Kursk State Medical University

Department of clinical pharmacology

Clinical pharmacology of ntimicrobial drug

Professor, doctor of medicine Mal G.S.

Kursk 2007

Introduction 1. An antimicrobial drug is a chemical substance that destroys disease-causing microorganisms with minimal damage to host tissues. 2. Chemotherapeutic agents include chemicals that combat disease in the body.

The History of Chemotherapy

1. Paul Ehrlich developed the concept of chemotherapy to treat microbial diseases; he predicted development of chemotherapeutic agents that would kill pathogens without harming the host. 2. Sulfa drugs came into prominence in the late 1930s. 3. Alexander Fleming discovered the first antibiotic, penicillin, in 1929; its first clinical trials were done in 1940.

Antibiotic
Antibiotic substance produced by one microorganism that is inhibitory or toxic against other microorganism

An antibiotic can be effective against a -narrow group of microbes or -broad group of microbes (broad-spectrum antibiotic)- disadvantage- eliminates also the normal microflora

The Spectrum of Antimicrobial Activity

1. Antibacterial drugs affect many targets in a prokaryotic cell. 2. Fungal, protozoan, and helminthic infections are more difficult to treat because these organisms have eukaryotic cells. 3. Narrow-spectrum drugs affect only a select group of microbes gram-positive cells, for example; broad-spectrum drugs affect a large number of microbes. 4. Small, hydrophilic drugs can affect gram-negative cells. 5. Antimicrobial agents should not cause excessive harm to normal microbiota. 6. Superinfections occur when a pathogen develops resistance to the drug being used or when normally resistant microbiota multiply excessively.

The Action of Antimicrobial Drugs

1. General action is either by directly killing microorganisms (bactericidal) or by inhibiting their growth (bacteriostatic). 2. Some agents, such as penicillin, inhibit cell wall synthesis in bacteria. 3. Other agents, such as chloramphenicol, erythromycin, tetracyclines, and streptomycin, inhibit protein synthesis by acting on 70S ribosomes. 4. Agents such as polyrnyxin B cause injury to plasma membranes. 5. Rifampin and the quinolones inhibit nucleic acid synthesis. 6. Agents such as sulfanilamide act as antimetabolites by competitively inhibiting enzyme activity.

Antibacterial antibiotics:
1. 2. Bactericidal kills the microbes Bacteriostatic inhibits the growth

Sites of antimicrobial action:

Cell wall synthesis Protein synthesis DNA synthesis Synthesis of metabolites

Table 1. Activity (range) of various antimicrobial classes. Microorganism Bacteria Aminoglycoside s Beta-lactams Chloramphenic ol Lincosamides Macrolides Pleuromutilins Tetracyclines Quinolones Sulfonamides Trimethoprim + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Mycoplasma + Rickettsia Chlamydia Protozoa

Adapted from Prescott, JF and Baggot, JD. Antimicrobial Therapy in Veterinary Medicine. Second Edition.

Table 2. Antibacterial activity (spectrum) of antimicrobial agents. Aerobic bacteria Anaerobic bacteria

Spectrum

Gram (+)

Gram (-)

Gram (+)

Gram (-)

Examples

Broad Intermediate

+ + +

+ + +

+ + +

cefoxitin, chloramphenicol, imipenam, tetracyclines carbenicillin, ticarcillin, ceftiofur, penicillin/clavulanic acid, cephalosporins ampicillin, amoxicillin aztreonam, polymyxin

Narrow + + + + +

+ +

benzyl penicillin G aminoglycosides, spectinomycin, sulfonamides, trimethoprim enrofloxacin

+ + +

lincosamides, macrolides, pleuromutilins, vancomycin bacitracin

nitroimidazoles

variable activity

Table 5. Basic Pharmacokinetics of Antimicrobial Drugs. Absorption Aminoglycosides None oral; Good IM, SC Distribution Extracellular fluid only (ECF); Not CNS ECF; Some get CNS Elimination Renal (filtration)

Cephalosporins

Fair oral; Good IM, SC

Renal (acid pump); Renal (filtration) Renal (filtration) Hepatic (secretion); Hepatic (metabolism) Renal (acid pump); Renal (filtration) Renal (filtration); Hepatic (metabolism); Hepatic (secretion)

Fluoroquinolones Macrolides

Good oral Variable oral; Fair to Good IM Variable oral; Variable IM, SC Good oral; Good IM

TBW TBW; Good intracellular

Penicillins

ECF; Variable with drug

Sulfonamides

ECF, TBW

Tetracyclines

Variable oral

TBW

Renal (filtration); GI (doxycycline)

Table 3. Mechanisms of action of antimicrobial agents.

Cell wall synthesispenicillins, cephalosporins, bacitracin, vancomycin.

