fundamentals antimicrobial agents

Cell Wall InhibitorsCell Wall Inhibitors

www.freelivedoctor.comwww.freelivedoctor.com

IntroductionIntroductionThe penicillins constitute one of the most The penicillins constitute one of the most important groups of antibiotics. Although important groups of antibiotics. Although numerous other antimicrobial agents have numerous other antimicrobial agents have been produced since the first penicillin been produced since the first penicillin became available, these still are widely became available, these still are widely used, major antibiotics, and new used, major antibiotics, and new derivatives of the basic penicillin nucleus derivatives of the basic penicillin nucleus still are being produced. Many of these still are being produced. Many of these have unique advantages, such that have unique advantages, such that members of this group of antibiotics are members of this group of antibiotics are presently the drugs of choice for a large presently the drugs of choice for a large number of infectious diseases.number of infectious diseases.


HistoryHistory

The penicillins were the first antibiotics The penicillins were the first antibiotics discovered as natural products from the mold discovered as natural products from the mold Penicillium. In 1928, Sir Alexander Fleming, Penicillium. In 1928, Sir Alexander Fleming, professor of bacteriology at St. Mary's professor of bacteriology at St. Mary's Hospital in London, was culturing Hospital in London, was culturing Staphylococcus aureus. He noticed zones of Staphylococcus aureus. He noticed zones of inhibition where mold spores were growing. inhibition where mold spores were growing. He named the mold He named the mold Penicillium rubrumPenicillium rubrum. It . It was determined that a secretion of the mold was determined that a secretion of the mold was effective against Gram-positive bacteria. was effective against Gram-positive bacteria.


1928 - Alexander Fleming 1928 - Alexander Fleming Bread mold (Bread mold (Penicillin notatumPenicillin notatum) growing on ) growing on

petri dishpetri dish 1939 - Florey, Chain, and Associates1939 - Florey, Chain, and Associates

Began work on isolating and synthizing large Began work on isolating and synthizing large amounts of Penicillin.amounts of Penicillin.

1944 - Used in WWII to treat infections1944 - Used in WWII to treat infections Late 1940’s - available for general use in Late 1940’s - available for general use in

USUS


StructureStructure Penicillins as well as cephalosporins are Penicillins as well as cephalosporins are

called beta-lactam antibiotics and are called beta-lactam antibiotics and are characterized by characterized by threethree fundamental fundamental structural requirements: structural requirements: the fused beta-lactam structure (shown in the blue the fused beta-lactam structure (shown in the blue

and red rings, and red rings, a free carboxyl acid group (shown in red bottom a free carboxyl acid group (shown in red bottom

right), right), one or more substituted amino acid side chains one or more substituted amino acid side chains

(shown in black). (shown in black). The lactam structure can also be viewed as the The lactam structure can also be viewed as the

covalent bonding of pieces of two amino acids - covalent bonding of pieces of two amino acids - cysteine (blue) and valine (red). cysteine (blue) and valine (red). www.freelivedoctor.comwww.freelivedoctor.com

thiazolidine ring (A) connected to a b-lactam ring (B), to which is attached a side chain (R).


The penicillin nucleus itself is the chief structural requirement for biological activity;

metabolic transformation or chemical alteration of this portion of the molecule causes loss of all significant antibacterial activity


Clinically useful families of beta-Clinically useful families of beta-lactam compounds include the lactam compounds include the penicillinspenicillins, , cephalosporinscephalosporins, , monobactamsmonobactams carbapenemscarbapenems


ClassificationClassification

Penicillins (penicillin G) – greatest activity Penicillins (penicillin G) – greatest activity against gram+, gram-cocci, non-beta-against gram+, gram-cocci, non-beta-lactamase-producing anaerobeslactamase-producing anaerobes

Antistaphylococcal penicillins (nafcillin) – Antistaphylococcal penicillins (nafcillin) – resistant to staphylococcal beta-lactamases, resistant to staphylococcal beta-lactamases, active to staphylococci and streptococciactive to staphylococci and streptococci

Extended-spectrum penicillins (ampicillin) – Extended-spectrum penicillins (ampicillin) – retain antibacterial spectrum of penicillin retain antibacterial spectrum of penicillin with improved activity against gram- with improved activity against gram- organisms, but are destroyed by beta-organisms, but are destroyed by beta-lactamases.lactamases.


Mechanisms of Drug Mechanisms of Drug Actions by Enzyme Actions by Enzyme

Inhibition:Inhibition: All penicillin derivatives produce their All penicillin derivatives produce their

bacteriocidal effects by inhibition of bacteriocidal effects by inhibition of bacterial cell wall synthesis. bacterial cell wall synthesis. Specifically, the cross linking of Specifically, the cross linking of peptides on the mucosaccharide peptides on the mucosaccharide chains is prevented. If cell walls are chains is prevented. If cell walls are improperly made cell walls allow water improperly made cell walls allow water to flow into the cell causing it to burst. to flow into the cell causing it to burst.


