Dr. Mahmoud H. Taleb 1 Lecture 6: Antimicrobial therapy.

Dr. Mahmoud H. TalebDr. Mahmoud H. Taleb 11

Lecture 6:Antimicrobial therapy


DefinitionDefinitionAntibiotics are antibacterial substances produced by various species of Antibiotics are antibacterial substances produced by various species of

microorganisms (bacteria, fungi, and actinomycetes) that suppress microorganisms (bacteria, fungi, and actinomycetes) that suppress

the growth of other microorganisms. Common usage often extends the growth of other microorganisms. Common usage often extends

the term the term antibioticsantibiotics to include synthetic antimicrobial agents to include synthetic antimicrobial agents..

- Antibiotics differ markedly in - Antibiotics differ markedly in physicalphysical, , chemical,chemical, and and pharmacological pharmacological

propertiesproperties, in , in antimicrobial spectraantimicrobial spectra, and in , and in mechanisms of action.mechanisms of action.

- Antimicrobial drugs are effective in the treatment of infections - Antimicrobial drugs are effective in the treatment of infections

because of because of their selective toxicity.their selective toxicity.

- Antimicrobial agents are among the most commonly used and - Antimicrobial agents are among the most commonly used and

misused of all drugs.misused of all drugs.


Bacterial Resistance

** Bacterial resistance to an antimicrobial agent is attributable to three general mechanisms

1- The drug does not reach its target (deactivation of transport mechanisms or activation of efflux mechanisms).

2- The drug is not active (inactivation of the drug or failure to activate prodrug).

3- The target is altered.


- Antimicrobials have three general uses

1- Empirical therapy or initial therapy: the antimicrobial should cover all the likely pathogens because the infecting organism(s) has not yet been defined.

2- Definitive therapy or pathogen-directed therapy: once the infecting microorganism is identified, definitive antimicrobial therapy should be instituted with a narrow-spectrum, low-toxicity agent to complete the course of treatment.

3- Prophylactic or preventive therapy.

Clinical uses of antimicrobial agents


Optimal and judicious selection of antimicrobial agents for Optimal and judicious selection of antimicrobial agents for the therapy of infectious diseases requires clinical judgment the therapy of infectious diseases requires clinical judgment and detailed knowledge of pharmacological and and detailed knowledge of pharmacological and microbiological factors. microbiological factors.

- A generally accepted systematic approach to the selection - A generally accepted systematic approach to the selection and evaluation of an antimicrobial regimen involves the and evaluation of an antimicrobial regimen involves the following steps:following steps:

Confirming the presence of infection.Confirming the presence of infection. Identification of the pathogen.Identification of the pathogen. Selection of rational antimicrobial therapy.Selection of rational antimicrobial therapy. Monitor therapeutic response. Monitor therapeutic response.

Antimicrobial regimen selection


1- Confirming the presence of infection

a) Careful history and physical examination b) Fever

c) White blood cell count d) Pain and inflammation


22 . .Identification of pathogenIdentification of pathogen

3. Selection of rational antimicrobial therapy3. Selection of rational antimicrobial therapy

- To select rational antimicrobial therapy for a given clinical - To select rational antimicrobial therapy for a given clinical situation, a variety of factors must be considered. These situation, a variety of factors must be considered. These include the severity and acuity of the disease, host factors, include the severity and acuity of the disease, host factors, drug factors, and the necessity for using multiple agents. drug factors, and the necessity for using multiple agents.

- In addition, there are generally accepted drugs of choice for - In addition, there are generally accepted drugs of choice for the treatment of most pathogens .the treatment of most pathogens .


a) Drug factorsa) Drug factors

1.1. Pharmacodynamic factorsPharmacodynamic factors Pharmacodynamic factors include pathogen susceptibility testing, Pharmacodynamic factors include pathogen susceptibility testing,

drug bactericidal versus bacteriostatic activity, and drug drug bactericidal versus bacteriostatic activity, and drug synergism, antagonism, and postantibiotic effects.synergism, antagonism, and postantibiotic effects.

- Bactericidal agents can be divided into two groups: agents that - Bactericidal agents can be divided into two groups: agents that exhibit exhibit

Concentration-dependent killingConcentration-dependent killing (eg, aminoglycosides and (eg, aminoglycosides and quinolones) and agents that exhibit quinolones) and agents that exhibit

Time dependent killingTime dependent killing (eg,(eg, -lactams and vancomycin). -lactams and vancomycin). Postantibiotic effectPostantibiotic effect- Persistent suppression of bacterial growth after limited exposure - Persistent suppression of bacterial growth after limited exposure

to an antimicrobial agent is known as the postantibiotic to an antimicrobial agent is known as the postantibiotic effect (PAE). effect (PAE).