Protein synthesis chloramphenicol, tetracyclines, aminoglycosides, macrolides, lincosamides, pleuromutilins Cell membrane Polymyxin, aminoglycosides, amphotericin, imidazoles vs fungi

Nucleic acid function Intermediary metabolism

nitroimidazoles, nitrofurans, quinolones, rifampin (some antiviral compounds especially antimetabolites) sulfonamides, trimethoprim

Oral Administration
Availability (purchase) Most antimicrobials available Oral aminoglycosides are "topical" (for GI tract infection) Not all members of beta-lactams available orally Appropriate Uses Appropriate for mild to moderate infections Inappropriate for life threatening infections Inappropriate for systemic action of aminoglycosides

Intravenous Administration
Availability Most antimicrobials available
all aminoglycosides all tetracyclines, chloramphenicol, macrolides all representative actions for beta-lactams most sulfonamides

Some available forms are nearly unsuitable (Tribrissen 48%)

Appropriate Uses
Life threatening infections When intramuscular is contraindicated
tissue irritation thrombocytopenia, hemostatic disorder, etc. severe dehydration (limits absorption see below)

When steady sustained concentrations are desired (rarely indicated)

done by constant intravenous infusions

To avoid injection site residues

Patient pharmacokinetics
Absorption is always the most variable (as compared to IM, SC) between patients when the oral route is used Even greater variability with disease states
Enteritis Motility Disorders GI blood flow disturbances Liver disease

Rarely a good route for ruminants

slow release from rumen metabolized by rumen microflora

Intramuscular (IM) / Subcutaneous (SC) Administration

Availability Most antimicrobials available
all aminoglycosides tetracyclines, chloramphenicol, macrolides

Reasons for SC vs IM may be regulatory or physiologic Subcutaneous route should be avoided if:
the drug is irritating ambient temperature is cold animal is dehydrated IM route is also out if the patient is in shock

Appropriate Uses
Life threatening infections
use rapidly absorbed products (also avoids prolonged residues)

When oral route is inappropriate

vomiting absorption affected by GI disease ruminants

Patient pharmacokinetics
Most predictable of the routes Continuous (steady state) infusions no longer in vogue Peak concentrations may be toxic (or waste drug)
most iv "bolus" antibiotics should be given over 5 - 30 minutes

Absorption
Chloramphenicol
oral - usually good im, sc - usually good. some controversy between dose forms

Macrolides (and lincosamides)

oral - usually good im, sc - usually good

Absorption
Tetracyclines
oral - usually good im, sc - usually good. "Sustained release" dose form available.

Sulfonamides
oral - usually good, some specific forms are not absorbed well by design (e.g. sulfasalazine). im, sc - usually good

Distribution
Most distribute to intracellular space organic bases - tissue concentrations >> plasma concentrations erythromycin, clindamycin, azithromycin, trimethoprim, metronidazole

Distribution
Improves (higher concentrations in cells, CNS, prostate) as lipophilicity increases Tetracyclines
least lipophilic to most lipophilic tetracycline, oxytetracycline < < doxycycline < minocycline

sulfonamides behavior depends on pKa and surrounding conditions sulfisoxazole

low pKa = 5.0 ionized in blood stream lower Vz

sulfamethazine
pKa = 7.0 less ionized higher Vz

Lipid soluble (relatively less water soluble)

Elimination Hepatic - microsomal or biliary excretion
Lipid solubility reduces renal clearance Biliary excretion may lead to prolonged exposure of GI microflora Rates of elimination vary between species All first order at therapeutic doses

Variably soluble (Fairly soluble in both water and lipid)

Elimination Route varies with solubility Low lipid solubility - renal elimination High lipid solubility - hepatic elimination, "GI" elimination Biliary excretion may lead to prolonged exposure of GI microflora

Table 4. Basic Pharmacodynamics of Antimicrobial Drugs. Mehanism of Action Aminoglycosides Protein synthesis, Cell membrane leak Cell Wall Synthesis General Spectrum Gram (-), Gram (+), Not anaerobes Gram (+), Gram (-) Resistance Mechanism Inactivation, Exclusion, Reduced affinity Inactivation, Exclusion, Reduced Affinity Toxicity Nephrotoxic, NMJ block, Ototoxic, Vestibular Hypersensitivity, Immune reactions, Drug Fevers

Cephalosporins

Fluoroquinolones

DNA Gyrase

Gram (+), Gram (-), Mycoplasma, Not anaerobes Gram (+), Mycoplasma

Altered binding

Cartilage damage (juveniles)

Macrolides

Protein synthesis

Exclusion

GI intolerance, NMJ block, Myocardial depression

Penicillins

Cell Wall Synthesis

Gram (+), Gram (-)

Inactivation, Exclusion, Reduced Affinity Competition, Alternate Pathways, Reduced Affinity

Hypersensitivity

Sulfonamides

Folic Acid Synthesis

Gram (+), Gram (-), Protozoa

Immune reactions (KCS, polyarthritis), Nephrotoxic, Hemolytic anemia, depression anemia

Tetracyclines

Protein synthesis

Gram (+), Gram (-), Exclusion mycoplasma, Rickettsia, Chlamydia

Nephrotoxic, GI irritation, Hepatotoxic, Phototoxic, Dental/Bone (juveniles)

