Antimicrobial drugs

Chemotherapy: The use of drugs to treat a disease.

Antimicrobial drugs: Interfere with the growth of microbes within a host.

Antibiotic of biological origin:

Produced by a microbe, inhibits other microbes.

Today distinction blurred → many newer "antibiotics" are biological products that are Chemically modified or Semi synthesised.

Different types of antimicrobial drugs:

Antibacterial drugs

Antiviral drugs

Antifungal drugs

Antiprotozoan drugs

Antihelminthic drugs

Features of ant imicrobial drugs

Most modern antibiotics come from species of microorganisms that live in the soil.

To commercially produce antibiotic:

Select strain and grow in broth

When maximum antibiotic concentration reached, extract

from medium

Purify

Chemical alter to make it more stable

Features of Ant imicrobial Drugs:

Spectrum of Act iv i tyAntimicrobial medications vary with respect to the range of microorganisms they kill or inhibit.

Some kill only limited range : Narrow-spectrum antimicrobial

While others kill wide range of microorganisms: Broad-spectrum antimicrobial.

Mechanisms of action of Antibacterial Drugs

Inhibit cell wall synthesis

Inhibit protein synthesis

Inhibit nucleic acid synthesis

Injury to plasma membrane

Inhibit synthesis of essential metabolites

Antibacterial Antibiotics

Inhibitors of Cell Wall Synthesis: PenicillinNatural and semisynthetic penicilins contain

β-lactam ring.

Natural penicillins produced by Penicillium are effective against Gram + cocci and spirochetes.

Semisynthetic penicillins: made in laboratory by adding different side chains onto β-lactam ring ⇒ penicillinase resistant and broader spectrum of activity .

Penicillinase ( -lactamase):β Bacterial enzyme that destroys natural penicillins.

Penicillinase resistant penicillins: Methicilin replaced by Oxacilin and Nafcilin due to MRSA

Extended-spectrum penicilins: Ampicilin, Amoxicilin; new: Carboxypenicilins and Ureidopenicillins

(also good against P. ae rug ino sa)

STRUCTURE AND MODE OF ACTION RESEMBLES

PENICILINS

More stable to bacterial

β-lactamases than penicilinsBroader spectrum ⇒

used against penicillin-resistant strains

First-generation: Narrow spectrum, gram-positive.

Example Cefadroxyl, Cephalexin.

Second-generation: Extended spectrum includes

gram-negative.

Example Cefuroxime, Cefaclor.

Third-generation: Includes pseudomonads; mostly

injected, some oral.

Example Cefexime, Ceftriaxone.

Fourth-generation: Most extended spectrum

Example Cefepime, Cefpirome.

Fifth-generation: Specifically target against

resistant strains of bacteria.

Example Ceftobiprole.

Glycopeptide from Streptomyces

Inhibition of cell wall synthesis

Used to kill MRSA

Emerging Vancomycin resistance:

VRE and VRSA

Polyenes, such as nystatin and amphotericin B, for systemic fungal

infections. Inhibition of ergosterol synthesis ⇒

fungicidal Nephrotoxic

Griseofulvin from Penicillium. Systemic/oral.

Binds to tubulin ⇒ For Tine ae

They are smallest infective agents consisting essentially of nucleic acid (either DNA or RNA) enclosed in a protein coat or capsid.

VIRUS

Pox viruses (Smallpox)

Herpes viruses (chicken pox, herpes etc)

Adeno viruses (sore throat, conjunctivitis)

Hepadna viruses (serum hepatitus)

Papilloma viruses (Warts)

RNA VIRUSES

Orthomyxo Viruses (Influenza)

Paramyxo Viruses (Measules, Mumps)

Rubella Viruses (German Measules)

Rhabdo Viruses (Rabies)

Picorna Viruses (Colds, Meningitis, Poliomyelitis)

Retro Viruses (AIDS,T-Cell leukemia)

Arena Viruses (Meningitis, Lassa fever)

Arbo Viruses (Arthopod-borne encephalitis, Yellow Fever)

Replication of a DNA virus in a host cell

Mechanism Action of Antiviral drugs

Inhibition of penetration of host cell.

Amnatadin and rimnatadin inhibit uncoating

and are effective against influenza A

viruses.

Gammaglobulins neutralize viruses.

Inhibition of Nucleic acid Synthesis

Inhibition of Nucleic acid Synthesis-I Acyclovir- Selectively inhibit viral DNA

polymerases.

Example: Herpes viruses.

Gancyclovir-Supressing the replication of DNA.

