BETA LACTAM & OTHER CELL WALL- & MEMBRANE ACTIVE ANTIBIOTICS

Introduction
The 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 widely used, major antibiotics, and new derivatives of the basic penicillin nucleus still are being produced. Many of these have unique advantages, such that members of this group of antibiotics are presently the drugs of choice for a large number of infectious diseases.

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

 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

Structure
Penicillins as well as cephalosporins are called beta-lactam antibiotics and are characterized by three fundamental structural requirements:
the fused beta-lactam structure a free carboxyl acid group one or more substituted amino acid side chains The lactam structure can also be viewed as the covalent bonding of pieces of two amino acids - cysteine and valine

Chemical Properties of Penicillins

The compound consists of 2 basic structures: 1. Thiazolidine Ring 2. Beta-Lactam Ring - site of action of Beta- lactamase - site of action of Amidase - site of attachment of side chain, R, which determines many of the antibacterial and pharmacologic characteristics of a derivative (Spectrum and penicillin-resistance)

Chemical Properties of Penicillins

derivatives of benzylpenicillin, from which the methyl benzene radical is split off by amidase producing 6-aminopenicillanic acid, the parent compound of all semisynthetic penicillins.

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

Cell Wall production

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

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

 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, 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-alanylD-alanine synthetase.

 The second stage, UDP-acetylmuramylpentapeptide 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.)

 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 mimicks 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.

Binding to PBPs results in:

Inhibition of transpeptidase: transpeptidase catalyzes the cross-linking of the pentaglycine bridge with the fourth residue (D-Ala) of the pentapeptide. The fifth residue (also D-Ala) is released during this reaction. Spheroblasts are formed. Structural irregularities: binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects.

Beta Lactam Antibiotics & Other Cell Wall Synthesis Inhibitors

PENICILLINS CEPHALOSPORINS BETA LACTAMASE INHIBITORS CARBAPENEMS OTHER CELL WALL SYNTHESIS INHIBITORS

Classification
Penicillins (penicillin G) greatest activity against gram+, gram-cocci, non-betalactamase-producing anaerobes Antistaphylococcal penicillins (nafcillin) resistant to staphylococcal beta-lactamases, active to staphylococci and streptococci Extended-spectrum penicillins (ampicillin) retain antibacterial spectrum of penicillin with improved activity against gramorganisms, but are destroyed by betalactamases

PENICILLINS
CLASSIFICATION Penicillinase Resistant (Antistaphylococcal Penicillins) 1. Methicillin (Staphcillin) 2. Nafcillin ( Unipen, Nafcil, Nallpen) 3. Isoxazolyl penicillins i. Oxacillin iii. Dicloxacillin ii. Cloxacillin iv. Flucloxacillin

PENICILLINS
CLASSIFICATION Penicillinase Resistant resistant to staphylococcal beta-lactamases active against staphylococci and streptococci but inactive against enterococci & anaerobic bacteria, and gram-negative cocci & rods.

Penicillinase Susceptible
A.Narrow Spectrum 1. Benzylpenicillin Penicillin G 2. Phenoxymethyl penicillin- Penicillin V - greatest activity against gram-positive organisms, gram negative cocci, and non-beta lactamase producing anaerobes and little activity against gram-negative rods. - Susceptible to hydrolysis by betalactamases

Penicillinase Susceptible
B Extended Spectrum A. Aminopenicillins a.1 Ampicillin a.2 Esters a.2.1. Bacampicillin a.2.2. Pivampicillin a.2.3. Talampicillin a.3. Amoxicillin C. Ureido-penicillin c.1. Mezlocillin c.2. Azlocillin c.3. Piperacillin c.4. Apalcillin B. Carboxypenicillins b.1. Carbenicillin b.1.1 Indanyl Carbenicillin b 1.2 disodium carbenicilli b.1.3 Disodium Carbenicillin b.2 Ticarcillin b.3 Temocillin

Penicillinase Susceptible

retain the antibacterial spectrum of penicillin improved activity against gram (-) organisms destroyed by beta-lactamases

Mechanisms of Action:
inhibit the last step in the peptidoglycan synthesis of the cell wall Underlying: = inhibition of transpeptidase enzymes = activation of penicillin binding proteins (PBPs) = activation of autolysins (murein hydrolases)

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 the mucosaccharide chains is prevented. If cell walls are improperly made cell walls allow water to flow into the cell causing it to burst.

:Mechanisms of Resistance:
inactivation of antibiotic by Beta lactamases - modification of PBPs - impaired penetration of drug to target PBPs - presence of an efflux pump

Resistance to -Lactams Gram pos.

PHARMACOKINETICS
ABSORPTION: vary with the preparation Impaired by food and drugs parenteral complete and rapid Nafcillin not suitable for oral administration Dicloxacillin, Amoxicillin, Ampicillin acid stable

 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.

