-LACTAM ANTIBIOTICS ________________________________________________________________________

The -lactam antibiotics share a common structure and mechanism of actioninhibition of synthesis of the bacterial peptidoglycan cell wall. This class includes Penicillins, Cephalosporins, Carbapenems and Monobactams.

1. PENICILLINS : Penicillin is an antibiotic produced by the Penicillium notatum mould.

The antibiotic effect was originally discovered by a young French medical student Ernest Duchesne studying Penicillium glaucum in 1896 but his work was forgotten. It was later rediscovered in 1928 by Alexander Fleming who noticed that a halo of inhibition of bacterial growth in a culture of Staphylococcus around a contaminant blue-green mould. From the culture plate, Fleming concluded that the mould was releasing a substance that was inhibiting bacterial growth. He grew a pure culture and discovered that the fungus wasPenicillium notatum - he later named the bacterial inhibiting substance penicillin after the Penicillum notatum that released it. Unfortunately, Fleming was convinced after conducting some more experiments that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931. It would prove to be the discovery that changed modern medicine. Its chemical structure was determined by Dorothy Crowfoot Hodgkin, enabling synthetic production. A team of Oxford research scientists led by Australian Howard Walter Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass producing the drug. Penicillin has since become the most widely used antibiotic to date and is still used for many Gram-positive bacterial infections.

Penicillins constitute one of the most important groups of antibiotics. Although numerous other antimicrobial agents have been produced since the first penicillin became available, these still are used widely, and major antibiotics and new derivatives of the basic penicillin nucleus still are being produced.

Chemistry.

The basic structure of the penicillins, consists of a thiazolidine ring (A) connected to a -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. The side chain determines many of the antibacterial and pharmacological characteristics of a particular type of penicillin. Several natural penicillins can be produced depending on the chemical composition of the fermentation medium used to culture Penicillium. Penicillin G (benzylpenicillin) has the greatest antimicrobial activity of these and is the only natural penicillin used clinically. For penicillin G, the side chain is a phenyl-methyl substituentSemisynthetic Penicillins. The discovery that the the basic 6-aminopenicillanic acid could be obtained from cultures of P. chrysogenum that were depleted of side-chain precursors led to the development of the semisynthetic penicillins. Side chains can be added that alter the susceptibility of the resulting compounds to inactivating enzymes (-lactamases) and that change the antibacterial activity and the pharmacological properties of the drug. 6-Aminopenicillanic acid is now produced in large quantities with the aid of an amidase from P. chrysogenum .This enzyme splits the peptide linkage by which the side chain of penicillin is joined to 6-aminopenicillanic acid..

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Unitage (Units) of Penicillin.

The international unit (IU) of penicillin is the specific penicillin activity contained in 0.6 g of the crystalline sodium salt of penicillin G. One milligram of pure penicillin G sodium equals 1667 international 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 PENICILLIN

Mechanism of Action Penicillins and Cephalosporins.

The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework structure . In gram-positive microorganisms, the cell wall is 50 to 100 molecules thick, but it is only 1 or 2 molecules thick in gram-negative bacteria. The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains. The biosynthesis of the peptidoglycan involves about 30 bacterial enzymes and may be considered in three stages. The first stage: precursor formation, takes place in the cytoplasm. The product, uridine diphosphate (UDP)-acetylmuramyl-pentapeptide, 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. D-Cycloserine is a structural analog of D-alanine and acts as a competitive inhibitor of both the racemase and the synthetase

During reactions of the second stage,

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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 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 -lactam antibiotics and glycopeptide antibiotics such as vancomycin (by a different mechanism than the -lactams;). Stereomodels reveal that the conformation of penicillin is very similar to that of D-alanyl-D-alanine. The transpeptidase probably is acylated by penicillin; that is, penicilloyl enzyme apparently is formed, with cleavage of the CON

bond of the -lactam ring.