Synergistic
action of the combination is significantly greater than the sum of the actions of each component. sequential inhibition of successive steps in metabolism (trimethoprim-sulfonamide) sequential inhibition of cell wall synthesis (mecillinamampicillin) facilitation of drug entry of one antibiotic by another (betalactam - aminoglycoside) inhibition of inactivating enzymes (ampicillin - clavulanic acid) prevention of emergence of resistant populations (erythromycin - rifampin)

Antagonistic action of the combination is significantly less than the sum of the actions of each component. Most commonly cited is "bacteriostatic drug inhibits action of bacteriocidal". Usually, bacteriostatic activity is sufficient for cure and you only waste money. Antagonism is only evident (clinically) when the patient is dependent on the antimicrobial for survival or cure. Two antimicrobials may compete for the same binding site. This is unlikely to have a clinical effect as each site can only be inhibited once. You just wasted some more money. One antimicrobial may inhibit of cell permeability to a second antimicrobial. Frequency and significance of this is uncertain. One antimicrobial may cause "derepression" of resistance enzymes for a second. Administration of older beta-lactam can increase production of beta-lactams directed against new cephalosporins.

Susceptibility of Individual Isolates

Isolate a bacterial "isolate" commonly refers to an individual bacterial strain isolated from infected material taken from a patient. The colonies on a plate in a microbiology lab each arise from a single bacteria, but all the colonies (of one type) are taken to represent an isolate from the patient. Minimum Inhibitory Concentration (MIC) MIC is the concentration of antimicrobial required to inhibit the growth of a particular bacterial isolate in vitro. Dose regimens in common use generally produce plasma concentrations 2s - 4 x the MIC. Clinically the MIC is used to assign an organism to a susceptibility category (sensitive, intermediate, resistant).

MIC50
the concentration that will inhibit 50% of the isolates of a given bacterial class (e.g. genre). The numeric subscript may be any percentage historical isolates. Useful in selection of drugs for suspected organisms or isolates of unknown susceptibility. Selection of drugs that can be administered to produce an MIC90 in the target tissue for the suspected organism should have a higher success rate for a given situation.

Dose form controls rate of release

simple neutral salts in aqueous vehicle are rapidly released from injection site esters, oily vehicles, procaine salt etc. are slowly released from injection site

CEPHALOSPORINS
Cephalosporins are probably used more than any other single class for surgical prophylaxis Good spectrum (in a general sense) Considerable safety Tissue penetration is likely to be sufficient as confirmed experimentally. Good activity against Staphylococcus spp., anaerobes excepting certain Bacteroides spp., and gram negative organisms including the EnterobacteriaceaeEffective against this range of organisms but is less active against gram negative infectionsEffective against this range of organisms AND against anaerobes that may be resistant to other beta lactams. Reserve for Bacteroides fragilis.Activity for Klebsiella spp. and Pseudomonas spp. Use for Anticipated "E. coli from hell"

Cell wall
Penicillin - interferes with the formation of peptidoglycan layer in the cell wall of bacteria (not present in eucaryotic cells). Bactericidal. 1. Natural penicillin
- Narrow spectrum antibiotic (staphylococci, streptococci, and spirochetes) - It is rapidly excreted from the body. - More efficient when injected than when taken orally. - It is susceptible to penicilinases (enzymes that cleave the penicillin molecule).

2. Semisynthetic penicillins are partially produced by Penicillium and partially by chemical process. (The shape of a molecule is changed)

Commonly Used Antimicrobial Drugs

Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis 1. All penicillins contain a b-lactam ring. Penicillins inhibit peptidoglycan synthesis. 2. Natural penicillins produced by Penicillium are effective against gram-positive cocci and spirochetes. 3. Penicillinases (b -lactamases) are bacterial enzymes that destroy natural penicillins. 4. Semisynthetic penicillins are made in the laboratory by adding different side chains onto the b -lactam ring made by the fungus. 5. Semisynthetic penicillins are resistant to penicillinases and have a broader spectrum of activity than natural penicillins. 6. The monobactam aztreonam affects only gram-negative bacteria.

Commonly Used Antimicrobial Drugs

7. Cephalosporins inhibit cell wall synthesis and are used against penicillin-resistant strains. 8. Carbapenems are broad-spectrum antibiotics that inhibit cell wall synthesis. 9. Polypeptides such as bacitracin and polymyxin B are applied topically to treat superficial infections. 10. Bacitracin inhibits cell wall synthesis primarily in grampositive bacteria. 11. Vancomycin inhibits cell wall synthesis and may be used to kill penicillinase-producing staphylococci. 12. Isoniazid (INH) inhibits mycolic acid synthesis in mycobacteria. INH is administered with rifampin or ethambutol to treat tuberculosis. 13. The antimetabolite ethambutol is used with other drugs to treat tuberculosis.

Tetracycline
- Interferes with attachment of tRNA to mRNA - Bactriostatic - Produced by Streptomyces -Broad-spectrum, effective against Gr+ and Gr- bacteria, rickettsias and chlamidias - Good penetration of the body tissue.