Cell Wall productionCell Wall production

The cell walls of bacteria are essential for their The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue that provides rigid mechanical stability by virtue of its highly cross-linked latticework structure of its highly cross-linked latticework structure

The peptidoglycan is composed of glycan chains, The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by acetylmuramic acid) that are cross-linked by peptide chains. (NAG-NAM). peptide chains. (NAG-NAM).

In gram-positive microorganisms, the cell wall is In gram-positive microorganisms, the cell wall is 50 to 100 molecules thick, but it is only 1 or 2 50 to 100 molecules thick, but it is only 1 or 2 molecules thick in gram-negative bacteriamolecules thick in gram-negative bacteria


The biosynthesis of the peptidoglycan The biosynthesis of the peptidoglycan involves about 30 bacterial enzymes and involves about 30 bacterial enzymes and may be considered in three stages. may be considered in three stages. The first stage, precursor formation, takes place

in the cytoplasm. The product, uridine diphosphate (UDP)-acetylmuramyl-pentapeptide, called a "Park nucleotide" accumulates in cells when subsequent synthetic stages are inhibited.

The last reaction in the synthesis of this compound is the addition of a dipeptide, D-alanyl-D-alanine. Synthesis of the dipeptide involves prior racemization of L-alanine and condensation catalyzed by D-alanyl-D-alanine synthetase.


The second stage, UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked (with the release of the uridine nucleotides) to form a long polymer.

The third and final stage involves the completion of the cross-link. This is accomplished by a transpeptidation reaction that occurs outside the cell membrane. The transpeptidase itself is membrane bound. The terminal glycine residue of the pentaglycine bridge is linked to the fourth residue of the pentapeptide (D-alanine), releasing the fifth residue (also D-alanine)


It is this last step in peptidoglycan synthesis that is inhibited by the beta-lactam antibiotics. .

Penicillin binds at the active site of the transpeptidase enzyme that cross-links the peptidoglycan strands. It does this by mimicking the D-alanyl-D-alanine residues that would normally bind to this site. Penicillin irreversibly inhibits the enzyme transpeptidase by reacting with a serine residue in the transpeptidase. This reaction is irreversible and so the growth of the bacterial cell wall is inhibited.


Related targets for the actions of penicillins and cephalosporins; these are collectively termed penicillin-binding proteins (PBPs) (PBPs)

Covalently bind to a heterologous Covalently bind to a heterologous group of proteins called penicillin-group of proteins called penicillin-binding proteins binding proteins These PBPs may number These PBPs may number 3 to 6 in any given bacteria. 3 to 6 in any given bacteria.

There functions are diverse: catalyze the There functions are diverse: catalyze the transpeptidase reaction, maintam shape, transpeptidase reaction, maintam shape, forms septums during division, Inhibit forms septums during division, Inhibit autolytic enzymes. autolytic enzymes.


Binding to PBPs results in:Binding to PBPs results in: Inhibition of transpeptidase: Inhibition of transpeptidase:

transpeptidase catalyzes the cross-transpeptidase catalyzes the cross-linking of the pentaglycine bridge with linking of the pentaglycine bridge with the fourth residue (D-Ala) of the the fourth residue (D-Ala) of the pentapeptide. The fifth reside (also D-pentapeptide. The fifth reside (also D-Ala) is released during this reaction. Ala) is released during this reaction. Spheroblasts are formed.Spheroblasts are formed.

Structural irregularities: Structural irregularities: binding to binding to PBPs may result in abnormal elongation, PBPs may result in abnormal elongation, abnormal shape, cell wall defects.abnormal shape, cell wall defects.


Figure 45-2. The transpeptidase reaction in Staphylococcus aureus that is inhibited by penicillins and cephalosporins.


Figure 45-3. Comparison of the structure and composition of gram-positive and gram-negative cell walls.


PharmacokineticsPharmacokinetics Oral Administration of Penicillin G. About one-third of

an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions.

Gastric juice at pH 2 rapidly destroys the antibiotic. The decrease in gastric acid production with aging accounts for better absorption of penicillin G from the gastrointestinal tract of older individuals.

Absorption is rapid, and maximal concentrations in blood are attained in 30 to 60 minutes. The peak value is approximately 0.5 unit/ml (0.3 mg/ml) after an oral dose of 400,000 units (about 250 mg) in an adult.