There are additional, related targets for the actions of penicillins and cephalosporins; these are collectively termed penicillin-binding proteins (PBPs). All bacteria have several such entities; for example, S. aureus has four PBPs, whereas Escherichia coli has at least seven. The PBPs vary in their affinities for different -lactam antibiotics, although the interactions eventually become covalent. The higher-molecular-weight PBPs of E. coli (PBPs 1a and 1b) include the transpeptidases responsible for synthesis of the peptidoglycan. Other PBPs in E. coli include those that are necessary for maintenance of the rodlike shape of the bacterium and for septum formation at division.Inhibition of the transpeptidases causes spheroplast formation and rapid lysis. However, inhibition of the activities of other PBPs may cause delayed lysis (PBP 2) or the production of long, filamentous forms of the bacterium (PBP 3). The lethality of penicillin for bacteria appears to involve both lytic and nonlytic mechanisms. Penicillin's disruption of the balance between PBP-mediated peptidoglycan assembly and murein hydrolase activity results in autolysis. Nonlytic killing by penicillin may involve holin-like proteins in the bacterial membrane that collapse the membrane potential.

Mechanisms of Bacterial Resistance to Penicillins and Cephalosporins.

Although all bacteria with cell walls contain PBPs, -lactam antibiotics cannot kill or even inhibit all bacteria because by various mechanisms bacteria can be resistant to these agents. The microorganism may be intrinsically resistant because of structural differences in the PBPs that are the targets of these drugs. Furthermore, a sensitive strain may acquire resistance of this type by the development of high-molecular-weight PBPs that have decreased affinity for the antibiotic. Because the -lactam antibiotics inhibit many different PBPs in a single bacterium, the affinity for -lactam antibiotics of several PBPs must decrease for the organism to be resistant. Altered PBPs with decreased affinity for -lactam antibiotics are acquired by homologous recombination between PBP genes of different bacterial species.

Other instances of bacterial resistance to the -lactam antibiotics are caused - by the inability of the agent to penetrate to its site of action In gram-positive bacteria,

the peptidoglycan polymer is very near the cell surface. Some gram-positive bacteria have polysaccharide capsules that are external to the cell wall, but these structures are not a barrier to the diffusion of the -lactams; the small -lactam antibiotic molecules can penetrate easily to the outer layer of the cytoplasmic membrane and the PBPs, where the final stages of the synthesis of the peptidoglycan take place. The situation is different with gram-negative bacteria. Their surface structure is more complex, and their inner membrane, which is analogous to the cytoplasmic membrane of gram-positive bacteria,

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is covered by the outer membrane, lipopolysaccharide, and capsule The outer membrane functions as an impenetrable barrier for some antibiotics.

- Some small hydrophilic antibiotics, however, diffuse through aqueous channels in the outer membrane that are formed by proteins called porins. Broader-spectrum penicillins, such as ampicillin and amoxicillin, and most of the cephalosporins diffuse through the pores in the E. coli outer membrane significantly more rapidly than can penicillin G. The number and size of pores in the outer membrane vary among different gram-negative bacteria. An extreme example is P. aeruginosa, which is intrinsically resistant to a wide variety of antibiotics because it lacks the classical high-permeability porins

- Active efflux pumps serve as another mechanism of resistance, removing the antibiotic from its site of action before it can act. This is an important mechanism of -lactam resistance in P. aeruginosa, E. coli, and Neisseria gonorrhoeae

- Bacteria also can destroy -lactam antibiotics enzymatically. -Lactamases are capable of inactivating certain of these antibiotics and may be present in large quantities Different microorganisms elaborate a number of distinct -lactamases, although most bacteria produce only one form of the enzyme. The substrate specificities of some of these enzymes are relatively narrow, and these often are described as either penicillinases or cephalosporinases. Other "extended spectrum" enzymes are less discriminant and can hydrolyze a variety of -lactam antibiotics.

In general, gram-positive bacteria produce and secrete a large amount of -lactamase. Most of these enzymes are penicillinases. In gram-negative bacteria, -lactamases are found in relatively small amounts but are located in the periplasmic space between the inner and outer cell membranes . Since the enzymes of cell wall synthesis are on the outer surface of the inner membrane, these -lactamases are strategically located for maximal protection of the microbe. -Lactamases of gram-negative bacteria are encoded either in chromosomes or in plasmids, and they may be constitutive or inducible. The plasmids can be transferred between bacteria by conjugation. These enzymes can hydrolyze penicillins, cephalosporins, or both .