Inhibition of nucleic acid synthesis

Rifamycin
Inhibits the synthesis of mRNA Used for treatment of mycobacterial infections (tuberculosis) Good penetration of tissues Bactericidal.

Injury to the plasma membrane Interfering with the metabolism

Polymixin B
- Changes the permeability of plasma membrane (gr bacteria) - Bactericidal - Bacteria require PABA ( para-aminobenozoic acid) for synthesis of folic acid (essential for synthesis of nucleic bases)

Inhibitors of Nucleic Acid (DNA/RNA) Synthesis 1. Rifamycin inhibits mRNA synthesis; it is used to treat tuberculosis. 2. Quinolones and fluoroquinolones inhibit DNA gyrase for treatment of urinary tract infections. Competitive Inhibitors of the Synthesis of Essential Metabolites 1. Sulfonamides competitively inhibit folic acid synthesis. 2. TMP-SMX (trimethoprim-sulfamethoxazole) competitively inhibits dihydrofolic acid synthesis for treatment of urinary tract and intestinal infections.

Antifungal drugs
Amphotericin B
- The most commonly used antifungal antibiotic - Produced by Streptomyces - It combines with sterols (components of fungal plasma membrane) causing an increase of its permeability - Toxic to kidneys.

Griseofulvin
Effective against fungi infecting hair and nails. Binds to keratin Taken orally Interferes with fungal reproduction

Antiprotozoan and Antihelminthic Drugs

1. Chloroquine, quinacrine, diiodohydroxyquine, pentamidine, and metronidazole are used to treat protozoan infections. 2. Chloroquine and quinacrine stop DNA synthesis by intercalation between base pairs. 3. Antihelminthic drugs include niclosamide, mebendazole, praziquantel, and piperazine. 4. Mebendazole disrupts microtubules; pyantel pamoate paralyzes intestinal roundworms.

Antiviral drugs
Viruses cause 60% of infectious diseases. There is a limited number of antiviral drugs (endocellular pathogens). Acyclovir
effective against herpesvirus (genital herpes) The drug has a structure similar to quanosine nucleoside (component of DNA) A false nucleotide is formed that stops further synthesis of DNA.

Zidovudine
Used for treating AIDS patients The drug blocks the reverse transcriptase synthesis of DNA from RNA

Antiviral Drugs
1. Amantadine blocks penetration or uncoating of influenza A virus. 2. Nucleoside and nucleotide analogs such as acyclovir, AZT, ddI, and ddC inhibit DNA or RNA synthesis. 3. Protease inhibitors, such as indinavir and saquinavir, block activity of an HIV enzyme essential for assembly of a new viral coat. 4. Alpha-interferons inhibit the spread of viruses to new cells.

Classification of semisynthetic penicillins

1. Acid resistant alternatives to penicillin G, Phenoxymethyl penicillin (penicillin V), Phenethicillin 2. Penicillinase resistent penicillins
Methicillin,Oxacillin, Cloxacillin, Picloxacillin, Flucloxacillin, Nafcillin.

3. Extended spectrum penicillins

a) Aminopenicillins: Ampicillin, Bacampicillin, Pivampicillin, Hetacillin, Amoxicillin. b) Carboxypenicillins; Carbenicillin indanyl, Carbenicillin phenyl (Carfecillin), Ticarcellin. c) Ureidopenicillins: Azlocillin, Mezlocillin, Piperacillin. d) Mecillinam (Amdinocillin )

-lactamase inhibitors - Clavulanic acid, Sulbactam

Antimicrobial drugs
B. Mechanism of Action 1. Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitratin. 2. Cause Lekage from cell membranes: Polypeptides - Polymyxins, Colistin, Bacitracin; Polyenes - Amphotericin-B, Nystatin, Hamycin. 3. Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin. 4. Cause misreading of m-RNA code (bind to SOS ribosomes): Aminoglycoside-Streptomycin. 5. Interfere with DNA function: Rifampicin, Noriloxacin, Metronidazole. 6. Interfere with DNA sinthesis: Idoxuridine-, Acyclovir, Zidovudine. 7. Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimetoprim, Pyrimethamine, Ethanbutol.

Antimicrobial drugs (2)

C. Type of organisms aganist which primary active. 1. Antibacterial: Penicillins, Aminoglycosides, Erithmomycin etc. 2. Antifungal: Griseofulvin, Amphotericin B, Ketoconazole etc. 3. Antiviral: Idoxuridine, Acyclovir, Amantadine, Zidovudine etc. 4. Antiprotozoal: Chloroguine, Pyrimethamine, Metronidazole, Diloxanide. 5. Athelmintic: Mebendazole, Piperazine, Pyrantel, Niclosamide etc.

Antimicrobial drugs
Spectrum of activiti:
Narrow spectrum Penicillin G Streptomycin Erythromycin Broad spectrum Tetracyclines Chloramphenicol Primarily bactericidal Penicillins Cephalosporins Polypeptides Vancomycin Aminoglycosides Nalidixis acid Rifampin Ciprofloxacin Clotrimoxazol Isoniazid Actinomycetes Aminoglycosides Tetracyclines Chloramphenicol Macrolides Polyenes

Type of action

Primarily bacteriastatic Sulfonamides Tetracyclines Chloramphenicol Erythromycin Ethambutol Fungi Penicillin Cephalosporin Griseofulvin

Antibiotics are obtained from

Bacteria Polymyxin Colistin Bacitracin Tyrothricin Aztreonam

Schematic presentation summarizing the targets of antibiotic action.