Ingestion of food may interfere with enteric absorption of all penicillins, perhaps by adsorption of the antibiotic onto food particles. Thus, oral penicillin G should be administered at least 30 minutes before a meal or 2 hours after. Despite the convenience of oral administration of penicillin G, this route should be used only in infections in which clinical experience has proven its efficacy.


Oral Administration of Penicillin V. The sole virtue of penicillin V in comparison with penicillin G is that it is more stable in an acidic medium, and therefore is better absorbed from the gastrointestinal tract.

On an equivalent oral-dose basis, penicillin V (K+ salt PEN-VEE K, V-CILLIN K, others) yields plasma concentrations two to five times greater than those provided by penicillin G. The peak concentration in the blood of an adult after an oral dose of 500 mg is nearly 3 mg/ml. Once absorbed, penicillin V is distributed in the body and excreted by the kidney in the same manner as penicillin G.


Parenteral Administration of Penicillin G

After intramuscular injection, peak concentrations in plasma are reached within 15 to 30 minutes. This value declines rapidly, since the half-life of penicillin G is 30 minutes.

Repository preparations of penicillin G are employed. The two such compounds currently favored are penicillin G procaine (maintained for as long as 4 to 5 days.) and penicillin G benzathine. (duration of antimicrobial activity in the plasma is about 26 day)

Such agents release penicillin G slowly from the area in which they are injected and produce relatively low but persistent concentrations of antibiotic in the blood.

Intrathecal administration is inadvisable particularly with benzylpenicillin as it can cause convulsions.


Distribution. Penicillin G is distributed widely throughout the body,

but the concentrations in various fluids and tissues differ widely. Its apparent volume of distribution is about 0.35 liters/kg. Approximately 60% of the penicillin G in plasma is reversibly bound to albumin. Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine.

While probenecid markedly decreases the tubular secretion of the penicillins, this is not the only factor responsible for the elevated plasma concentrations of the antibiotic that follow its administration. Probenecid also produces a significant decrease in the apparent volume of distribution of the penicillins.


Cerebrospinal Fluid. Penicillin does not readily enter the CSF when the meninges are normal. However, when the meninges are acutely inflamed, penicillin penetrates into the CSF more easily. Although the concentrations attained vary and are unpredictable, they are usually in the range of 5% of the value in plasma and are therapeutically effective against susceptible microorganisms.


Excretion Under normal conditions, penicillin G is rapidly

eliminated from the body, mainly by the kidney but in small part in the bile and by other routes. Approximately 60% to 90% of an intramuscular dose of penicillin G in aqueous solution is eliminated in the urine, largely within the first hour after injection.

The half-time for elimination is about 30 minutes in normal adults (upto 10 hours in renal failure) . Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion.

Renal clearance approximates the total renal plasma flow. The maximal tubular secretory capacity for penicillin in the normal male adult is about 3 million units (1.8 g) per hour.


Clearance values are considerably lower in neonates and infants, because of incomplete development of renal function; as a result, after doses proportionate to surface area, the persistence of penicillin in the blood is several times as long in premature infants as in children and adults.

The half-life of the antibiotic in children less than 1 week old is 3 hours; by 14 days of age it is 1.4 hours. After renal function is fully established in young children, the rate of renal excretion of penicillin G is considerably more rapid than in adults.


Unitage of Penicillin

The international unit of penicillin is the specific penicillin activity contained in 0.6 mg of the crystalline sodium salt of penicillin G. One milligram of pure penicillin G sodium thus equals 1667 units; 1.0 mg of pure penicillin G potassium represents 1595 units. The dosage and the antibacterial potency of the semisynthetic penicillins are expressed in terms of weight.

The minimum inhibitory concentration(MIC) of any penicillin is usually given in ug/ml

Most penicillins ae dispensed as the sodium or potassium salt of the free acid.


Therapeutic Uses Pneumococcal Infections

Pneumococcal Meningitis Pneumococcal Pneumonia

Streptococcal Infections Streptococcal Pharyngitis (including Scarlet Fever) Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis

Staphylococcal Infections Meningococcal Infections Gonococcal Infections Syphilis Actinomycosis Diphtheria Anthrax Clostridial Infections Fusospirochetal Infections Rat-Bite Fever Listeria Infections Lyme Disease Erysipeloid Surgical Procedures in Patients with Valvular Heart Disease


The antimicrobial activity of The antimicrobial activity of carbenicillin,carbenicillin, its its indanyl ester (carbenicillin indanyl), andindanyl ester (carbenicillin indanyl), and ticarcillinticarcillin is extended to include is extended to include Pseudomonas, Enterobacter,Pseudomonas, Enterobacter, and and ProteusProteus species.species.

