Antimicrobial therapy takes advantage of the biochemical differences between microorganisms and humans

Antimicrobial drugs should have selective toxicity towards the invading microorganism without harming the cells of the host

This selective toxicity is usually relative rather than absolute, requiring careful control of the drug concentration

Selection of an appropriate antimicrobial agent requires knowing:

1. The microorganism

2. The organism’s susceptibility to a particular agent

3. The site of infection

4. Patient factors

5. The safety of the drug

6. The cost of therapy

Some patients require empiric treatment

(Immediate administration of drugs prior to bacterial identification and susceptibility testing)

Bacteriostatic drugs arrest the growth and replication of bacteria, thus limit the spread of infection until the body’s immune system attacks and eliminates the organism◦ If the drug is removed before the immune system has

eliminated the organism, remaining viable organisms can begin a second cycle of infection

Bactericidal drugs kill bacteria, they are often used in seriously ill patients

Some antimicrobials can be bacteriostatic against one organism and bactericidal for another◦ Example: chloramphenicol is bacteriostatic against

gram-negative rods and is bactericidal against other organisms such as S. pneumoniae

Minimum inhibitory concentration (MIC): the lowest concentration of antibiotic that inhibits bacterial growth

Minimum bactericidal concentration (MBC): the minimum concentration of antibiotic that kills the bacteria under investigation

Patient factors taken into consideration when selecting an antimicrobial agent◦ Immune system

◦ Renal dysfunction

◦ Hepatic dysfunction

◦ Poor perfusion

◦ Age

◦ Pregnancy

◦ Lactation

Oral route is chosen for mild infections, and is favorable for outpatients

Parenteral route is used for more serious infections, or when the anti-microbial agent of choice has poor GI absorption such as vancomycin, amphotericin B and aminoglycosides

Pharmacodynamics of the drug (the relationship of drug concentrations to antimicrobial effects

Pharmacokinetics of the drug (ADME)

Concentration dependent killing

Time dependent (concentration-independent killing)

Postantibiotic effect

Concentration dependent killing

• Rate of bacterial killing increases as the concentration increases from 4-64 fold MIC

• e.g. aminoglycosides like tobramycin

• Administration by once-a-day bolus infusion achieves high peak levels, causing rapid killing of the pathogen

Time dependent (concentration-independent) killing

• Increasing concentration to higher multiplies of MIC does not increase the rate of killing

• e.g. β-lactams, glycopeptides, macrolides, clindamycin

• Administration by extended (3-4 hours) or continuous (24 hours) infusion achieves prolonged time above MIC and kills more bacteria

Penicillins

Cephalosporins

Tetracyclines

Aminoglycosides

Macrolides

Fluoroquinolones

Other

Narrow-spectrum antibioticsActing on a single or limited groupe.g. isoniazid is only active against mycobacteria Extended-spectrum antibioticsEffective against gram positive organisms ad also

against a significant number of gram negativee.g. ampicillin Broad-spectrum antibioticsDrugs affecting a wide variety of microbial species(Can cause superinfections)e.g. tetracycline and chloramphenicol

It is advisable to treat patients with a single agent that is more specific to the infecting organism to reduce possibility of superinfections, decrease resistance and toxicity

In certain situations combinations of antibiotics are needed for example treatment of tuberculosis requires the use of drug combinations

Bacteria is resistant to an antibiotic if the maximal level of the antibiotic does not stop their growth◦ Some organisms are inherently resistant to antibiotics

Ex. Gram negative bacteria are inherently resistant to vancomycin

◦ Microbial species that are normally responsive to a particular drug may develop more virulent or resistant strains through spontaneous mutation or acquired resistance and selection

◦ Some organisms may become resistant to more than one antibiotic

Antibiotics use for prevention is restricted to situations where the benefit outweighs the risks of bacterial resistance and superinfections such as:◦ Prevention of tuberculosis or meningitis

among individuals who are in close contact with infected patients

◦ Treatment prior to most surgical procedures to decrease the incidence of infection afterwards

