Anti Bacterials

7/29/2019 Anti Bacterials

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Cell Wall Inhibitors

Robert L. Copeland, Ph.D.28 January 2013


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IntroductionThe penicillins constitute one of the mostimportant groups of antibiotics. Althoughnumerous other antimicrobial agents have beenproduced since the first penicillin becameavailable, these still are widely used, majorantibiotics, and new derivatives of the basicpenicillin nucleus still are being produced. Manyof these have unique advantages, such that

members of this group of antibiotics are presentlythe drugs of choice for a large number ofinfectious diseases.


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History

The penicillins were the first antibioticsdiscovered as natural products from the mold

Penicillium. In 1928, Sir Alexander Fleming,professor of bacteriology at St. Mary's Hospitalin London, was culturing Staphylococcus aureus.He noticed zones of inhibition where mold

spores were growing. He named the moldPenicillium rubrum. It was determined that asecretion of the mold was effective againstGram-positive bacteria.


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1928 - Alexander Fleming

Bread mold (Penicillin notatum) growing on petri dish

1939 - Florey, Chain, and Associates Began work on isolating and synthizing large amounts

of Penicillin.

1944 - Used in WWII to treat infections

Late 1940s - available for general use in US


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Structure

Penicillins as well as cephalosporins are calledbeta-lactam antibiotics and are characterized bythree fundamental structural requirements:

the fused beta-lactam structure (shown in the blueand red rings,

a free carboxyl acid group (shown in red bottomright),

one or more substituted amino acid side chains(shown in black).

The lactam structure can also be viewed as thecovalent bonding of pieces of two amino acids -

cysteine (blue) and valine (red).


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

chain (R).


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The penicillin nucleus itself is the chiefstructural requirement for biological

activity; metabolic transformation or chemical

alteration of this portion of the molecule

causes loss of all significant antibacterialactivity


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Clinically useful families of beta-lactamcompounds include the

penicillins,

cephalosporins,

monobactams

carbapenems


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Classification

Penicillins (penicillin G) greatest activityagainst gram+, gram-cocci, non-beta-lactamase-producing anaerobes

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

Extended-spectrum penicillins (ampicillin)retain antibacterial spectrum of penicillin withimproved activity against gram- organisms, butare destroyed by beta-lactamases.


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Mechanisms of Drug Actions by

Enzyme Inhibition:All penicillin derivatives produce their

bacteriocidal effects by inhibition of

bacterial cell wall synthesis. Specifically,the cross linking of peptides on themucosaccharide chains is prevented. If

cell walls are improperly made cell wallsallow water to flow into the cell causing itto burst.


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Cell Wall production

The cell walls of bacteria are essential for their normalgrowth and development. Peptidoglycan is aheteropolymeric component of the cell wall that providesrigid mechanical stability by virtue of its highly cross-linked latticework structure

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

In gram-positive microorganisms, the cell wall is 50 to100 molecules thick, but it is only 1 or 2 molecules thickin gram-negative bacteria


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The biosynthesis of the peptidoglycan involvesabout 30 bacterial enzymes and may beconsidered in three stages. The first stage, precursor formation, takes place in

the cytoplasm. The product, uridine diphosphate(UDP)-acetylmuramyl-pentapeptide, called a "Parknucleotide" 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 racemizationof L-alanine and condensation catalyzed by D-alanyl-

D-alanine synthetase.


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

The third and final stage involves the completion of thecross-link. This is accomplished by a transpeptidationreaction that occurs outside the cell membrane. Thetranspeptidase itself is membrane bound. The terminalglycine residue of the pentaglycine bridge is linked to thefourth residue of the pentapeptide (D-alanine), releasingthe fifth residue (also D-alanine)


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

Penicillin binds at the active site of the transpeptidaseenzyme that cross-links the peptidoglycan strands. Itdoes this by mimicking the D-alanyl-D-alanine residuesthat would normally bind to this site. Penicillinirreversibly inhibits the enzyme transpeptidase byreacting with a serine residue in the transpeptidase. Thisreaction is irreversible and so the growth of the bacterialcell wall is inhibited.