Other extended-spectrum penicillins include Other extended-spectrum penicillins include mezlocillinmezlocillin and and piperacillin,piperacillin, which have useful which have useful antimicrobial activity against antimicrobial activity against Pseudomonas, Pseudomonas, Klebsiella,Klebsiella, and certain other gram-negative and certain other gram-negative microorganisms.microorganisms.


Mechanisms of Bacterial Resistance to Penicillins

Resistance to penicillins and other beta Resistance to penicillins and other beta lactams is due to one of four general lactams is due to one of four general mechanisms:mechanisms: Inactivation of the antibiotic by beta Inactivation of the antibiotic by beta

lactamaselactamase Modification of target PBPsModification of target PBPs Imparied penetration of drug to target Imparied penetration of drug to target

PBPsPBPs The presence of an efflux pump.The presence of an efflux pump.


There are more than 300 different types of this There are more than 300 different types of this enzyme. The process is genetically controlled enzyme. The process is genetically controlled commonly with plasmids.commonly with plasmids.

beta-lactamase production is particularly beta-lactamase production is particularly important in important in Staphylococci Staphylococci but other but other organisms such as organisms such as Neisseria gonorrhoeae Neisseria gonorrhoeae and and Hemophilus Hemophilus species also produce these species also produce these enzymes where as beta-hemolytic enzymes where as beta-hemolytic Streptococci Streptococci do not.do not.

• • In developed countries at least 80% of In developed countries at least 80% of Staphylococci Staphylococci now produce beta-lactamase.now produce beta-lactamase.


Other resistance Other resistance mechanismsmechanisms

A reductionA reduction in the permeability of the in the permeability of the outer membrane.outer membrane.

Thus there is a decreased ability of Thus there is a decreased ability of the drug to penetrate to the target the drug to penetrate to the target site.site.

The occurrence of modified penicillin The occurrence of modified penicillin binding sites. This mechanism is binding sites. This mechanism is responsible in methicillin resistance responsible in methicillin resistance in in Pneumococci.Pneumococci.


The penicillins described in this section are resistant to hydrolysis by staphylococcal penicillinase. Their appropriate use should be restricted to the treatment of infections that are known or suspected to be caused by staphylococci that elaborate the enzyme¾the vast majority of strains of this bacterium that are encountered in the hospital or in the general community. These drugs are less active than is penicillin G against other penicillin-sensitive microorganisms, including non-penicillinase-producing staphylococci.

The penicillinase-resistant penicillins remain the agents of choice for most staphylococcal disease, despite the increasing incidence of isolates of so-called methicillin-resistant microorganisms.


Adverse effectsAdverse effects Hypersensitivity Reactions.

Hypersensitivity reactions are by far the most common adverse effects noted with the penicillins, and these agents probably are the most common cause of drug allergy. There is no convincing evidence that any single penicillin differs from the group in its potential for causing true allergic reactions.

The basis of which is the fact that degradation The basis of which is the fact that degradation products of penicillin combine with host protein products of penicillin combine with host protein and become antigenic.and become antigenic.


These are cross-reactions between various types These are cross-reactions between various types of penicillins.of penicillins.

In approximate order of decreasing frequency, manifestations of allergy to penicillins include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis The overall incidence of such reactions to the penicillins varies from 0.7% to 10% in different studies.

Very high doses of penicillin G can cause seizures Very high doses of penicillin G can cause seizures in kidney failure.in kidney failure.


Stevens Johnson SyndromeStevens Johnson Syndrome

Adverse drug reactions. Adverse drug reactions. Painful Blistering of the skin and mucous Painful Blistering of the skin and mucous

membrane involvment. membrane involvment. In many cases preceded with flu like In many cases preceded with flu like

symptoms and high fever. symptoms and high fever. As it evolves the skin literally sloughs off. As it evolves the skin literally sloughs off. Ocular involvement includes severe Ocular involvement includes severe

conjunctivis, iritis, palpebral edema, conjunctivis, iritis, palpebral edema, conjunctival and corneal blisters and conjunctival and corneal blisters and erosions, and corneal perforation. erosions, and corneal perforation.


Management of the Patient Potentially Allergic to

Penicillin. Evaluation of the patient's history is the most

practical way to avoid the use of penicillin in patients who are at the greatest risk of adverse reaction. The majority of patients who give a history of allergy to penicillin should be treated with a different type of antibiotic.

"Desensitization" occasionally is recommended for patients who are allergic to penicillin and who must receive the drug. This procedure consists of administering gradually increasing doses of penicillin in the hope of avoiding a severe reaction and should be performed only in an intensive care setting.


Apparent toxic effects that have been reported include bone marrow depression, granulocytopenia, and hepatitis. The last-named effect is rare but is most commonly seen following the administration of oxacillin and nafcillin.