Classification of Penicillins : The classification of penicillins is based on their antimicrobial spectrum.

1. Natural Penicillins: a) Acid labile penicillin: crystalline penicillin G (benzyl penicillin) b) Acid resistant penicillins: penicillin V (phenoxymethyl penicillin), phenethicillin( phenoxy ethyl penicillin). c) Repository /depot preparation/form penicillins: Procaine penicillin,, Benzathine penicillin ( repository forms of penicillin G)

The natural penicillins were the first agents in the penicillin family to be introduced for clinical use. The natural penicillins are based on the original penicillin-G structure. Penicillin V is the drug of choice for the treatment of streptococcal pharyngitis. It is also useful for anaerobic coverage in patients with oral cavity infections.Effective against many Gram positive cocci-- Streptococcus (pyrogens and pneumonia--for viridans and agalactiae combine with an aminoglycoside); Gram positive rods--Bacillus anthracis, Cornybacterium diptheriae, most Clostridium (perfringens, tetani but not difficile); Spirochetes--Treponema palladium; limited Gram negative coverage-- Neisseria species and Bacteroides species, excluding fragilis.

2. Narrow spectrum -lactamase (penicillinase) Resistant Penicillins : (Antistaphylococcal penicillins)

a)Non isoxazolyl penicicllins- temocillin, nafcillin, methicillin, b) Isoxazolyl penicillins--oxacillin, cloxicillin, dicloxacillin, and flucloxacillin.

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These compounds have large R groups which sterically hinder access to the -lactam bond. These drugs are reserved for - lactamase-producing Staphylococcus aureus

3. Broad spectrum penicillins : a) Aminopenicillins /Aminobenzyl penicillins: ampicillin,amoxicillin(amoxycillin) and

ampicillin prodrugs/precursors (bacampicillin, pivampicillin, hetacillin , talampicillin) b) Amidopenicillins eg: mecillinam (amidinopenicillin)

These are acid-resistant and may be admnistered orally. Their spectrum of activity is extended to include some Gram negative bacteria, most notably: Hemophillus influenzae, Escherichia coli and the indole-negative Proteus mirabilis. They retain good activity against Neissaria species. These drugs have decreased activity against most of the Gram positive species which are covered by the natural penicillins

4. Extended spectrum Penicillins: ( Antipseudomonal penicillins)i) Carboxypenicillins: carbenicillin and ticarcillin. These drugs in addition to the Gram

negative coverage of the aminopenicillins; also have action against Pseudomonas species, Enterobacter species, and the indole-positive Proteus species (vulgaris, rettgeri, and morganii)

ii) Ureidopenicillins: azlocillin, mezlocillin, and piperacillin. azlocillin and piperacillin have 10 times greater activity than the carboxypenicillins. In addition, the spectrum of mezlocillin and piperacillin is extended to include Klebsiella species.

Absorption, Distribution, Metabolism, ExcretionThe penicillins differ in their acid stability. Some are acid-labile (penicillin G, methicillin.

carbenicillin, and the ureidopenicillins). Some are acid-stable and can be admnistered orally (penicillinV, ampicillin, amoxacillin, and the isoxazolyl penicillins). All are well absorbed following parenteral administration, though injections may be painful. Sodium and potassium (penciillinmG , ampicilliin etc)salts were used and amoxicillin trihydrate salt is used..After absorption, penicillins are widely distributed throughout body water. Penicillins do not achieve high levels in the CSF. Furthermore, an active transport process pumps penicillins out of the CSF and into the bloodstream. This mechanism is blocked by probencid. Nevertheless, in cases of meningitis,inflamation increases the permeability and penicillins may achieve high levels (i.e. ampicillin or amoxacillin is used to treat meningitis due to Haemophillus influenza). Penicillins are not metabolized to any significant extent. They are predominantly eliminated unchanged via the kidney. Most of the dose (90%) is actively secreted by the renal tubules; the remainder is freely filtered. Active secretion can be blocked by probenicid., an uricosuric agent

Repository Forms of Penicillin G: After intramuscular injection, Penicillin G procaine (PAM; aluminum monostearate- adjuvant used) is more slowly absorbed than Penicillin G sodium salt. An injection of 300,000 Int. units will maintain adequate plasma levels for 24 hours. Intramuscular injection of Benzathine Penicillin G has the slowest rate of absorption. The frequency of administration is once in 72-96hours.