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Related targets for the actions of penicillins andcephalosporins; these are collectively termedpenicillin-binding proteins (PBPs)

Covalently bind to a heterologous group ofproteins called penicillin-binding proteinsThese PBPs may number 3 to 6 in any givenbacteria.

There functions are diverse: catalyze thetranspeptidase reaction, maintam shape, formsseptums during division, Inhibit autolyticenzymes.


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Binding to PBPs results in: Inhibition of transpeptidase:

transpeptidase catalyzes the cross-linking ofthe pentaglycine bridge with the fourthresidue (D-Ala) of the pentapeptide. The fifthreside (also D-Ala) is released during thisreaction. Spheroblasts are formed.

Structural irregularities: binding to PBPsmay result in abnormal elongation, abnormalshape, cell wall defects.


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Figure 45-2. The transpeptidase reaction in Staphylococcus aureus that is

inhibited by penicillins and cephalosporins.


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


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Pharmacokinetics Oral Administration of Penicillin G. About one-third

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

Gastric juice at pH 2 rapidly destroys the antibiotic. Thedecrease in gastric acid production with aging accounts forbetter absorption of penicillin G from the gastrointestinaltract of older individuals.

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

Ingestion of food may interfere with enteric absorption ofall penicillins, perhaps by adsorption of the antibiotic ontofood particles. Thus, oral penicillin G should beadministered at least 30 minutes before a meal or 2 hoursafter. Despite the convenience of oral administration of

penicillin G, this route should be used only in infections inwhich clinical experience has proven its efficacy.


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Oral Administration of Penicillin V. The sole virtueof penicillin V in comparison with penicillin G is that it ismore stable in an acidic medium, and therefore is betterabsorbed from the gastrointestinal tract.

On an equivalent oral-dose basis, penicillin V (K+ saltPEN-VEE K, V-CILLIN K, others) yields plasmaconcentrations two to five times greater than thoseprovided by penicillin G. The peak concentration in theblood of an adult after an oral dose of 500 mg is nearly

3 mg/ml. Once absorbed, penicillin V is distributed in thebody and excreted by the kidney in the same manner aspenicillin G.


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Parenteral Administration of Penicillin G

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

Repository preparations of penicillin G are employed. Thetwo such compounds currently favored are penicillin Gprocaine (maintained for as long as 4 to 5 days.) andpenicillin G benzathine. (duration of antimicrobial activity inthe plasma is about 26 day)

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

Intrathecal administration is inadvisable particularly withbenzylpenicillin as it can cause convulsions.


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Distribution. Penicillin G is distributed widely throughout the body, but

the concentrations in various fluids and tissues differwidely. Its apparent volume of distribution is about 0.35liters/kg. Approximately 60% of the penicillin G in plasmais reversibly bound to albumin. Significant amounts appear

in liver, bile, kidney, semen, joint fluid, lymph, andintestine.

While probenecid markedly decreases the tubular

secretion of the penicillins, this is not the only factorresponsible for the elevated plasma concentrations of theantibiotic that follow its administration. Probenecid alsoproduces a significant decrease in the apparent volume ofdistribution of the penicillins.


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Cerebrospinal Fluid. Penicillin does notreadily enter the CSF when the meninges are

normal. However, when the meninges areacutely inflamed, penicillin penetrates into theCSF more easily. Although the concentrationsattained vary and are unpredictable, they are

usually in the range of 5% of the value inplasma and are therapeutically effective againstsusceptible microorganisms.


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Excretion Under normal conditions, penicillin G is rapidly eliminated

from the body, mainly by the kidney but in small part in thebile and by other routes. Approximately 60% to 90% of anintramuscular dose of penicillin G in aqueous solution is

eliminated in the urine, largely within the first hour afterinjection.

The half-time for elimination is about 30 minutes in normaladults (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 thenormal male adult is about 3 million units (1.8 g) per hour.


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Clearance values are considerably lower in neonates andinfants, because of incomplete development of renalfunction; as a result, after doses proportionate to surface

area, the persistence of penicillin in the blood is severaltimes as long in premature infants as in children andadults.

The half-life of the antibiotic in children less than 1 weekold is 3 hours; by 14 days of age it is 1.4 hours. After renal

function is fully established in young children, the rate ofrenal excretion of penicillin G is considerably more rapidthan in adults.