Regardless of the route by which the drug is administered, but most strikingly when it is given by mouth, penicillin changes the composition of the microflora by eliminating sensitive microorganisms. This phenomenon is usually of no clinical significance, and the normal microflora is reestablished shortly after therapy is stopped. In some persons, however, superinfection results from the changes in flora. Pseudo-membranous colitis, related to overgrowth and production of a toxin by C. difficile, has followed oral and, less commonly, parenteral administration of penicillins.


Adverse effects contAdverse effects cont

Convulsions and encephalopathy Convulsions and encephalopathy can occur, can occur, especially at higher doses and especially if especially at higher doses and especially if administered intrathecally (NOT advised).administered intrathecally (NOT advised).

Interstitial nephritis Interstitial nephritis (Methicillin)(Methicillin) Coomb's positive hemolytic anemiaCoomb's positive hemolytic anemia Neutropenia Neutropenia (especially the b-lactamase -(especially the b-lactamase -

resistant penicillins)resistant penicillins) Decreased platelet aggregation Decreased platelet aggregation

(carbenicillin and ticarcillin)(carbenicillin and ticarcillin) Hypernatremia and hypokalemia Hypernatremia and hypokalemia

(carbenicillin)(carbenicillin)


Drug-drug InteractionsDrug-drug Interactions

Penicillins bind to and inactivate Penicillins bind to and inactivate aminoglycosides. This is a form of chemical aminoglycosides. This is a form of chemical antagonism. If an aminoglycoside and a antagonism. If an aminoglycoside and a penicillin are combined. they MUST NOT be penicillin are combined. they MUST NOT be administered simultaneously through the same administered simultaneously through the same I.V. line or through the same syringe. They will I.V. line or through the same syringe. They will crystallize and precipitate in the line or in the crystallize and precipitate in the line or in the vessels! vessels!

When an aminoglycoside and a penicillin are When an aminoglycoside and a penicillin are administered, the infusions should be staggered administered, the infusions should be staggered by about 1 to 2 hours.by about 1 to 2 hours.


Classification of the Penicillins and Summary Classification of the Penicillins and Summary of Their Pharmacological Propertiesof Their Pharmacological Properties

1.1. Penicillin G and its close congener penicillin V are highly active Penicillin G and its close congener penicillin V are highly active against sensitive strains of gram-positive cocci, but they are against sensitive strains of gram-positive cocci, but they are readily hydrolyzed by penicillinase. Thus, they are ineffective readily hydrolyzed by penicillinase. Thus, they are ineffective against most strains of Staphylococcus aureus.against most strains of Staphylococcus aureus.

2.2. The penicillinase-resistant penicillins (methicillin, nafcillin, The penicillinase-resistant penicillins (methicillin, nafcillin, oxacillin, cloxacillin, and dicloxacillin) have less potent oxacillin, cloxacillin, and dicloxacillin) have less potent antimicrobial activity against microorganisms that are sensitive to antimicrobial activity against microorganisms that are sensitive to penicillin G, but they are effective against penicillinase-producing penicillin G, but they are effective against penicillinase-producing Staph. aureus.Staph. aureus.

3.3. Ampicillin, amoxicillin, bacampicillin, and others comprise a Ampicillin, amoxicillin, bacampicillin, and others comprise a group of penicillins whose antimicrobial activity is extended to group of penicillins whose antimicrobial activity is extended to include such gram-negative microorganisms as Haemophilus include such gram-negative microorganisms as Haemophilus influenzae, E. coli, and Proteus mirabilis. Unfortunately, these influenzae, E. coli, and Proteus mirabilis. Unfortunately, these drugs and the others listed below are hydrolyzed readily by broad-drugs and the others listed below are hydrolyzed readily by broad-spectrum b-lactamases that are found with increasing frequency in spectrum b-lactamases that are found with increasing frequency in clinical isolates of these gram-negative bacteria.clinical isolates of these gram-negative bacteria.


CephalosporinsCephalosporins

Mechanism of ActionMechanism of Action: Cephalosporins are composed : Cephalosporins are composed of a dihydrothiazine ring and a bof a dihydrothiazine ring and a b-lactam ring. -lactam ring. The The mechanism of action is mechanism of action is identical to penicillins.identical to penicillins.

Mechanism of ResistanceMechanism of Resistance: : Same as penicillins. Same as penicillins. Cephalosporins are less susceptible to Cephalosporins are less susceptible to Staphylococcus Staphylococcus

beta-lactamase; therefore have a broader spectrum of beta-lactamase; therefore have a broader spectrum of activity; however they are not the drug of choice. activity; however they are not the drug of choice. Other bacteria are resistant, because they produce Other bacteria are resistant, because they produce distinct beta-lactamases. Methicillin-resistant distinct beta-lactamases. Methicillin-resistant Staphylococcus Staphylococcus is resistant to most cephalosporins.is resistant to most cephalosporins.

