positive organisms e.g. Streptococci and Staphylococci

• Ureidopenicillins: active against certain gram positive and gram negative organisms

• Cephalosporins: Broad spectrum of activity gram negative and positive organisms

• Carbapenems : has a broad spectrum of activity even against ESBL producing organisms

TOXICITY

• Serious Allergy : to B-Lactam drugs in the form of immediate hypersensitivity reaction occurs in ~0.004-0.015% of treatment courses

• Mild idiopathic reactions e.g. rash in up to 25% esp. with ampicillin

• 10-20% of those allergic crossreact with cephalosporins

• In renal impaired patients Benzylpenicillin can produce neurotoxicity in high doses

NEVER GIVE INTRATHECIALLY:B-Lactam antibiotics

RESISTANCE TO BLACTAM ANTIBIOTICS

• 3 Mechanisms• Alteration in target site: MRSA produces an

additional PBP, which has lower affinity for B-Lactams and thus cell wall synthesis continues even when other PBP`s are inhibited: Resistant to all B-Lactam antibiotics

• Alteration in access to the target: Gram negative bacteria display this , porin channels alter structure and B-Latam antibiotic cannot get to their target

RESISTANCE TO B-LACTAM ANTIBIOTICS

• Production of B-Lactamases: these enzymes are produced by the bacteria and catalyse the hydrolysis of the B-Lactam ring , so that antibiotic is inactive, some inactivate some e.g. ampicillin but not others cloxacillin or meropenem

To overcome this mechanism of resistance , B-Lactamase inhibitors are added to the antibiotic e.g. clavulanic acid added to ampicillin = augmentin

CELL WALL SYNTHESIS INHIBITORS

Glycopeptides• Large molecules , e.g vancomycin,

teicoplanin• Mechanism of Action: Act at an earlier

stage than Blactams , interfers with cell wall synthesis by binding to D-ala-D-ala at the end of the pentapeptide chains, part of growing cell wall

Absortion/Excretion

• Must be given I.V. for systemic infections as not absorbed from the intestinal tract (useful property when treating C.difficile diarrhoea, when need to treat the organism in the bowel lumen)

• Excretion by the Kidneys

Spectrum Of Activity

• NB: Only active against GRAM-POSITIVE organisms

• Used to treat Staphylococci resistant to B-Lactam antibiotics e.g.MRSA or in patients allergic to B-Lactam drugs

TOXICITY

• Redman Syndrome: must be given slowly over at least an hour I/V

• Potentially Ototoxic• Potentially

Nephrotoxic• Important to assay

blood levels

RESISTANCE

• Resistance can occur especially in enterococci i.e. Vancomycin resistant enterococci (VRE)- may be chromosomal or plasmid mediated

ANTIBIOTICS THAT INHIBIT PROTEIN SYNTHESIS

AMINOGLYCOSIDESStructure: Related molecules containing

either strepitidine(streptomycin) or 2-deoxystreptamine (e.g. gentamicin)

Mechanism of Action: Aminoglycosides kill and inhibit organisms by intering with the binding of formylmethionyl- t RNA to the ribosome, this prevents the formation of initiation complexes from which protein synthesis proceeds.

AMINOGLYSOCIDESABSORPTION/EXCRETION

• Cannot be given orally as it is not absorbed from the gut , so must be given I/V OR I/M

• They do not penetrate well into tissues, bone or cross the blood brain barrier

• They are excreted by the KIDNEYS

AMINOGLYSOCIDES-USES

• GRAM-NEGATIVE SERIOUS INFECTION esp. SEPTICAEMIA e.g. Pseudomonas at dose 5-7 mg.kg per day once daily dosing

• Syneristic activity with B-Lactam antibiotics against Staphylococci and Streptococci

• STREPTINOMYCIN

Used for mycobacterial infections and B-Lactam resistant N.gonorrhoeae

AMINOGLYSOCIDES-TOXICITIES

• Potentially NEPHROTOXIC and OTOTOXIC

• Small therapeutic range , therefore ANTIBIOTIC ASSAY very important especially if patient at risk or has renal impairment

AMINOGLYSOCIDES-RESISTANCE

2 MechanismsMost important is the production of

aminoglycoside-modifying enzymes- often plasmid mediated and transferable between bacteria, the aminoglycoside ia altered in structure resulting in change of uptake of antibiotic, this occurs by one-step mutation

The 2nd mechanism is alterations in cell permeability of cell wall through porin channels

PROTEIN SYNTHESIS INHIBITORS-MACROLIDESetc

• Macrolides, Lincosamides, Streptogramins

• These group share overlapping sites on ribosomes and resistance to macrolides confers ressitance to the other two groups

• Examples: Macrolides-erythromycin and Lincosamides-clindamycin

MACROLIDES

• STRUCTURE: Large cyclic molecules which all contain a macrocyclic lactone ring

• Mechanism of Action: Erythromycin binds to the 23S r RNA in the 50S subunit of the ribosomes and blocks the translocation step in protein synthesis, thereby preventing the release of t RNA after peptide bond formation