 -Lactam antibiotics Route of administration

Class
Penicillins -Lactamase susceptible Narrow spectrum Enteric active Enteric active and antipseudovonal

Parenteral
Penicillin G Ampicillin Carbenicillin, Ticarcillin, Mezlocillin, Azlocillin, Piperacillin

Oral

Penicillin V Amoxicillin, Ampicillin Indanyl, Carbenicillin

-Lactamase resistant Methicillin, Oxacillin, Nafcillin Ticarcillin Cloxacillin, Dicloxacfflin Antistaphylococcal combinations plus clavulanic acid, Ampicillin plus Amoxicillin plus clavulanic with p-Lactamase inhibitors Sulbactam acid Cephalosporins First generation Second generation Haemophilus active Bacleroides active Third generation Extended-spectrum Extended-spectrum and antipseudomonal Carbapenems Cephalexin, Cephradine, Cefadroxil

Cefazolin, Cephalothin, Cephapirin

Cefamandole, Cefuraxine, Cefonicid, Cefaclor, Cefuroxime Axetin, Ceforanide Cefixime, Cefpozil, Cefpodoxime, Loracarbef None Cefoxitin, Cefotetan, Cefmetazole Ceftriaxone, Cefotaxime, Ceftizoxime None Ceftaxidime, Cefoperazone Imipenem-cilastatin None

CEPHALOSPORINGS
Parenteral First generation Cephalothin, Cephapirin, Cefazolin, Cephaloridine Cefamandole, Cefoxitin, Cefuroxime Third generation Cefotaxime, Ceftizoxime, Ceftriazone, Moxalactam Fourth generation Ceftazidime, Cefoperazone Cefixime Cephalexin, Cephradine, Cefadroxil Cefaclor Oral

Second generation

Drug characteristics
cephalothin, cephaprin, cephradine, cefazolin, cefamandole and cefsulodin Peak tissue concentrations within the first hour after administration Effective concentrations are maintained for at least 5 hours cefoxitin and ceftazidime Peak concentration somewhat later Effective tissue concentrations are achieved within the first hour Effective concentrations are maintained for at least 5 hours ampicillin, oxacillin, ticarcillin, and piperacillin Peak within the first hour after administration Effective concentrations of penicillins maintained for 4 to 6 hours aminoglycoside Peak concentration 1.0 - 1.5 hours after intravenous administration MICs were maintained for 4.0 to 6.0 hour clindamycin Effective concentrations of clindamycin may not be achieved during the first dose interval Accumulate in excess of the MIC within the first 2 - 3 dose intervals Stable concentrations are then maintained for greater than 6 hours (after last dose)

AMINOGLYCOSIDES (1)
DRUG DOSAGE SPECIAL FEATURES TOXICITY USES Aminacin / 7.5mg/kg i.m.. Semi-synthetic Mainly highResistant Gramor i.v. twice derivative of Amikin/ tone deafness negative infections daily t'/2 = 2h kanamycin, velatively especially Pseudomonas and Mic 2mg/ml resistant to enzyme Klebsiella. An Proteus Mic inactivation compared alternative for 6mg/ml to gentamicin and gentamicinPseudomonas tobramycin resistant strains. aeroginosa Can also be given iT., iP. Torbamyci 50-80mg i.m. 8 Active aganist some hourly n /Nebcin/ Pseudomonas strains Kinetics resistant to similar to gentamicin streptomycin; t'/2\ - 2h Vestibular toxicity Pseudomonas infections as alternative to gentamicin /but cross-resistance with gentamicin is frequent/ Alternative to gentamicin

Netitfmicin 6mg/kg daily Similar to gentamicin Probably less oto- and /Netillin/ in 2 or 3 nephrotoxic divided doses than gentamicin Capreomy cin Ig i.m./day Onky active aganist mycobacteria Eosinophilia and drug

Tuberculosis only

AMINOGLYCOSIDES (2)
DRUG Neomycin SPECIAL TOXICITY USES FEATURES Not now used Mixture of Sensitisation is Topical for systemically neomycins BandC used topically. staphilococcae and Topical use Gram-negative because of (skin or ear) infections. Gut deafness may produce sterilisation in liver 4g/day orally. irreversible disease. Inhalation deafness. DOSAGE

Framycetin Not now used Could be neomycin Local Mainly gut systemically B or similar to it -sensitisation sterilisation and 2-4g/day topical applications orally. Paramomycin Not used systemically l-2g/day orally. Effective against Entamoeba Histolytica (probably also Taenia) Intestinal infections, amoebicide, anthelmintic