Indications: The common infectious diseases of livestock in which penicillins are preferred agents include Blackleg , Strangles Actinomycosis, Erysipelas , Tetanus, leptospirosis Malignant edema and susceptible bacterial infections of respiratory tract, reproductive tract, joints skin and soft tissue infections etc. Adverse / Side effects

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Penicillins are among the least toxic drugs known. The most common side effect of penicillin is diarrhea. Nausea, vomiting, and upset stomach are also common. In rare cases penicillins can cause immediate and delayed allergic reactions - specifically, skin rashes, fever, and anaphylactic shock. Penicillins are classed as category B during pregnancy. 1. Hypersensitivity: The most common side effect. The most serious allergic reaction is anaphylaxis, a severe allergic reaction that can cause skin rash, hives, itching, difficulty breathing, shock, and unconsciousness. An early sign of anaphylaxis is a feeling of warmth and flushing. If any of these occurs, the medicine should be stopped and emergency help sought immediately. Anaphylactic shock occurs more frequently after parenteral administration but can occur with oral use.2. Convulsions and encephalopathy can occur, especially at higher doses and especially if administered intrathecally (NOT advised).3. Interstitial nephritis (Methicillin)4. Coomb's positive hemolytic anemia5. Neutropenia (especially the beta -lactamase -resistant penicillins)6. Decreased platelet aggregation (carbenicillin and ticarcillin)7. Hypernatremia and hypokalemia (carbenicillin)

Other most common side effects are mild diarrhea, vomiting, headache, vaginal itching and discharge, sore mouth or tongue, or white patches in the mouth or on the tongue. These problems usually go away as the body adjusts to the drug and do not require medical treatment unless they continue or they are bothersome. On rare occasions some types of penicillin may cause severe abdominal or stomach cramps, pain, or bloating or severe or bloody diarrhea.

Drug-drug Interactions Penicillins bind to and inactivate aminoglycosides. This is a form of chemical antagonism. If an aminoglycoside and a penicillin are combined. they should be administered simultaneously through the same I.V. line or through the same syringe. They will crystallize and precipitate in the line or in the vessels! When an aminoglycoside and a penicillin are administered, the infusions should be staggered by about 1 to 2 hours. Carboxy- or Ureidopenicillins and aminoglycosides are synergistic in their anti-pseudomonas activity. Penicillin is synergestic with streptomycin. Antibacterials, bacteriostatic, such as: Chloramphenicol or Tetracycline (because penicillin G acts only on cells that are actively reproducing, bacteriostatic antibiotics such as chloramphenicol or tetracycline may decrease the efficacy of penicillin G by depressing the activity of target cells) are antagonistic with penicillins, the administration of phenylbutazone concurrently with penicillin G may cause higher plasma concentrations of penicillin G, resulting in lower distribution of penicillin G to the tissues

Penicillins disadvantages:  acid lability - most of these drugs are destroyed by gastric acid short duaration of action - because of this short half-life, the penicillins must be

administered at short intervals, usually every 4 hours lack of activity against most Gram-negative organisms drug hypersensivity - about 10% of population has allergy many patients experience GI upset painful if given intramuscularly

Penicillins advantages:  bactericidal against sensitive strains relatively nontoxic have excellent tissue penetration efficacious in the treatment of infections

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relatively inexpensive in comparison with other antibiotics. Newer penicillins are resistant to stomach acid or have a broader spectrum, such as

ampicillin and amoxicillin

Aminopenicillins: These agents have similar antibacterial activity and a spectrum that is broader than the antibiotics heretofore discussed. They all are destroyed by -lactamase (from both gram-positive and gram-negative bacteria).

Antimicrobial Activity: Ampicillin and the related aminopenicillins are bactericidal for both gram-positive and gram-negative bacteria. However, concurrent administration of a -lactamase inhibitor such as clavulanate or sulbactam or tazobactam markedly expands the spectrum of activity of these drugs.