ClassificationClassification: The cephalosporins are classified as : The cephalosporins are classified as first, second, third generation or forth first, second, third generation or forth generation generation cephalosporins. This classification is cephalosporins. This classification is dependent on the antimicrobial activity.dependent on the antimicrobial activity.


Cephalosporins

First Generation Second Generation Third Generation Fourth Generation

* Oral Agent

Cefadroxil * Cefaclor * Cefdinir Cefepime

Cefazolin Cefamandole Cefoperaxone

Cefelixin * Cefonicid Cefotaxime

Cephalothin Ceforanide Ceftazidime

Cephaprin Cefotetan Ceftibuten

Cephradine * Cefoxitin Ceftizoxime

Cefuroxime

moxalactammoxalactamCeftriaxone


First generation First generation cephalosporins:cephalosporins:

cephalothin, cefazolin, cefalexin. cephalothin, cefazolin, cefalexin. These drugs These drugs have good activity against most Gram positive cocci have good activity against most Gram positive cocci (Streptococcus, pneumococcus (Streptococcus, pneumococcus but not or but not or methicillin-resistant methicillin-resistant Staphylococcus). Staphylococcus). They are They are more active against Gram negative organisms more active against Gram negative organisms (Escherichia co1i Kiebsiella pneumoniae, (Escherichia co1i Kiebsiella pneumoniae, and the and the indole negative indole negative Proteus mirabilis) Proteus mirabilis) than are the than are the natural penicillins. They are effective against some natural penicillins. They are effective against some anaerobic cocci anaerobic cocci (Peptococcus (Peptococcus and and Peptosteptococcus, Peptosteptococcus, but NOT but NOT Bacteroides fragilis). Bacteroides fragilis).

They are ineffective against They are ineffective against Pseudomonas Pseudomonas aeruginosa, Enterobacter, aeruginosa, Enterobacter, and indole-positive and indole-positive Proteus Proteus species. species.

These drugs do not cross the blood-brain barrier.These drugs do not cross the blood-brain barrier.www.freelivedoctor.comwww.freelivedoctor.com

Second generation Second generation cephalosporins:cephalosporins:

cefuroxime, cefamandole, cefoxitin, cefuroxime, cefamandole, cefoxitin, cefaclor. cefaclor. The spectrum is extended to The spectrum is extended to more Gram negative bacteria more Gram negative bacteria Enterobacter Enterobacter species, species, Klebsiella Klebsiella species, and indole-species, and indole-positive positive Proteus Proteus species. Also, species. Also, Haemophilus influenza Haemophilus influenza is covered by is covered by cefuroxime, cefamandole, cefaclor; cefuroxime, cefamandole, cefaclor; Bacteroides fragilis Bacteroides fragilis by cefoxitin. by cefoxitin.

These drugs do not achieve adequate These drugs do not achieve adequate levels in the CSF.levels in the CSF.


Third generation Third generation cephalosporins:cephalosporins:

moxalactam, cefaperazone, ceftazidirne, moxalactam, cefaperazone, ceftazidirne, ceftriaxone. ceftriaxone. These drugs demonstrate These drugs demonstrate extended Gram negative coverage, are more extended Gram negative coverage, are more resistant to nonresistant to non-Staphylococcus -Staphylococcus b-lactamase, b-lactamase, and readily cross the blood-brain barrier. The and readily cross the blood-brain barrier. The spectrum is extended to include: spectrum is extended to include: Enterobacter, Pseudomonas Enterobacter, Pseudomonas (ceftazidime and (ceftazidime and cefaperazone only), cefaperazone only), Serratia, Serratia, bb-lactamase -lactamase producing producing Haemophillus influenza Haemophillus influenza and and Neisseria Neisseria species. species.

Only cetizoxime and moxalactam retain good Only cetizoxime and moxalactam retain good activity against activity against Bacteroides fragilis.Bacteroides fragilis.


Fourth generationFourth generation

forth generation of cephalosporins forth generation of cephalosporins (e.g. cefepime) are available, these (e.g. cefepime) are available, these are comparable to third-generation are comparable to third-generation but more resistant to some beta but more resistant to some beta lactamases.lactamases.


PharmacokineticsPharmacokinetics

Some cephalosporins may be given orally Some cephalosporins may be given orally but most are given parenterally (IM or IV).but most are given parenterally (IM or IV).

They are widely distributed in the body like They are widely distributed in the body like penicillins.penicillins.