Vancomycin / Vancocin/

1 gi.v. 12 Activity against Deafness, local Septicaemia Gram-positive complicated by hourly venous maintains organisms of main thrombosis endocarditis due to Staph. or Strep. therapeutic interest clinically especially for Enterocolitis due level of 10 staphylococcus, Staph. or mg/ml t1/2= 4-

MECHANISMS OF ACTION AND DISTANSE FOR MAJOR CLASSES OF ANTIBACTERIAL AGENTS

ANTIBACTERIAL AGENT -lactams (penicillins and cefalosporins) MAJOR CELLULAR TERCET Cell wall MECHANISM OF ACTION Inhibits cell wall cross - linking MAJOR MECHANISMS OF RESISTANCE 1. Drug inactivation (-lactamase) 2. Insensitive target (altered penicillinbinding protein) 3. Decreased permetability (altered gramnegative outer - membrane porins)

Vancomycin Bacitracin

Cell wall Cell wall

Interferes with the Alteration of target (substitution of addition of new cell terminal amino acid of peptidoglycan wall subunitis subunit) Prevents addition of cell wall subunits by inhibiting recycling of membrane lipid carrier Binds to 50 s ribosomal subunit Binds to 50 s ribosomal subunit Binds to 50 s ribosomal subunit Not defined

Macrolides (Erythromycin) Lincosamides (Clindamycin) Chloramphenicol tetracycline

Protein synthesis Protein synthesis Protein synthesis

Alteration of target (ribosomal methylation) Alteration of target (ribosomal methylation) Drug inactivation (chloramphenicol acethyltransferase) 1 . Decreased intracellular drug accumulation (active et flux)

CURRENT USE OF ANTIMICROBIAL AGENTS IN THE THERAPY OF INFECHIONS

Gram-positive cocci Diseases First Streptococcus agalactiae /group B/ Bacteremia Meningitis Ampicillin or Penicillin G +aminoglycoside Drug order of choice Second Cephalosporin Cephalosporin Third Erythromycin Chloramphehicol

Streptococcus bovis Streptococcus /anaerobis species/

Endocarditis Bacteremia bacteremia endocarditis brain and other abscesses sinusitis

See viridans streptococci Penicillin G Cephalosporin Clindamycin Chloramphehicol Erythromycin

Streptococcus pneumoniae /pneumococcus/

Pneumonia Penicillin G or V Arthritis Sinusitis Otitis

Cephalosporin Erythromycin

Chloramphehicol Clindamycin Trimethoprim Sulfamethoxazole

Meningitis or other serious infections

Penicillin G

Cefuroxime or a Chloramphehicol third - generation cephalosporin

CURRENT USE OF ANTIMICROBIAL AGENTS IN THE THERAPY OF INFECHIONS Gram-negative Diseases Drug order of choice
Bacilli First Second Third

Escherichia coli

Urinary tract infection

Trimethoprimsulfamethoxazole ampicillin + aminoglycoside

Cephalosporin Aztreonam penicillin+ penicillinase nitrofurantion inhibitor aminoglycoside tetracycline ciprofloxacin or norfloxacin sulfonamide

Other infections Ampicillin + an Aminoglycoside aminoglycoside penicillin+ penicillinase bacteremia cephalosporin inhibitor aztreonam Enterobacter Urinary tract species and other infections Proteus mirabilis Urinary tract and other infections Cephalosporin aminoglycosi Ampicillin or amoxicillin

Trimethoprim sulfamethoxa-zole

broad-spectrum penicilltt Trimethoprim aztreonam sulfamethoxa-zole imipenem Cephalosporin aminoglycoside Aztreonam imipenem Aztreonam

Proteus other Urinary tract species and other infections Pseudomonas Urinary tract aeruginosa infection

Aminoglycoside Broad-spectrum cephalosporin penicillhn penicillin+ penicillinase inhibitor Broad-spectrum Aminoglycoside penicill in aztreonam

CURRENT USE OF ANTIMICROBIAL AGENTS IN THE THERAPY OF INFECTIONS

Gramnegative cocci Neisseria gonorrhoeae (gonococcus) Diseases First Penicillinaseproducing Penicillinsensitive Ceftriaxone Ampicillin + probenecid or amoxicillin + probenecid Penicillin G + probenecid Penicillin G Drug order of choice Second Third

Cefuroxime or Ciprofloxacin cefoxitin Ceftriaxone or Erythromycin tetracicline Ciprofloxacin

Neisseria Meningitis meningitidis bacteremia (meningococcus )

Cefuroxime or a Chloramphenicol third generation of cephalosporin Ceftriaxone Minocycline Ciprofloxacin

Carrier state Rifampin (posttreatment) Branhamella catarrhalis

Otitis Sinusitis Beta-lactamase Trimetoprim- Ciprofloxacin inhibitor + sulfonathoxazol Tetracycline Pneumonia

CURRENT USE OF ANTIMICROBIAL AGENTS IN THE THERAPY OF INFECHIONS

Gram-positive Bacilli Diseases First Penicillin g Penicillin g erythromycin Drug order of choice Second Third