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Unitage of Penicillin

The international unit of penicillin is the specific penicillinactivity contained in 0.6 mg of the crystalline sodium saltof penicillin G. One milligram of pure penicillin G sodiumthus equals 1667 units; 1.0 mg of pure penicillin Gpotassium represents 1595 units. The dosage and theantibacterial potency of the semisynthetic penicillins areexpressed in terms of weight.

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

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


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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


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The antimicrobial activity ofcarbenicillin, itsindanyl ester (carbenicillin indanyl), andticarcillinis extended to include Pseudomonas,Enterobacter, and Proteusspecies.

Other extended-spectrum penicillins include

mezlocillinand piperacillin, which have usefulantimicrobial activity against Pseudomonas,Klebsiella, and certain other gram-negativemicroorganisms.


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Mechanisms of Bacterial

Resistance to Penicillins Resistance to penicillins and other beta

lactams is due to one of four general

mechanisms: Inactivation of the antibiotic by beta

lactamase

Modification of target PBPs Imparied penetration of drug to target PBPs

The presence of an efflux pump.


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There are more than 300 different types of thisenzyme. The process is genetically controlledcommonly with plasmids.

beta-lactamase production is particularlyimportant in Staphylococcibut other organismssuch as Neisseria gonorrhoeaeand Hemophilusspecies also produce these enzymes where asbeta-hemolytic Streptococcido not.

In developed countries at least 80% ofStaphylococcinow produce beta-lactamase.


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Other resistance mechanisms

A reductionin the permeability of theouter membrane.

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

The occurrence of modified penicillinbinding sites. This mechanism is

responsible in methicillin resistance inPneumococci.


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The penicillins described in this section are resistant to hydrolysisby staphylococcal penicillinase. Their appropriate use should berestricted to the treatment of infections that are known orsuspected to be caused by staphylococci that elaborate theenzymethe vast majority of strains of this bacterium that areencountered in the hospital or in the general community. Thesedrugs are less active than is penicillin G against other penicillin-sensitive microorganisms, including non-penicillinase-producingstaphylococci.

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


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Adverse effects

Hypersensitivity Reactions. Hypersensitivityreactions are by far the most common adverseeffects noted with the penicillins, and these agentsprobably are the most common cause of drugallergy. There is no convincing evidence that anysingle penicillin differs from the group in itspotential for causing true allergic reactions.

The basis of which is the fact that degradationproducts of penicillin combine with host protein andbecome antigenic.


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These are cross-reactions between various types ofpenicillins.

In approximate order of decreasing frequency,

manifestations of allergy to penicillins includemaculopapular rash, urticarial rash, fever,bronchospasm, vasculitis, serum sickness, exfoliativedermatitis, Stevens-Johnson syndrome, and anaphylaxisThe 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 in

kidney failure.


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Stevens Johnson Syndrome

Adverse drug reactions.

Painful Blistering of the skin and mucousmembrane involvment.

In many cases preceded with flu like symptomsand high fever.

As it evolves the skin literally sloughs off.

Ocular involvement includes severe conjunctivis,iritis, palpebral edema, conjunctival and cornealblisters and erosions, and corneal perforation.


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Management of the Patient

Potentially Allergic to Penicillin.

Evaluation of the patient's history is the most practicalway to avoid the use of penicillin in patients who are atthe greatest risk of adverse reaction. The majority of

patients who give a history of allergy to penicillin shouldbe treated with a different type of antibiotic.

"Desensitization" occasionally is recommended forpatients who are allergic to penicillin and who mustreceive the drug. This procedure consists of

administering gradually increasing doses of penicillin inthe hope of avoiding a severe reaction and should beperformed only in an intensive care setting.


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Apparent toxic effects that have been reported include bonemarrow depression, granulocytopenia, and hepatitis. Thelast-named effect is rare but is most commonly seenfollowing 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, penicillinchanges the composition of the microflora by eliminatingsensitive microorganisms. This phenomenon is usually of noclinical significance, and the normal microflora is

reestablished shortly after therapy is stopped. In somepersons, however, superinfection results from the changes inflora. Pseudo-membranous colitis, related to overgrowth andproduction of a toxin by C. difficile, has followed oral and,less commonly, parenteral administration of penicillins.