Ampicillin is the prototype of the group, is stable in acid ; well absorbed after oral administration.. Adjustment of the dose of ampicillin is required in the presence of renal dysfunction. Ampicillin appears in the bile, undergoes enterohepatic circulation, and is excreted in appreciable quantities in the feces.

Amoxicillin. a penicillinase-susceptible semisynthetic penicillin, is a close chemical and pharmacological relative of ampicillin The drug is stable in acid and is designed for oral use. It is absorbed more rapidly and completely from the gastrointestinal tract than is ampicillin, which is the major difference between the two. The antimicrobial spectrum of amoxicillin is essentially identical to that of ampicillin, with the important exception that amoxicillin appears to be less effective than ampicillin for shigellosis. Amoxicillin is the most active of all the oral -lactam antibiotics against both penicillin-sensitive and penicillin-resistant S. pneumoniae . Unlike ampicillin, presence of food in GI tract does nopt significantly affect the absorption of this drug. The incidence of GI side effects (diarrhoea) with amoxicillin is much less than that of ampicillin.OTHER BETA LACTAMS

2. Cephalosporins: dealt sepeartely

3. PENEMS(CARBAPENEMS): Carbepenems are a new class of drugs which are structurallv similar to the penicillins. They are derived from Streptomyces species, that differ from penicillin by substitution of a CH2 group for the sulphur in the five membered ring attached to the beta lactam ring. They currently have the widest activity of any antibiotics , being highly active against a wide variety of gram positive and gram ngative bacteria and are resistant to many beta –lactamases.Mechanism of action: Imipenem, like other beta lactams, binds to penicillin binding proteins. Hence it disrupts cell wall synethesis and is bactericidal. Their major target is PBP-2, which they attack through a separate porin (whichmakes them resistant to efflux pumps). PBP-2 exists in low copy numbers which means that it isa much more selective target and requires action at fewer receptors to trigger lysis. Antimicrobial spectrum: Imipenem differs from the penicillins in its antimicrobial spectrum. It is a broad-spectrum antibiotic with excellent activity against a variety of gram positive and gram negative organism (both aerobic and anaerobic), by comparison to third and fourth generation cepahalosporins.. It is resistant to most forms of beta-lactamase including that produced by staphylococcus. However, methicillin-resistant staphylococcus is usually resistant to imipenem. Susceptible organisms include: Streptococci, Enterococci. Staphylococci, Listeria, Enterobacteriaceae, Pseudomonas, Bacteroides, and Clostridium. The high activity of imipenem is attributed to its stability against most of the β-lactamases (including ESBL) and it's ability to