Bacillus anthracis "Malignant pustule" pneumonia Corynebacterium diphtheriae Pharygitis, laryngotracheitis, pneumonia, other local lesions carrier state

Erythromycin Cephalosporin tetracycline chloramphehicol Erythromycin penicillin g Cephalosporin clindamycin rifampin -

Corynebacterium Endocarditis infectid species aerobic foreigh bodies and anaerobic bacteremia /dihtheroids/ Listeria monocytogenes Meningitis

Penicillin g+aminoglycoside vancomycin Ampicillin or penicillin+-

Rifampin+ penicillin g ampicillin+ sulbactam Trimethoprimsulfamethoxa-

Bacteremia

Gentamicin

Sole

Erythromycin tetracycline chloramphehicol

Erysipelothrix rhusiopathiae Clostridium

Erysipeloid Gas gangrene

Penicillin g Penicillin g

Erythromycin Chloramphehicol tetracycline Cefoxitin Imipenem

Empirical antimicrobial therapy for the management of hospitalized patients with community-acquired pneumonia
Patogen Penicillin G First-generation Second or third cephalosporin generation cephalosporin + + + + + + + + + +

S. pneumoniae S. aureus H. influenzae M.catarrhalis Anaerobic gram positive cocci Anaerobic gram negative bacilli

Pathogen

Empirical oral antimicrobial therapy for outpatient management of community-acquired pneumonia

Penicillin G
+ + + + + + + + + + + + + +

Amoxillin Cefuroxime Trimethopim clavulanate Sulfamethoxazole

S.pneumoniae H.influenzae M.catarrhalis Anaerobes M.pneumoniae C.pneumoniae L.pneumoniae

Empirical antimicrobial therapy for the management of hospitalized patients with community-acquired pneumonia
Pathogen Metronidazole Trimethoprim Erythromycin Ampicillm sulfamethoxazol sulbactam e ++ + + + ++ + + + + +

S. pneumoniae S. aureus H. influenzae M. catarrhalis Anaerobic grampositive cocci Anaerobic gramnegative bacilli C. pneumoniae

Empirical oral antimicrobial therapy for outpatient management of community-acquired pneumonia

Pathogen S.pneumoniae H. influenzae M.catarrhalis Anaerobes M.pneumonia e C.pneumonia Doxycvclin Erythromycin Ciprofloxacin e + + + + + + + + + + + + +

Mechanism of action and resistance for major classes of antibacterial agent (1)
Antibacterial agent Major cellular target Mechanism of action Major mechanisms of resistance

Aminoglycoside Protein s (Gentamycin) synthesis Mupirocin Protein synthesis

Binds to 30-S Drug inactivation ribosomal subunit (aminoglycoside-modifying enzyme) Inhibits isoleucine Insensitive target (mutation T-RNA synthetase of target gene or acquisition of gene for new, insensitive enzyme) Production of insensitive targets [dihydropteroic acid (sulfonamides) and dihydrofolic acid (trimethoprim)] that bypass metabolic block Insensitive target (mutation of polymerase gene)

Sulfonamides and Trimethoporim

Cell Competitively metabolism inhibits eniymes involved in two steps of folk acid biosynthesis DNAsynthesis Inhibits DNAdependent RNA polymerase

Rifampin

Mechanism of action and resistance for major classes of antibacterial agent (2)
Antibacterial agent Major cellular target Mechanism of action Major mechanisms of resistance

Metronidasole DNAIntracellular by Not defined synthesis generates short-lived reactive intermediates by electron transfer system Quinolones DNAInhibition of DMA synthesis gyrase (a subunit) 1. Insensitive target (mutation of gyrase genes) 2. Decreased inti acellular accumulation Not defined

Novobiocin

DNAInhibition of DMA synthesis gyrase (a subunit)

Polymixins Cell Disrupts membrane Not defined (Polymixins B) membrane permeability by charge alteration Gramicidin Cell Forms pores Not defined

IMPORTANT DRUG-RESISTANT PATHOGENS IN HOSPITAL PRACTICE AND IN EXTENDED CARE FACILITIES Pathogen Common Sites Available Therapy of infection
Methicillin-resistant S. aureus Blood Lung Wounds/decubitus ulcers Skin/soft tissue Sinusitis Vancomycin Quinupristin-Dalfopristin Oxazolidinones Trimethoprin/ Sulfamethoxazole Rifampin (always in combination with another drug) Minocycline

Vancomycin-resistant enterococci

Urinary tract Blood Quinupristin-Dalfopristin Intraabdominal Oxazolidinones abscess Urinary tract Lung Ceftazidime (some Wounds strains) Dependent on in

Pseudomonas aeruginosa

EMPIRICAL TREATMENT REGIMENS FOR UNCOMPLICATED UTI

Condition Acute cystitis Most likely pathogen E. Coli S. saprophyticus P. mirabilis K. Pneumonia Enterococcus spp. P. mirabilis K. Pneumonia Enterococcus spp. Contributing factors Recommended empirical therapy none oral fluoroquinolones1,2or 2nd or 3rd generation cephalosporins3,4,5 Amoxicillin10/3days same as above but 7 days

male sex/diabetes age > 65/recent antibiotic use mild-moderate oral fluoroquinolones1,2 illness outpatient cefixime4 or cefpodoxime5 therapy Amoxicillin10 parenteral 3rd Severe illness or generation cephalosporins 6 or possible urosepsis quinolones +/- aminoglycoside7-8 hospitalization piperacillin/tazobactam9 until required clinically stable; shift to oral1,2, 3,4