Table. Bacteriostatic and bactericidal antibacterial agents.

BacteriostaticBactericidal

Chloramphenicol, Chloramphenicol, Clindamycin, EthambutolClindamycin, Ethambutol

Macrolides, Nitrofurantoin, Macrolides, Nitrofurantoin, Oxazolidinones, Oxazolidinones, Sulfonamides, Tetracyclines, Sulfonamides, Tetracyclines, TrimethoprimTrimethoprim

Aminoglycosides, Aminoglycosides, Bacitracin, Beta-lactam Bacitracin, Beta-lactam antibioticsantibiotics

Isoniazid, Metronidazole, Isoniazid, Metronidazole, Polymyxins, PyrazinamidePolymyxins, Pyrazinamide

Quinolones, Rifampin, Quinolones, Rifampin, VancomycinVancomycin


2. Pharmacokinetic factors2. Pharmacokinetic factors - Successful therapy depends on achieving a drug concentration - Successful therapy depends on achieving a drug concentration

that is sufficient to inhibit or kill bacteria at the site of the infection that is sufficient to inhibit or kill bacteria at the site of the infection without harming the patient. To accomplish this without harming the patient. To accomplish this therapeutic goal, several pharmacokinetic factors must be therapeutic goal, several pharmacokinetic factors must be evaluated.evaluated.

- The location of the infection to a large extent may dictate the - The location of the infection to a large extent may dictate the choice of drug and the route of administration. The minimal drug choice of drug and the route of administration. The minimal drug concentration achieved at the infected site should be concentration achieved at the infected site should be approximately equal to the MIC for the infecting organism, approximately equal to the MIC for the infecting organism, although in most instances it is advisable to achieve multiples of although in most instances it is advisable to achieve multiples of this concentration if possible.this concentration if possible.

- Penetration of drugs into sites of infection almost always depends - Penetration of drugs into sites of infection almost always depends on passive diffusion. The rate of penetration is thus proportional to on passive diffusion. The rate of penetration is thus proportional to the concentration of free drug in the plasma or extracellular fluid. the concentration of free drug in the plasma or extracellular fluid. Drugs that are extensively bound to protein thus may not penetrate Drugs that are extensively bound to protein thus may not penetrate to the same extent as those bound to a lesser extent. to the same extent as those bound to a lesser extent.

b- Status of the patientb- Status of the patientc- Safety factorc- Safety factord- Cost factor d- Cost factor


Chemotherapeutic SpectraA. Narrow-spectrum antibiotics

Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum. For example, isoniazid is active only against mycobacteria .

B. Extended-spectrum antibiotics

Extended spectrum is the term applied to antibiotics that are effective against gram-positive organisms and also against a significant number of gram-negative bacteria. For example, ampicillin is considered to have an extended spectrum, because it acts against gram-positive and some gram-negative bacteria .

C. Broad-spectrum antibiotics

Drugs such as tetracycline and chloramphenicol affect a wide variety of microbial species and are referred to as broad-spectrum antibiotics

. Administration of broad-spectrum antibiotics can drastically alter the nature of the normal bacterial flora and precipitate a superinfection of an organism such as Candida albicans, the growth of which is normally kept in check by the presence of other microorganisms.


Combination antimicrobial Combination antimicrobial therapytherapy

Combinations of antimicrobials generally are used to:Combinations of antimicrobials generally are used to:1- Broaden the spectrum of coverage for empirical therapy1- Broaden the spectrum of coverage for empirical therapy2- Synergism2- Synergism3- Prevent the emergence of resistance3- Prevent the emergence of resistance

Disadvantages of combination therapyDisadvantages of combination therapy1- Some combination of antimicrobial are potentially antagonistic.1- Some combination of antimicrobial are potentially antagonistic.

2- Increased risk of toxicity from two or more agents.2- Increased risk of toxicity from two or more agents.

3- Selection of multiple-drug-resistant microorganisms. 3- Selection of multiple-drug-resistant microorganisms.

4- Eradication of normal host flora with subsequent superinfection.4- Eradication of normal host flora with subsequent superinfection.

5- Increased cost to the patient.5- Increased cost to the patient.


Figure (5) Some clinical situations in which prophylactic antibiotics are indicated.


Figure (8)Summary of antimicrobial agents affecting cell wall synthesis.