MACROLIDES-ABSORBTION/EXCRETION

• Can be administer orally and I/V• Well distributed through the body, even for

intracellular organisms• Drug is concentrated in th liver and excreted

in the bile, some also seen in the urine• Uses: Active against gram-positive

organisms , alternative for Penicillin allergic patients, also active against Legionella, Campylobacter species and mycoplasmas, chlamydiae and rickettsiae

MACROLIDES-TOXICITY

• Relatively non-toxic but may cause nausea and vomiting after oral administration, occasionally causes jaundice

MACROLIDES-RESISTANCE

• Due to alteration in the 23S r RNA target by methylation of two adenine nucleotides in the RNA.

• Resistance is plasmid mediated and inducible ( i.e the presence of erythromycin induces expression of resistance )

INHIBITORS OF NUCLEIC ACID SYNTHESIS

• Inhibitors of Nucleic Acid Precursors: Sulphonamides, Trimethoprim

• Inhibitors of DNA replication: Quinolones

• Inhibitor of RNA polymerase: rifampicin

Quinolone Antibiotics

• Examples: Nalidixic acid, Ciprofloxacin

• Mechanism of Action: Inhibit the activity of DNA gyrase and thereby prevent supercoiling of the bacterial chromosome , this is specific to bacterial cells and thos enot affect mammalian cells

Quinolone Antibiotics

ABSORPTION etc• Adminstered mostly

orally, well absorbed from GI tract

• Excreted mostly in the urine

• Well distributed throughout the body

Spectrum of Activity• Gram negative bacteria• Urinary tract infections• Chlamydiae, Rickettsiae• Legionella species• Atypical mycobacteria• Levofloxacin

/Moxifloxacin have broader spectrum against Gram positive organsisms

QUINOLONES TOXICITY

• Gastrointestinal disturbances most common

• Neurotoxicity and Photosensitivity less common 1-2%

• In children possible toxic effects on cartilage development

• Again may result in normal flora upset

QUINOLONE RESISTANCE

• Spontaneous Chromosomal Resistance• 2 Forms• Changes in the DNA gyrase subunit

structure of the bacteria resulting in lower affinity for the drug

• Changes in cell wall permeability- if other drugs enter by this route there may be cross resistance

ANTIBIOTIC PROPHYLAXIS

• MICROBIAL FLORA

• CHOICE OF ANTIBIOTIC

• TIMING OF ADMINSTRATION

• DURATION

• SIDE EFFECTS

ANTIBIOTIC PROPHYLAXIS

• Patients undergoing certain Surgery e.g. abdominal surgery

• Patients with increased susceptibility to infection e.g. Prosthetic heart valves or post splenectomy

• Patient of normal susceptibility exposed to specific pathogens e.g. Neisseria meningitidis causing meningitis.

• Patients at risk of development of TB, e.g. HIV patients exposed to open TB

ANTIBIOTIC ASSAYS

• Assay when an antibiotic has a narrow therapeutic index e.g Aminoglysocides

• Assay when normal route of excretion iis impaired e.g. patient with renal impairment on vancomycin

• Assay in patients receiving prolonged therapy for serious infection e.g. endocarditis

• Assay in Neonates with serious infection• Assay if failure to respond to therapy• Assay to check compliance

EXAMPLE OF ANTIBIOTIC ASSAYS

• Aminoglysocides e.g. gentamicin

• Glycopeptides e.g. vancomycin

• Isoniazid : to ensure compliance with therapy especially in substance abusers

• Aminoglycosides and Glycopeptides : trough level: taken immediately before dose is given and Peak : taken 1 hour post dose

• Aminoglycosides: trough correlates with toxicity

• Glycopeptides: Trough correlates with adequate therapetic level.

ANTIVIRAL THERAPY

Prevention of viral infection• Virucides: e.g warts and cryotherapy• Antivirals: inhibit viral replication• Prevention of viral infections with the use

of standard precautions and vaccines e.g. Hepatitis B

• Immunoglobulin may be given in certain cases to prevent infection such as rabies

NEWER ANTIFUNGAL AGENTS

• ITRACONAZOLE

• LIPOSOMAL AMPHOTERICIN

• VORICONAZOLE

• DEVELOPING NEW AGENTS: ANTIFUNGAL PEPTIDES SUCH AS ECHINOCANDINS e.g. Capsofungin

HAART for HIV infection

• Highly Active Antiretroviral Therapy• PROTEASE INHIBITORS e.g Saquinavir• NUCLEOSIDE-REVERSE-TRANSCRIPTASE

INHIBITORS e.g ZDV, Didanosine (ddl), 3TC• NON-NUCLEOSIDE REVERSE-

TRANSCRIPTASE INHIBITORS e.g Nevirapine• Recommended antiretroviral: 2 NRTI`s + PI or

NNRTI`s