Some such as cefoperazone, cefotaxime, Some such as cefoperazone, cefotaxime, cefuroxime, ceftriaxone, and ceftazidime cefuroxime, ceftriaxone, and ceftazidime (third generation) also cross the blood-brain (third generation) also cross the blood-brain barrier and are drugs of choice for meningitis barrier and are drugs of choice for meningitis due to Gram-negative intestinal bacteria.due to Gram-negative intestinal bacteria.


Almost all are primally eliminated via Almost all are primally eliminated via the kidneys and are actively secreted the kidneys and are actively secreted by the renal tubules. Cefaperazone by the renal tubules. Cefaperazone and ceftriaxone are eliminated and ceftriaxone are eliminated through the biliary tract. through the biliary tract.


Adverse effectsAdverse effects Hypersensitivity reactions very similar to those that Hypersensitivity reactions very similar to those that

occur with penicillins may be seen.occur with penicillins may be seen. Nephrotoxicity and intolerance to alcohol (disulfiram Nephrotoxicity and intolerance to alcohol (disulfiram

like reaction) has been reported. (cefamandole, like reaction) has been reported. (cefamandole, cefotetan, moxalactam, cefoperazone )cefotetan, moxalactam, cefoperazone )

Diarrhea may occur with oral forms. Many second and Diarrhea may occur with oral forms. Many second and particularly third generation cephalosporins are particularly third generation cephalosporins are ineffective against Gram-positive organisms, ineffective against Gram-positive organisms, especially methicillin resistant especially methicillin resistant Staphylococci Staphylococci and and Enterococci.Enterococci.

During treatment with such drugs, these resistant During treatment with such drugs, these resistant organisms as well as fungi, often proliferate and organisms as well as fungi, often proliferate and may may induce induce superinfection.superinfection.

Hyperprothrombinemia, Thrombocytopenia, Platelet Hyperprothrombinemia, Thrombocytopenia, Platelet dysfunction. Administration of vitamin K (10mg) twice dysfunction. Administration of vitamin K (10mg) twice a week can prevent this.a week can prevent this.


Uses:Uses: A cephalosporin with or without an A cephalosporin with or without an

aminoglycoside is first-line treatment of aminoglycoside is first-line treatment of Klebsiella. Klebsiella.

First generation cephalosporins are used for First generation cephalosporins are used for surgical prophylaxis of wound infection. surgical prophylaxis of wound infection.

Third generation cephalosporins are used to Third generation cephalosporins are used to treat meningitis due to pneumococci, treat meningitis due to pneumococci, meningococci, and meningococci, and Haemophillus influenza. Haemophillus influenza.

Ceftriaxone is the drug of choice for treating Ceftriaxone is the drug of choice for treating beta-lactamase producing beta-lactamase producing Neisseria Neisseria gonorrhea.gonorrhea.


Drug interactionDrug interaction

Cephalosporins demonstrate Cephalosporins demonstrate synergistic activity when combined synergistic activity when combined with an aminoglycoside to treat with an aminoglycoside to treat Klebsiella.Klebsiella.


Carbapenems and Carbapenems and monobactamsmonobactams

Carbepenems are a new class of drugs which Carbepenems are a new class of drugs which are structurallv similar to the penicillins. These are structurallv similar to the penicillins. These drugs were developed to deal with drugs were developed to deal with beta‑lactamase producing Gram-negative beta‑lactamase producing Gram-negative organisms, which were resistant to broad organisms, which were resistant to broad spectrum and extended spectrum penicillins.spectrum and extended spectrum penicillins.

Carbapenems are derived from Carbapenems are derived from Streptomyces Streptomyces species and one example is the semisynthetic species and one example is the semisynthetic imipenemimipenem which acts in the same way as the which acts in the same way as the other beta-lactams.other beta-lactams.

The most extensively studied drug is The most extensively studied drug is imipenem.imipenem.


Imipenem:Imipenem: Mechanism of action: Mechanism of action: Imipenem, like other b-lactams, Imipenem, like other b-lactams,

binds to penicillin binding proteins. Hence it disrupts cell binds to penicillin binding proteins. Hence it disrupts cell wall synethesis and is bactericidal.wall synethesis and is bactericidal.

Antimicrobial spectrum: Antimicrobial spectrum: Imipenem differs from the Imipenem differs from the penicillins in its antimicrobial spectrum. It is a penicillins in its antimicrobial spectrum. It is a broad-broad-spectrum spectrum antibiotic with excellent activity against a antibiotic with excellent activity against a variety of gram positive and gram negative organism variety of gram positive and gram negative organism (both aerobic and anaerobic). (both aerobic and anaerobic). It is resistant to most forms It is resistant to most forms of b-lactamase, including that produced by of b-lactamase, including that produced by staphylococcus. staphylococcus. However, methicillin-resistant However, methicillin-resistant staphylococcus is usually resistant to imipenem. staphylococcus is usually resistant to imipenem. Susceptible organisms include: Streptococci, Enterococci. Susceptible organisms include: Streptococci, Enterococci. Staphylococci, Lister, Enterobacteriaceae, Pseudomonas, Staphylococci, Lister, Enterobacteriaceae, Pseudomonas, Bacteroides, and Clostridium.Bacteroides, and Clostridium.