I- Inhibitors of cell wall synthesisI- Inhibitors of cell wall synthesisA- β- Lactam cell wall inhibitorsA- β- Lactam cell wall inhibitors

11- Penicillins - All β-lactam antibiotics have the same bactericidal mechanism of action. They

block a critical (last) step in bacterial cell wall synthesis ( transpeptidation or cross- linkage).

- After penicillins have attached to receptors, peptidoglycan (murein) synthesis is inhibited because the activity of transpeptidation enzymes (transpeptidases) is blocked.

Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are susceptible to β- lactam antibiotics. Nonmultiplying organisms or those lacking cell walls (Mycobacteria, Protozoa, fungi, and virus)

are not susceptible.


Mechanism of resistanceMechanism of resistanceMicrobial resistance to penicillins is caused by four Microbial resistance to penicillins is caused by four

factors:factors:

1- Production of β-lactamases (penicillinases).1- Production of β-lactamases (penicillinases).

2- Lack of penicillin-binding proteins or decreased 2- Lack of penicillin-binding proteins or decreased affinity of penicillin-binding protein for β-lactam affinity of penicillin-binding protein for β-lactam antibiotic receptors or impermeability of cell antibiotic receptors or impermeability of cell envelope.envelope.

3- Failure of activation of autolytic enzymes in the 3- Failure of activation of autolytic enzymes in the cell wall (tolerance). cell wall (tolerance).

4- Cell wall-deficient (L) forms or mycoplasmas, 4- Cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans.which do not synthesize peptidoglycans.


Classification of penicillinsClassification of penicillinsPenicillins may be classified into four groups: Penicillins may be classified into four groups:

1- natural penicillins (G and V),1- natural penicillins (G and V),

2- antistaphylococcal penicillins (penicillinase 2- antistaphylococcal penicillins (penicillinase resistant), resistant),

3- aminopenicillins, and 3- aminopenicillins, and

4- antipseudomonal penicillins4- antipseudomonal penicillins..


Figure (3) stability of the penicillins to acid or the action of penicillinase.


Therapeutic uses of penicillin GTherapeutic uses of penicillin G


Adverse effectsAdverse effectsHypersensitivity reactionsHypersensitivity reactions- Hypersensitivity reactions are by far the most common adverse effects noted - Hypersensitivity reactions are by far the most common adverse effects noted

with the penicillins, and these agents probably are the most common cause with the penicillins, and these agents probably are the most common cause of drug allergy. penicillins includemaculopapular rash, urticarial rash, of drug allergy. penicillins includemaculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, and anaphylaxis.fever, bronchospasm, vasculitis, and anaphylaxis.

- It must be stressed that fatal episodes of anaphylaxis have followed the - It must be stressed that fatal episodes of anaphylaxis have followed the ingestion of very small doses of this antibiotic or skin testing with minute ingestion of very small doses of this antibiotic or skin testing with minute quantities of the drug.quantities of the drug.

Other toxicitiesOther toxicities- - The penicillins have minimal direct toxicity. Apparent toxic effects that have The penicillins have minimal direct toxicity. Apparent toxic effects that have

been reported include bone marrow depression, granulocytopenia, and been reported include bone marrow depression, granulocytopenia, and hepatitis.hepatitis.

- All penicillins in excessive doses, particularly in renal insufficiency, have - All penicillins in excessive doses, particularly in renal insufficiency, have been associated with seizures.been associated with seizures.

- - Many persons who take various penicillin preparations by mouth experience - - Many persons who take various penicillin preparations by mouth experience nausea, with or without vomiting, and some have mild to severe diarrhea.nausea, with or without vomiting, and some have mild to severe diarrhea.

- - Superinfection.Superinfection.


2-2- Cephalosporin Cephalosporin

Mechanism of action Mechanism of action - The mechanism of action of cephalosporins is analogous - The mechanism of action of cephalosporins is analogous

to that of the penicillins; binding to specific penicillin-to that of the penicillins; binding to specific penicillin-binding proteins, inhibition of cell wall synthesis, and binding proteins, inhibition of cell wall synthesis, and activation of autolytic enzymes in the cell wall. activation of autolytic enzymes in the cell wall.

Mechanism of resistanceMechanism of resistance Resistance to cephalosporins may be due to poor Resistance to cephalosporins may be due to poor

permeability of the drug into bacteria, lack of penicillin-permeability of the drug into bacteria, lack of penicillin-binding proteins, or degradation by β-lactamasesbinding proteins, or degradation by β-lactamases. .