Hypersensitivity◦ Penicillins can cause serious hypersensitivity problems

ranging from urticaria (hives) to anaphylactic shock

Direct toxicity◦ Aminoglycosides can cause ototoxicity by interfering with

membrane function in the hair cells of the organ of corti

Superinfections◦ Drug therapy especially broad spectrum antimicrobials

can lead to alterations to the normal flora of the upper respiratory, intestinal and genitourinary tracts permitting overgrowth of opportunistic organisms like fungi or resistant bacteria

◦ These infections are difficult to treat

Chemical structure

(β-Lactams or aminoglycosides)

Mechanism of action

(Cell wall synthesis inhibitors)

Their activity against a particular types of organisms

(Bacteria, fungi, viruses)

Interfere with bacterial cell wall synthesis(Mammalian cells do not have cell wall)

They are maximally effective in actively proliferating microorganismms

Have little or no effect on bacteria that are not growing and dividing

Include vancomycin and β-lactam antibiotics like penicillins and cephalosporins

Penicillins

Cephalosporins

Carbapenems

Monobactams

Other antibiotics

Amoxicillin (Amoxitid®, Amoxicare®, Moxepharm®, Moxypen®)

Ampicillin (Ampipharm®, Penibrin®)

Dicloxacillin

Oxacillin

Penicillin G

Penicillin V

Piperacillin

Ticarcillin

Widely effective and less toxic than other drugs

Resistance has limited their use

Nature of the side chain attached to aminopenicillanic acid determines:

Antimicrobial spectrum

Stability to stomach acid

Cross-hypersensitivity

Susceptibility to bacterial degradative enzymes

(β-lactamases)

Mechanism of action: ◦ Interfere with the last step of bacterial cell wall synthesis

(transpeptidation or cross linkage)

◦ The less osmotically stable cell membrane is exposed leading to cell lysis either through osmotic pressure or through activation of autolysins

◦ Bactericidal effect

Effective against rapidly growing organisms that synthesize a peptidoglycan cell wall

Inactive against organisms that lack peptidoglycan cell wall like mycobacteria, protozoa, fungi, and viruses

Bind to proteins on bacterial cell membrane, penicillin binding proteins (PBPs), bacterial enzymes involved in the synthesis of the cell wall and maintenance of bacterium morphology

This binding leads to morphological changes or lysis of bacteria

Alteration in some PBPs causes resistance(e.g. Methicillin resistant Saphylococcus aureus)

(MRSA)

Antibacterium spectrum depends on the ability of penicillin to cross the peptidoglycan wall and reach PBPs

Gram positive bacteria have cell walls easily penetrated by penicillins, in absence of resistance they’re susceptible to penicillins

Gram negative bacteria have an outer lipopolysacharidemembrane that represents a barrier for water soluble penicillins, which can cross through porins

Pseudomonas aeruginosa have restrictive porins and that’s why it’s resistant to many antimicrobials

Some organisms are naturally resistant to penicillins like organisms that lack cell wall such as mycoplasma

Acquired resistance to penicillins by plasmid transfer is a significant problem

Bacteria can gain resistance to multiple antibiotics after gaining resistant plasmids

Clavulanic acid

Sulbactam

Tazobactam

Have no significant antibacterial activity by themselves

Bind to and inactivate β-lactamases protecting the coadministered antibiotic

Route of administration◦ Determined by stability to gastric acid

◦ Ticarcillin, piperacillin and the combination of ampicillinwith sulbactam and ticarcillin with clavulanic acid, and piperacillin with tazobactam must be administered IV or IM

◦ Penicillin V, amoxacillin and amoxacillin + clavulanic acid are available only orally

◦ Others are effective orally, IV or IM

◦ Procaine penicillin G and benzathine penicillin G are administered IM as depot forms, they are slowly absorbed into the circulation and persist over a long time period

Most are incompletely absorbed after oral administration except amoxicillin

Absorption of penicillinase resistant penicillins is decreased by food in stomach, taken 30-60 minutes before meals or 2-3 hours postprandial