Inhibition of Nucleic acid Synthesis-II

Vidarabine- Selectively inhibit viral DNA polymerases.

Example : Varicella zoaster.

Rebavirine- Interefere in viral DNA synthesis.

Inhibition of Nucleic acid Synthesis-III

Foscarnet - inhibits viral DNA polymerase by attaching to the pyrophosphate binding site.

Zidovidine – Inhibits reverse transcriptase and effective in HIV.

Antiviral Mechanism of

Action

Nucleoside analogs inhibit DNA

synthesis

Acyclovir and newer derivatives:

Selective inhibition of herpes virus replication.

Acyclovir conversion to nucleotide analog only in

virus infected cells ⇒ very little harm to

uninfected cells!

Examples of Antiprotozoan:

Chloroquine: Malaria

Quinacrine: Giardia

Metronidazole (Flagyl): Vaginitis, anaerobic bacteria

Examples of Antihelminthic:

Niclosamide and praziquantel: Tapeworm.

Mebendazole: broadspectrum antihelmintic.

Ivermectin: nematodes, mites, lice .

Agar Disk Diffusion Method determines susceptibility of an organism to a series of antibiotics: Kirby-Bauer test

Antimicrobial resistance is the ability of microbes, such as bacteria, viruses, parasites, or fungi, to grow in the presence of a chemical (drug) that would normally kill it or limit its growth.

Evolution of drug resistance:

Vertical evolution due to spontaneous mutation

Horizontal evolution due to gene transfer

A variety of mutations can lead to antibiotic resistance

Mechanisms of antibiotic resistance :

Reduce entry of antibiotics into pathogenEnhanced export of antibiotics by eflux pumpRelease of microbial enymes that destroy the antibioticsAlteration of microbial proteins that transform pro-drug to the effective moietiesAlteration of target proteinsDeviation of alternate pathway to those inhibited by antibiotics

Resistance genes are often on plasmids or transposons that can be transferred between bacteria.

Resistance to Antibiotics

Misuse of Antibiot ics

Misuse of antibiotics selects for resistance mutants. Misuse includes

a) Treatment of nonresponsive infectionsb) Therapy of fever of unknown originc) Improper dosaged) Inappropriate reliance on chemotherapy alonee) Lack of adequate bacterioligical information

PROPHYLAXIS• General rule is monotherapy,except in some

situations combine therpy is used Therapy can be Prophlatic,Pre emptive,Emperical,

Definitive or Supparative

ProphylaxisPre-empetive Emperical Definitive Suppresive

No infection Infection Symptoms Pathogen isolation

Resolution

Prophlaxis :

It involves treating of patients who are not yet infected or not developed the diseaseGoal-To prevent development of potentially dangerous diseaseSingle effective non toxic drug can prevent infectionInfection in which prophylaxis is given includes pnemocystis jiroveci,toxoplasma gonidi,candia species,aspergillus sp,cytomegalovirus etcChemoprophylaxis are also given to prevent infection

Pre-emptive therapy

It is an early targeted therapy in high risk patients who already have a laboratory or other test indicating an asymptomatic patient is infectivePrinciple-Delivery of therapy prior to symptomsShort and defined duration

Emperical therapy

It is for symptomatic patient.The 1st consideration in selecting an antimicrobial drug is to determine if the drug is indicatedFor some patiens the cost of waiting a few days is low , these patients can wait for microbioligical evidence of infection without emperical treatmentIn patients were risk of waiting is high emperical therapy is relied on the clinical presentation which may suggest specific microorganism

Definitive therapy

Once pathogen has been isolated and susceptibility results are available,therapy should be streamlined to a narrow targeted antibioticsMonotherapy is prefered to decrease the risk of antimicrobial toxicity and selection of antimicrobial resistant pathogenProper antimicrobial dose and dose shedule are crucial to maximize efficacy and minimize toxicity

COMBINATION THERAPY

When the inhibitory or killing effect of two or more antimicrobial used together are significantly greater than expected from their effects when used individually synergism resultsMECHANISM : 1) Blockade of sequential steps in a metabolic

sequence2) Inhibition of enzymatic inactivation3) Enhancement of antimicrobial agent uptake

Eg: penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter.

Other combinations of drugs can be antagonistic.

MECHANISM : 1)Inhibion of cidal activity by static agent 2)Induction of enzymatic inactivation For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth.

Combination therapy is used for :

Preventing resistance to monotherapyAccelerating the rapidity of microbial killingEnhancing therapeutic efficacy by use of synergestic interactions or enhancing kill by a drug based on mutation generated by resist to another drugParadoxically reducing toxicity