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Adverse effects cont

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

Interstitial nephritis (Methicillin) Coomb's positive hemolytic anemia

Neutropenia (especially the b-lactamase -resistantpenicillins)

Decreased platelet aggregation (carbenicillin andticarcillin)

Hypernatremia and hypokalemia (carbenicillin)


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Drug-drug Interactions

Penicillins bind to and inactivate aminoglycosides. Thisis a form of chemical antagonism. If an aminoglycoside

and a penicillin are combined. they MUST NOT beadministered simultaneously through the same I.V.line or through the same syringe. They will crystallizeand precipitate in the line or in the vessels!

When an aminoglycoside and a penicillin are

administered, the infusions should be staggered byabout 1 to 2 hours.

Classification of the Penicillins and Summary of


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Classification of the Penicillins and Summary ofTheir Pharmacological Properties

1. Penicillin G and its close congener penicillin V are highly active against

sensitive strains of gram-positive cocci, but they are readily hydrolyzed bypenicillinase. Thus, they are ineffective against most strains ofStaphylococcus aureus.

2. The penicillinase-resistant penicillins (methicillin, nafcillin, oxacillin,cloxacillin, and dicloxacillin) have less potent antimicrobial activity against

microorganisms that are sensitive to penicillin G, but they are effectiveagainst penicillinase-producing Staph. aureus.

3. Ampicillin, amoxicillin, bacampicillin, and others comprise a group ofpenicillins whose antimicrobial activity is extended to include such gram-negative microorganisms as Haemophilus influenzae, E. coli, and Proteus

mirabilis. Unfortunately, these drugs and the others listed below arehydrolyzed readily by broad-spectrum b-lactamases that are found withincreasing frequency in clinical isolates of these gram-negative bacteria.


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Cephalosporins

Mechanism of Action: Cephalosporins are composed of adihydrothiazine ring and a b-lactam ring. The mechanismof action is identical to penicillins.

Mechanism of Resistance: Same as penicillins. Cephalosporins are less susceptible to Staphylococcusbeta-

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

Classification: The cephalosporins are classified as first,second, third generation or forth generationcephalosporins. This classification is dependent on theantimicrobial activity.


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Cephalosporins

Penicillins


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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

moxalactamCeftriaxone


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First generationcephalosporins:

cephalothin, cefazolin, cefalexin. These drugs havegood activity against most Gram positive cocci(Streptococcus, pneumococcusbut not or methicillin-resistant Staphylococcus). They are more active against

Gram negative organisms (Escherichia co1i Kiebsiellapneumoniae, and the indole negative Proteus mirabilis)than are the natural penicillins. They are effective againstsome anaerobic cocci (Peptococcusand Peptosteptococcus,but NOT Bacteroides fragilis).

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

These drugs do not cross the blood-brain barrier.


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Second generationcephalosporins:

cefuroxime, cefamandole, cefoxitin,cefaclor. The spectrum is extended to more

Gram negative bacteria Enterobacterspecies,Klebsiellaspecies, and indole-positive Proteusspecies. Also, Haemophilus influenzaiscovered by cefuroxime, cefamandole, cefaclor;

Bacteroides fragilisby cefoxitin. These drugs do not achieve adequate levels in

the CSF.


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Third generationcephalosporins:

moxalactam, cefaperazone, ceftazidirne,ceftriaxone. These drugs demonstrate extendedGram negative coverage, are more resistant to

non-Staphylococcusb-lactamase, and readilycross the blood-brain barrier. The spectrum isextended to include: Enterobacter, Pseudomonas(ceftazidime and cefaperazone only), Serratia, b-lactamase producing Haemophillus

influenzaand Neisseriaspecies. Only cetizoxime and moxalactam retain good

activity against Bacteroides fragilis.


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Fourth generation

forth generation of cephalosporins (e.g.cefepime) are available, these are

comparable to third-generation but moreresistant to some betalactamases.


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Pharmacokinetics

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

They are widely distributed in the body likepenicillins.

Some such as cefoperazone, cefotaxime,cefuroxime, ceftriaxone, and ceftazidime (third

generation) also cross the blood-brain barrierand are drugs of choice for meningitis due toGram-negative intestinal bacteria.