Hypersensitivity◦ The most common adverse effect of penicillins

Diarrhea◦ Due to disruption of the normal balance of intestinal

microorganisms

Nephritis ◦ All penicillins can cause interstitial nephritis (Especially

methicillin that’s why it is no longer used)

Neurotoxicity◦ Penicillins are irritating to neuronal tissue and can provoke

seizures

Hematologic toxicity◦ Decreased coagulation may happen with high doses of

piperacillin, ticarcillin and nafacillin

Cation toxicity (administered as sodium or potassium salt)◦ Aqueous penicillin G has high K load◦ Ticarcillin has a high sodium load

β-Lactam antibiotics

Closely related to penicillins in structure and function

Have the same mechanisms of action and resistance as penicillins

More resistant to certain β-lactamases than penicillins

Cephalosporins are ineffective against MRSA, L. monocytogenes, Clostridium difficile and enterococci

Antimicrobial spectrum◦ Cephalosporins are classified based on their bacterial

susceptibility and resistance to β-Lactamases to: Firsts generation

Cefazolin Cefadroxil (Biodroxil®) Cephalexin (Keflex®, Jeflex®, Cefacare®)

Second generation Cefuroxime sodium (Zinacef®) Cefuroxime axetil (Zinnat®, Zinaxim®)

Third generation Cefixime Ceftazidime (Fortum®) Ceftriaxone (Rocephin®) Cefotaxime (Claforan®)

Fourth generation Cefepime

Firsts generation cephalosporins◦ Act as penicillin G substitutes

◦ Resistant to staphylococcal penicillinases

◦ Effective against Proteus mirabilis, Klebsiella pneumoniae

Second generation cephalosporins◦ Greater activity against 3 additional gram negative

organisms H. influenzae, Enterobacter aerogenes and some Neisseria species

Third generation cephalosporins◦ Have enhanced activity against gram negative bacilli

including most enteric organisms

◦ Ceftriaxone and cefotaxime are agents of choice for treatment of meningitis

◦ Should be use with caution, because of possible induction and spread of antimicrobial resistance

Forth generation cephalosporins◦ Cefepime

Administered parenterally

Wide antibacterial spectrum against streptococci and staphylococci (MSSA only)

Adverse effects◦ Allergic reactions

Patients who had anaphylactic response, Stevens-Johnson syndrome or toxic epidermal necrolysis to penicillins should not be given cephalosporins

Antibiotics that target bacterial ribosome which differs structurally from mammalian cytoplasmicribosome

Mammalian mitochondiral ribosome closely resembles bacterial ribosome and so high levels of these drugs can cause toxic effects

Tetracyclines

Glycylcyclines

Aminoglycosides

Macrolides/Ketolides

Others

Demeclocycline

Doxycycline (Doxylin® , Doxal®, Doxy®)

Minocycline (Minoclin® , Minocin®)

Tetracycline (Tevacycline® , Brimocycline®)

Mechanism of action: Bind reversibly to the 30S subunit of the bacterial ribosome blocking the binding of aminoacyl t-RNA to mRNA-ribosome complex and inhibiting bacterial protein synthesis

Antibacterial spectrum◦ Broad-spectrum bacteriostatic antibiotics

◦ Effective against gram-positive and gram-negative bacteria and other microorganisms like mycoplasma and chlamydia

Resistance◦ Due to inability of the organism to accumulate the

drug by Mg2+ dependent efflux of the drug

◦ Enzymatic inactivation of the drug

◦ Producing bacterial proteins that prevent tetracyclines from binding to the ribosome

Any organism resistant to one tetracycline is resistant to all

Should not be taken with diary products due to formation of nonabsorbable chelates of the tetracycline with Ca+2

Should not be taken with magnesium and aluminum antacids

Can bind to Ca in bones and teeth

Adverse effects◦ Gastric discomfort: epigastric distress due to irritation of

gastric mucosa, drug can be taken with food to reduce the discomfort (except diary)

◦ Effects on calcified tissues: deposition in bone and primary dentition in growing children causing discoloration and hypoplasia of the teeth and temporary stunting of growth

◦ Fatal hepatotoxicity

◦ Phototoxicity

◦ Vestibular problems: diziness, nausea and vomiting

◦ Superinfections

Contraindicated in pregnant or breast-feeding women or in children less than 8 years of age.