Metabolism:Metabolism: Imipenem is rapidly Imipenem is rapidly hydrolyzed by the enzyme, hydrolyzed by the enzyme, dihydropeptidase, which is found in the dihydropeptidase, which is found in the brush border of the proximal renal tubule. brush border of the proximal renal tubule. It is always administered with cilastatin, an It is always administered with cilastatin, an inhibitor of dipeptidase.inhibitor of dipeptidase.

Side efects:Side efects: Individuals who are allergic Individuals who are allergic to the penicillins may demonstrate cross-to the penicillins may demonstrate cross-reactivity with imipenem. reactivity with imipenem. Imipemem may produce nausea and vomiting.Imipemem may produce nausea and vomiting. Seizures have been reported with high doses, Seizures have been reported with high doses,

particularly in patients with renal failure.particularly in patients with renal failure.


MeropenemMeropenem It is similar to imipenem.It is similar to imipenem. It is not degraded by It is not degraded by

dehydropeptidase, thus no cilastatin dehydropeptidase, thus no cilastatin is needed.is needed.

Excessive levels in kidney failure can Excessive levels in kidney failure can cause seizures with imipenem but not cause seizures with imipenem but not with meropenem.with meropenem.


MonobactamMonobactam Aztreonam: Aztreonam: This drug is a monocyclic beta-lactam This drug is a monocyclic beta-lactam

(a monobactam).(a monobactam). Mechanism of actionMechanism of action: : Aztreonam interacts with Aztreonam interacts with

penicillin binding proteins and induces the penicillin binding proteins and induces the formation of long filamentous bacteria.formation of long filamentous bacteria.

Antimicrobial spectrumAntimicrobial spectrum: : The antimicrobial The antimicrobial spectrum of aztreonam differs from that of other spectrum of aztreonam differs from that of other beta-lactams. It more closely resembles the beta-lactams. It more closely resembles the spectrum of the aminoglycosides. Gram positive spectrum of the aminoglycosides. Gram positive and anaerobic bacteria are resistant. Susceptible and anaerobic bacteria are resistant. Susceptible organisms include: (organisms include: (It has an unusual spectrum being It has an unusual spectrum being active only against Gram-negative aerobic rods) active only against Gram-negative aerobic rods) Enterobacteriaceae, Pseudomonas, Hemophillus Enterobacteriaceae, Pseudomonas, Hemophillus and Neisseria. Aztreonam is resistant to the beta-and Neisseria. Aztreonam is resistant to the beta-lactamase produced by gram negative organisms.lactamase produced by gram negative organisms.

Side effects:Side effects: Generally, the drug is well tolerated. Generally, the drug is well tolerated. Patients who are allergic to penicillins do not exhibit Patients who are allergic to penicillins do not exhibit cross-reactions with aztreonam.cross-reactions with aztreonam.www.freelivedoctor.comwww.freelivedoctor.com

betabeta-Lactamase -Lactamase InhibitorsInhibitors

Clavulanic Acid, Sulbactam and Clavulanic Acid, Sulbactam and tazobactamtazobactam

Mechanism of action:Mechanism of action: These drugs have These drugs have poor antimicrobial activity. They are poor antimicrobial activity. They are inhibitors of bacterial beta-lactamase. inhibitors of bacterial beta-lactamase.

They are potent inhibitors of many bacterial They are potent inhibitors of many bacterial beta-lactamases and can protect beta-lactamases and can protect hydrolyzable penicillins from inactivation by hydrolyzable penicillins from inactivation by these enzymes.these enzymes.

They are included in combination with They are included in combination with amoxacillin (Augmentum) or with ticaricillin. amoxacillin (Augmentum) or with ticaricillin. In particular, clavulanic acid is an irreversible, In particular, clavulanic acid is an irreversible, "suicide" inhibitor of beta-lactamase."suicide" inhibitor of beta-lactamase.


They are available only in fixed They are available only in fixed combinations with specific penicillins:combinations with specific penicillins:

Ampicillin + sulbactamAmpicillin + sulbactam Amoxicillin + clavulanic acidAmoxicillin + clavulanic acid Ticarcillin + clavulanate potassiumTicarcillin + clavulanate potassium Piperacillin + tazobactam sodiumPiperacillin + tazobactam sodium


fundamentals antimicrobial agents

Documents