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penetrate porin channels that usually exclude other drugs . The carbapenems are more rapidly bactericidal than the cephalosporins and less likely to induce release of endotoxin in an animal from gram-negative sepsis. Resistance to carbapenems has been extremely rare in veterinary medicine.Carbapenems are not absorbed after oral administration except a newer penem faropenem. They are widely distributed to ECF throughout the body and reach therapeutic concentration in most tissues .Imi[penem is almost exclusiovely eliminated through kidneys, being metabolized in renal tubules by dihydropepetidase enzyme. Imipenem is rapidly hydrolyzed by the enzyme, dihydropeptidase, which is found in the brush border of the proximal renal tubule. It is always administered with cilastatin, (an inhibitor of dihydropeptidase) to decrease renal tubular metabolism. This increases the elimination half life and allows the drug to be excreted in large amounts in active form into urine..Cilastatin does not affect the antibacterial activity. Meropenem, by contrast is stable to dihydropeptidase The disadvantages of carbapenems include induction of resistance, inconvenient administration, and high cost.Side effects: Individuals who are allergic to the penicillins may demonstrate cross-reactivity with imipenem. Imipenem may produce gastrointestinal disturbances: nausea and vomiting. Seizures have been reported with high doses. Hypersalivation and vocalization , indicating pain after IM amd SC administration in dogs was noticed. The empirical dose in dogs and cats is 5-10mg/kg, IV or deep IM, every 8 hours ,and in horse : 10-20mg/kg, IV, every 6 hours . Meropenem, one of the newest of the carbapenem class of drugs has antibacterial activityapproximately equal to, or greater than imipenem. Other characteristics are similar to imipenem. Its advantage over imipenem is that it is more soluble and can be administered in less fluid volume and more rapidly. For example, small volumes can be administered subcutaneously with almost complete absorption. There also is a lower incidence of adverse effects to the central nervous system, such as seizures The recommended empirical dose in dog is 2-5mg/kg, slow IV (with IV fluids) , every 6 hours; 5 -10mg/kg, deep IM every 8 hours or 8-12 mg/kg SC, every 8 -12 hours. Carbapenems are synergistic with aminoglycosides against P.aeruginosa. Carbapenems are used successfully in human patients for intra-abdominal infections, severe lower respiratory tract infections, septicemia and life threatening soft tissue infections and osteomyelitis. Meropenem is as effective as cefotaxime or ceftriaxione in treatment of bacterial meningitis.4. MONOBACTAMS Monobactams were developed in response to a desire for specific drugs aimed at gramnegative bacteria (as opposed to broad acting antibiotics). Eg: aztreonam, tigemonam Aztreonam only binds to gram negative PBP. It has no real beta-lactam ring and hence is very beta-lactamase stable. These drugs have a very narrow spectrum and are useful only against aerobic gram negative organisms, but they can be used instead of aminoglycoside drugs (which also work against gram negativebacteria) because of their far less nephrotoxic side-effect profile. Aztreonam: This drug is a monocyclic beta-lactam (a monobactam). : Aztreonam interacts with penicillin binding proteins and induces the formation of long filamentous bacteria.Antimicrobial spectrum: The antimicrobial spectrum of aztreonam differs from that of other beta-lactams. It more closely resembles the spectrum of the aminoglycosides. Gram positive and anaerobic bacteria are resistant. Susceptible organisms include: Enterobacteriaceae, Pseudomonas, Hemophillus and Neisseria. Aztreonam is resistant to the beta lactamase produced 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. Toxicity is similar to that of benzyl penicillin, with no apparent cross allergy. These do not cause the gastrointestinal disturbances associated with carbapenems and other broad spectrum beta lactam antibiotics. Their inactivity against gram positive bacteria may lead to superinfection with yeasts and gram positive aerobes including Enterococcus spp.and S.aureus

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The empirical dose in animals is 30-50mg/kg,IV every 8 hours. It is used in a wide variety of iinfections involving gram negative bacteria (urinary tract, lower respiratory tract, septicemia) with success as relatively nontoxic drug in human medicine. 5. TRIBACTAMSThey have a tricyclic structure related to that of carbapenems. Sanfeterinem cilexetil is the prodrug of sanfetrinem, has high stabil;ity to many beta lactamases and a broad spectrum of activity similar to that of carbapenems.

BETA LACTAMASE INHIBITORS Clavulanic Acid ( potassium clavulanate: the salt used) , Tazobactam and SulbactamClavulanic Acid: obtained from Streptomyces clavuligens. Mechanism of action: These drugs themselves have poor or no antibacterial activity. They are irreversible, "suicide" inhibitors of bacterial beta lactamases.. They are used in combination with amoxicillin ( amoxicillin+clavulanic acid: co-amoxyclav) ampicillin ( sulbactam. tazobactam) or with piperacillin, ticarcillin (clavulanic acid). Clavulanate permanently inactivates the beta-lactamase so that the beta-lactam can reach its target, the penicillin binding proteins (PBPs). Thus, clavulanic acid synergistically expands amoxicillin’s spectrum of activity against many strains of beta-lactamase producing bacteria that are resistant to amoxicillin alone. Amoxicillin+clavulanate is effective against methicillin-susceptible S. aureus(MRSA), plasmid determined beta-lactamase producing Escherichia coli, Klebsiella spp., Neisseria spp., as well as anaerobic organisms such as Bacteroides spp. The combination has a spectrum of activity similar to that of a first or second generation cephalosporin. Amoxicillin-clavulanic acid injection is not compatible with and should not be reconstituted or mixed with dextrose solution or sodium bicarbonate solution for injection or it should also not be mixed with any other medication. The commercial preparations have amoxicillin and clavulanate in the ratio of 4: 1 or 5:1. (fixed dose ratio). Although amoxicillin and clavulanate potasssium may also be effective against non-beta lactamase producing organisms susceptible to amoxicillin alone, the combination drug should be reserved for use in the treatment of infections caused by, or suspected of being caused by, beta-lactamase producing organisms when amoxicillin alone would be ineffective. The initial binding of ß-lactamases to clavulanic acid is a reversible one, which is followed by covalent binding, leading to irreversible inactivation of both the ß-lactamase and clavulanic acid. This is possible even at lower plasma concentrations of clavulanic acid. The side effects of amoxicillin-clavulanic acid combination are similar to that of the penicillins. Nausea, vomiting and diarrhoea may be seen in dogs and cats. The combination should not be administered orally to herbivores or by injection to horses, rabbits, guinea pigs, hamsters or gerbils. The dosage