Contraindicated in renally impaired patients except doxycycline (excreted into bile)

Amikacin

Gentamicin

Tobramycin

Streptomycin

Neomycin

Have been used for serious infections

Being replaced due to their toxicities such as the third and forth generation cephalosporins

Diffuse through the porins in the outer membranes and have an oxygen-dependent system that transport the drugs through the cytoplasmic membrane

Mechanism of action: Bind to the 30S subunit and interferes with assembly of functional ribosomal apparatus or cause 30 S subunit misreading of genetic code

Aminoglycosides synergize with β-lactam antibiotics which enhance diffusion of aminoglycosides in to the bacterium due to their action of cell wall inhibition

Aminoglycosides are bactericidal, the exact mechanism is unkown

Effective in combination for the emperictreatment of infections suspected to be due to aerobic gram negative bacilli including P. aeruginosa, usually combined with β-lactamantibiotics or vancomycin

Resistance can be caused by◦ Decreased uptake of the drug◦ Plasmid associated synthesis of enzymes that inactivate

aminoglycosides

Adverse effects ◦ Ototoxicity◦ Nephrotoxicity◦ Neuromuscular paralysis◦ Allergic reactions (dermatitis in topically applied

neomycin)

serum levels should be monitored to avoid toxicity Contraindicated in pregnancy

Erythromycin (Erythro Teva® , Erythrotab® , Erythrolet®)

Azithromycin (Zmax® , Azimex® , Azicare® , Zitrocin®)

Clarithromycin (Klacid® , Klaridex® , Klaricare®)

Telithromycin (Ketolide)

Mechanism of action:◦ Irreversibly bind to the 50S subunit of the bacterial

ribosome inhibiting the translocation steps of protein synthesis

◦ Bacteriostatic, but may be bactericidal at higher doses

Adverse effects◦ Epigastric distress

◦ Cholestatic jaundice

◦ Ototoxicity

(Dalacin C®, Clindacin®)

Same mechanism of action as erythromycin

Effective against gram positive cocci including MRSA

Similar resistance mechanisms as erythromycin

Adverse effects◦ Skin rashes

◦ Potentially fatal pseudomembranous colitis due to overgrowth of C. difficile (vancomycin or metronidazole is used for this condition)

Fluoroquinolones 1st generation◦ Nalidixic acid

Fluoroquinolones 2nd generation◦ Ciprofloxacin (Floxin®, Ciprocare®, Ciprodex®)

◦ Norfloxacin

◦ Ofloxacin (Oflodex®)

Fluoroquinolones 3rd generation◦ Levoflaxin (Tavanic®, Levo®)

Fluoroquinolones 4th generation◦ Moxifloxacin (Megaxin®)

Newer fluorinated quinolones offer◦ Greater potency

◦ Broader spectrum of antimicrobial activity

◦ Greater in vitro efficacy against resistant microorganisms

◦ Sometimes a better safety profile

Compared to ciprofloxacin, newer compounds are more active against gram positive organisms and have favorable activity against gram negative organisms

Fluoroquinolones have wide antimicrobial spectrum, and favorable pharmacokinetic and adverse effects profiles

Their overuse has led to the emergence of resistant microorganisms

Mechanism of action◦ Enter the bacterium by passive diffusion through

porins

◦ Inhibit replication of bacterial DNA by interfering with the actions of DNA gyrase (topoisomerase II) and topoisomerase IV during bacterial growth and reproduction

◦ Binding of the quinolone to both enzymes and DNA forms a complex that inhibits the resealing step and can cause cell death by inducing cleavage of DNA

◦ Topoisomerase IV is required for cell division

DNA gyrase enzyme is a bacteriospecifictarget, cross-resistance with other antimicrobial drugs is rare. But resistance is increasing in multi-drug resistant microorganisms