Acute pyelonephritis

1 Norfloxacin (400 mg) or ofloxacin 200 mg Q 12 hrs 6. Ceftriaxone 2 g Q 24hrs 2 Ciprof!oxacin 500 mg Q 12hrs 7. Ciprofloxacin 200-400 mg Q 12hrs 8. Tobramycin/gentamicin 160mg loading then 80mg Q8hrs 3. Cefuroxime axetil 500 mg Q 12hrs 9. Piperacillin/tazobactam 4.5 g Q 8hrs 4. Cefixime 200-400 mg Q 12-24 hrs 10. Amoxicillin 500 mg Q 6hrs 5. Cefpodoxime 100-200 mg Q 12hrs

Drug

ALTERNATIVE PROPHYLACTIC REGIMENS FOR DENTAL, ORAL, OR UPPER RESPIRATORY TRACT PROCEDURES IN PATIENTS WHO ARE AT RISK

Dosing Regimen*

Patients unable to take oral medications

Amplcillin Intravenous or intramuscular administration of ampicillin 2.0 g 30 min before procedure; then intravenous or intramuscular administration of ampicillin 1.0 g, or oral administration of amoxicillin 1.5 g, 6 h after initial dose

Ampicillin/ainoxicillin/penicillin - allergic patients unable to take oral medications

Clindamycin Intravenous administration of clindamycin 300 mg, 30 min before procedure and intravenous or oral administration of 150 mg 6 hr after initial dose

Patients considered high risk and not candidates for standard regimen
Ampicillin, Intravenous or intramuscular administration of ampicillin 2.0 g plus gentamicin, gentamicin 1.5 mg/kg (not to exceed 80 mg), 30 min before procedure; and amoxicillin followed by amoxicillin 1.5 g orally 6 hr after initial dose; alternatively, the parenteral regimen may be repeated 8 hr after initial dose

Ampicillin/amoxicillin/penicillin-allergic patients considered high risk

Effectiveness of Chemotherapeutic Agents

Drug Resistance 1. Resistance may be due to: i) prevention of penetration of the drug to its target site (lack of entry) ii) enzymatic destruction or inactivation of a drug iii) cellular or metabolic changes at target site(s) iv) rapid efflux (pumping of drug out of cell) (greater exit). 2. Hereditary drug resistance, called resistance (R) factor, is carried by plasmids and transposons. 3. Resistance can be minimized by the discriminate use of drugs in appropriate concentrations and dosages.

Effects of Combinations of Drugs

1. Some combinations of drugs are synergistic; they are more effective when taken together. 2. Some combinations of drugs are antagonistic; when taken together, both drugs become less effective than when taken alone. The Future of Chemotherapeutic Agents 1. Many bacterial diseases, previously treatable with antibiotics, have become resistant to antibiotics. 2. Chemicals produced by plants and animals are providing new antimicrobial agents, including antimicrobial peptides. 3. New antimicrobials include DNA that is complementary to specific genes in a pathogen; the DNA will bind to the pathogen's DNA or mRNA and inhibit protein synthesis.

Pteridine + Para-amino benzole acid (PABA) Blocked by Sulfonamides Dihydropteroic Acid Glutamate Dihydrofolic Acid Blocked by Trimethoprim Tetrahydrofolic Acid Colactors essential for synthesis of DNA, RNA or Proteins

Sites of Antimetabolite Action

CHEMOTHERAPY
Dose reduction needed in Drugs to be renal failure avoided Chloramphenicol Metronidazole Clindamycin Isoniazid Rifampin Erythromycin Pyrazinamide Talampicillin Tetracyclines Even in mild failure Aminoglycosides Cephalosporins Vancomycin Amphotericin Ethambutol Flucytosin

Only in moderate, severe failure Metronidazol Clotrimazole Carbenicillin Fluoroduinolones

Cephalothin Cephaloridine Nalidixic acid Nitrofurantion Talampicillin Tetracyclines (except doxycycline)

ANTIMALARIAL DRUGS AND THEIR LOCUS OF ACTION

DRUG BIOLOGICAL ACTIVITY BLOOD SCHIZONTOCIDE 4 AMINOOUINOLONE: CHLOROQUINE ACYLAMINOALCOHOLS : QUININE MEFLOQUINE ANTIMETABOLITES: PROGUANIL PYRIMETHAMINE SULFADOINE DAPSONE ANTIBIOTICS: TETRACICLINE DOXYCYCLINE 8- AMINOOUINOLONE : PRIMAQUINE ++ ++ ++ + + + + TISSUE SCHIZONTOCIDE 0 0 0 + 0 0 0