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Almost all are primally eliminated via thekidneys and are actively secreted by the

renal tubules. Cefaperazone andceftriaxone are eliminated through thebiliary tract.


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Adverse effects Hypersensitivity reactions very similar to those that occur

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

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

Diarrhea may occur with oral forms. Many second andparticularly third generation cephalosporins are ineffectiveagainst Gram-positive organisms, especially methicillinresistant Staphylococciand Enterococci.

During treatment with such drugs, these resistant organisms

as well as fungi, often proliferate and may inducesuperinfection.

Hyperprothrombinemia, Thrombocytopenia, Plateletdysfunction. Administration of vitamin K (10mg) twice aweek can prevent this.


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Uses:

A cephalosporin with or without anaminoglycoside is first-line treatment ofKlebsiella.

First generation cephalosporins are used forsurgical prophylaxis of wound infection.

Third generation cephalosporins are used totreat meningitis due to pneumococci,

meningococci, and Haemophillus influenza.

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


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Drug interaction

Cephalosporins demonstrate synergisticactivity when combined with an

aminoglycoside to treat Klebsiella.


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Carbapenems andmonobactams

Carbepenems are a new class of drugs which arestructurallv similar to the penicillins. These drugswere developed to deal with beta-lactamase

producing Gram-negative organisms, which wereresistant to broad spectrum and extendedspectrum penicillins.

Carbapenems are derived from Streptomycesspecies and one example is the semisyntheticimipenem which acts in the same way as theother beta-lactams.

The most extensively studied drug is imipenem.


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

to penicillin binding proteins. Hence it disrupts cell wallsynethesis and is bactericidal.

Antimicrobial spectrum:Imipenem differs from the penicillins

in its antimicrobial spectrum. It is a broad-spectrumantibioticwith excellent activity against a variety of gram positive andgram negative organism (both aerobic and anaerobic). It isresistant to most forms of b-lactamase, including thatproduced by staphylococcus. However, methicillin-resistant

staphylococcus is usually resistant to imipenem. Susceptibleorganisms include: Streptococci, Enterococci. Staphylococci,Lister, Enterobacteriaceae, Pseudomonas, Bacteroides, andClostridium.


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Metabolism:Imipenem is rapidly hydrolyzed bythe enzyme, dihydropeptidase, which is found inthe brush border of the proximal renal tubule. It

is always administered with cilastatin, aninhibitor of dipeptidase. Side efects:Individuals who are allergic to the

penicillins may demonstrate cross-reactivity withimipenem. Imipemem may produce nausea and vomiting. Seizures have been reported with high doses,

particularly in patients with renal failure.


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Meropenem

It is similar to imipenem.

It is not degraded by dehydropeptidase,thus no cilastatin is needed.

Excessive levels in kidney failure can

cause seizures with imipenem but not withmeropenem.

b


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Monobactam Aztreonam: This drug is a monocyclic beta-lactam (a

monobactam). Mechanism of action:Aztreonam interacts with penicillin

binding proteins and induces the formation of longfilamentous bacteria.

Antimicrobial spectrum:The antimicrobial spectrum of

aztreonam differs from that of other beta-lactams. It moreclosely resembles the spectrum of the aminoglycosides.Gram positive and anaerobic bacteria are resistant.Susceptible organisms include: (It has an unusual spectrumbeing active only against Gram-negative aerobic rods)Enterobacteriaceae, Pseudomonas, Hemophillus and

Neisseria. Aztreonam is resistant to the beta-lactamaseproduced by gram negative organisms.

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


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beta-Lactamase Inhibitors Clavulanic Acid, Sulbactam and

tazobactam Mechanism of action:These drugs have poor

antimicrobial activity. They are inhibitors of

bacterial beta-lactamase. They are potent inhibitors of many bacterial

beta-lactamases and can protect hydrolyzablepenicillins from inactivation by these enzymes.

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


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They are available only in fixedcombinations with specific penicillins:

Ampicillin + sulbactamAmoxicillin + clavulanic acid

Ticarcillin + clavulanate potassium

Piperacillin + tazobactam sodium

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Anti Bacterials