Sulbactam: (penillinic acid sulfone) is a synthetic derivative of 6-aminopenicillanic acid. It is poorly absorbed orally, but a double ester linkage of sulbactam with ampiicillin has been developed to proiduce the prodrug sultamicillin, which is well absorbed orally and release two drugs in the intestinal wall. Sulbactam has no antibacterial activity by itself, but reversibly binds the same groups of beta-lactamases as clavulanic acid, though affinity being several times lower than clavulanate. Sulbactam has been also been combined with some of the cephalosporins

Tazobactam: is another beta lactamase inhibitor, similar in activity to clavulanic acid and sulbactam. The combination of tazobactam plus piperacillin has the broadest antoibacterial activity of the penicillins.

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Vancomycin - Vancomycin was developed in the 1950’s when there were a lot of gram-positive infections and clinicians wanted better anti-staph drugs. However, Vancomycin wasn’t as active as many penicillins on a per/weight basis, so it was not used a great deal until the emergence of methicillin resistant Staph aureus (MRSA) and MRSE (Vancomycin was also highly toxic). The mecA gene in these organisms had mutated the PBP-2 protein which affected binding (and was often linked to overexpression of beta-lactamases as well) and resulted in resistant bacteria . However, Vancomycin is useful against these resistant strains because it uses a different process and blocks both the transpeptidase and carboxypeptidase steps in cell wall biosynthesis.Vancomycin binds to the terminal D-ala-D-ala pentapeptide and causes a block in the crosslinking process. It is quite useful against gram-positive organisms including the highly resistant pneumococci. However, Vancomycin doesn’t work against gram-negative bacteria because it is far too big to get through the gram-negative porins.Properties: Vancomycin is a small glycoprotein that is active against gram positives including Streptococci, Cornybacteria, Clostridia, Listeria, and Bacilius species. Vancomycin is also active against MRSA and resistant Pneumococci in the CNS. Vancomycin is 55% protein bound which gives it a half-life of approximately seven hours (with normal creatinine clearance). It is usually eliminated through renal excretion, so a change in dosing is a necessary adjustment for people with renal dysfunction. Resistant mutations are rare except for some strains of EnterococciSide effects: The “Red man syndrome” refers to a histamine mediated flushing of the face, neck and trunk, which may be associated with hypotension and usually occurs during infusion. Nephrotoxicity was seen in early preparations of this drug, but currently there is renal damage or ototoxicity in less than 1% of patients. Once again, Vancomycin is an important treatment for MRSA and also for highly resistant strains of S. pneumococci (these can only be killed by Vancomycin). Also, high doses of Vancomycin are able to penetrate the BBB and get into the CNS. (This is important because the levels of penicill in required to kill resistant bacteria cannot be achieved in the CNS under normal circumstances and cannot treat infections such as meningitis). However, it is also important to note that the number of Vancomycin resistant Enterococci have increased significantly in recent years due to selection of resistant strains. The method of resistance generally involves a changein the D-ala-D-ala binding site for Vancomycin. The resistant organism instead makes D-ala-Dlactate, which is not a good receptor/binding site for Vancomycin. The issue of most concern is the possibility that these recently emerging resistant strains may pass on the resistance operon (of 6 genes) to other organisms such as S. aureus and S. epidermidis

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