Dr. Mahmoud H. TalebDr. Mahmoud H. Taleb 2424Classification and therapeutc uses of cephalosporinClassification and therapeutc uses of cephalosporin


PharmacokineticsPharmacokinetics

-Cephalexin, cephradine, cefaclor, cefadroxil, cefprozil,

ceftibuten, and cefuroxime axetil are absorbed readily after oral administration. Cefprozil, cefdinir, ceftibuten, and cefditoren are also effective orally. The other cephalosporins can be administered intramuscularly or intravenously. - Cephalosporins are excreted primarily by the kidney; dosage thus should be altered in patients with renal insufficiency. Probenecid slows the tubular secretion of most cephalosporins. Cefpiramide and cefoperazone are exceptions because they are excreted predominantly in the bile. Cefotaxime is deacetylated in

vivo .


- Several cephalosporins penetrate into CSF in sufficient concentration to be useful for thetreatment of meningitis. These include cefotaxime, ceftriaxone, and cefepime.

- Cephalosporins also cross the placenta, and they are found in high concentrations in synovial and pericardial fluids. Penetration into the aqueous humor of the eye is relatively good after systemic administration of third-generation agents.

- Concentrations in bile usually are high, with those achieved after administration of cefoperazone and cefpiramide being the highest.

- Drugs like ceftriaxone that have extensive protein binding (85–95%) may displace bilirubin from serum albumin. - Cefuroxime and cefadroxil have long half-lives that permit twice-daily dosing


Adverse effectsAdverse effects HypersensitivityHypersensitivity - Hypersensitivity reactions to the cephalosporins are the most common side effects, and - Hypersensitivity reactions to the cephalosporins are the most common side effects, and

there is no evidence that any single cephalosporin is more or less likely to cause such there is no evidence that any single cephalosporin is more or less likely to cause such sensitization. sensitization.

- The reactions appear to be identical to those caused by the penicillins, perhaps related to - The reactions appear to be identical to those caused by the penicillins, perhaps related to the shared β-lactam structure of both groups of antibiotics. the shared β-lactam structure of both groups of antibiotics.

- Immediate reactions such as anaphylaxis, bronchospasm, and urticaria are observed. More - Immediate reactions such as anaphylaxis, bronchospasm, and urticaria are observed. More commonly, maculopapular rash develops, usually after several days of therapy; this may or commonly, maculopapular rash develops, usually after several days of therapy; this may or may not be accompanied by fever and eosinophilia. may not be accompanied by fever and eosinophilia. - Because of the similar structures of the penicillins and cephalosporins, patients who are - Because of the similar structures of the penicillins and cephalosporins, patients who are allergic to one class of agents may manifest cross-reactivity to a member of the other class. allergic to one class of agents may manifest cross-reactivity to a member of the other class. Immunological studies have demonstrated cross-reactivity in as many as 20% of patients Immunological studies have demonstrated cross-reactivity in as many as 20% of patients who are allergic to penicillin, but clinical studies indicate a much lower frequency (about 1%) who are allergic to penicillin, but clinical studies indicate a much lower frequency (about 1%) of such reactions. of such reactions.

- There are no skin tests that can reliably predict whether a patient will manifest an allergic - There are no skin tests that can reliably predict whether a patient will manifest an allergic reaction to the cephalosporins. reaction to the cephalosporins.

Other toxicitiesOther toxicities - The cephalosporins have been implicated as potentially nephrotoxic agents.- The cephalosporins have been implicated as potentially nephrotoxic agents. - Diarrhea can result from the administration of cephalosporins.- Diarrhea can result from the administration of cephalosporins. - Serious bleeding related either to hypoprothrombinemia, thrombocytopenia, and/or platelet - Serious bleeding related either to hypoprothrombinemia, thrombocytopenia, and/or platelet

dysfunction has been reported with several β-lactam antibiotics especially cefotetan, dysfunction has been reported with several β-lactam antibiotics especially cefotetan, cefomandole and cefoperazone.cefomandole and cefoperazone.

- Disufiram- like reactions. When cefomandole and cefoperazone. - Disufiram- like reactions. When cefomandole and cefoperazone. Other β-lactam antibioticsOther β-lactam antibiotics Important therapeutic agents with a β-lactam structure that are neither penicillins nor Important therapeutic agents with a β-lactam structure that are neither penicillins nor

cephalosporins have been developed. They have the same mechanism of action as penicillin.cephalosporins have been developed. They have the same mechanism of action as penicillin.


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Dr. Mahmoud H. Taleb 1 Lecture 6: Antimicrobial therapy.

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