 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

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 days)

 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: cannot penetrate the blood brain barrier Probenecid and certain organic acids can inhibit transfer from CSF to blood stream Bacterial meningitis: 1-5 mcg/ml = 18-24 M units/day

PHARMACOKINETICS
METABOLIZED: by the liver to penicillanic/penicillenic acid; penicillamine, penicilloid acid & other penicilloyl derivatives ( allergenic metabolites ) EXCRETION: kidneys renal excretion inhibited by probenecid Nafcillin biliary excretion Oxacillin, dicloxacillin, cloxacillin- kidney & biliary excretion

ADVERSE EFFECTS:
1. Hypersensitivity reactions - most common major antigenic determinant penicilloyl polylysine (PPL) 2. Gastrointestinal disturbances after oral administration 3. Convulsions following rapid IV injection

ADVERSE EFFECTS:
4. Accidental injection into the sciatic nervesevere pain and nerve dysfunction persisting for weeks 5. Chronic use may cause: - hepatitis - overgrowth of minor/atypical organisms following use of broad spectrum preparations

Specific toxicities
Procaine Penicillin G after accidental IV injection: - pulmonary embolism - acute psychotic reactions Oxacillin and Nafcillin: - hepatitis - granulocytopenia, bone marrow depression Disodium Carbenicillin and high dose Penicillin G Na - hypernatremia

Specific toxicities
Penicillin G Potassium - hyperkalemia with high doses Penicillin G Sodium - Jarisch-herxheimer reaction Carbenicillin and Ticarcillin - bleeding diathesis Methicillin - interstitial nephritis Ampicillin - pseudomembranous colitis

 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.

Unitage of Penicillin

Penicillin G
Antimicrobial spectrum: Streptococci, meningococci, enterococci, penicillin-susceptible pneumococci, nonbeta- lactamase producing staphylococci, treponema pallidum & many other spirochetes, Bacillus anthracis, Clostridium species, actinomyces & other gram (+) rods & non-beta-lactamaseproducing gram (-) anaerobic organisms.

Penicillin G
Antimicrobial spectrum: effective doses : 4 - 24 million units/ day IV in 4 -6 div doses depending upon the organisms, the site and severity of infections inhibitory for enterococci at 18 -24 mil units with an aminoglycoside

B. Procaine Penicillin G IM
Peak in 1-3 hrs; T - 12 hrs. uncomplicated pneumococcal pneumonia or gonorrhea

C. Benzathine Penicillin G mean duration of antimicrobial activity 26 days a single IM inj, 1.2 mil units for Betahemolytic streptococcal pharyngitis IM once q 3-4 weeks prophylaxis against reinfection with beta-hemolytic streptococci 2.4 Mil units IM once a week for 1-3 weeks- syphilis

D. Penicillin V
oral form in minor infections relative poor bioavailability; dosing 4x a day Gram (+) aerobic activities similar to Penicillin G 5-10x less active against gram (-) microbes, esp. Neisseria and certain anaerobes better absorbed from the GIT

E. Ampicillin and Amoxicillin

same spectrum of activity oral for UTI, sinusitis, otitis and lower resp inf most active of the oral beta lactams vs pen resistant pneumococci s Ampicillin but not amoxicillin is effective for shigellosis

E. Ampicillin and Amoxicillin

not used to treat uncomplicated salmonella gastroenteritis somewhat less active than Pen G vs gram (+) cocci enterococcal grp. D and viridans grp of streptococci Listeria monocytogenes H. influenza. And E. coli

Ampicillin doses:
Mild infections: Adults - 1 - 4 gm/day Severe infections : Adult - 6 - 12 gm/day

F. ESTERS OF AMPICILLIN
No inherent antimicrobial activity as esters, but pharmacologically active following hydrolysis to ampicillin 50% higher blood concentration than Ampicillin and Amoxicillin

G. CARBOXYPENICILLINS and UREIDOPENICILLINS

Gram (-) aerobes Pseudomonas aeruginosa Bacteroides fragilis; but in higher amount/dose Carboxypenicillins certain indole (-) Proteus Ureidopenicillins - Klebsiella

H. PENICILLINASE RESISTANT
indication is infection by beta lactamase producing staphylococci, streptococci and pneumococci also susceptible Isoxazolyl penicillins .25 - 0.5 g orally every 4-6 hrs 15 - 25mg/kg/d for children mild localized staphylococcal infections

H. PENICILLINASE RESISTANT
relatively acid stable and well absorbed, food interferes with absorption Oxacillin or Nafcillin, 8-12 g/d given by intermittent IV infusion of 1-2 g every 4-6 hours serious systemic staphylococcal Infxns Methicillin no longer used bec. of its nephrotoxicity

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 MUST NOT 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.

Classification of the Penicillins and Summary of Their Pharmacological Properties

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

 3. Ampicillin, amoxicillin, bacampicillin, and others comprise a group of penicillins 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 are hydrolyzed readily by broad-spectrum blactamases that are found with increasing frequency in clinical isolates of these gramnegative bacteria.

Cephalosporins
First Generation Cefadroxil * Cefazolin Cefelixin * Cephalothin Cephaprin Cephradine * Second Generation Cefaclor * Cefamandole Cefonicid Ceforanide Cefotetan Cefoxitin Third Generation Cefdinir Cefoperaxone Cefotaxime Ceftazidime Ceftibuten Ceftizoxime Fourth Generation Cefepime Cefpirome

Cefuroxime

moxalactam Ceftriaxone

* Oral Agent

CEPHALOSPORINS
A. First Generation 1. Cephaloridine Loridine, Ceporan 2. Cephalothin Keflin 3. Cephalexin Keflex, Ceporex 4. Cefazolin Kefzol, Ancef 5. Cephradine Anspor, Velosef 6. Cephapirin Cefadyl 7. Cephadroxil Duricef

CEPHALOSPORINS
B. Second Generation
1. Cefaclor Ceclor 2. Cefoxitin Mefoxin 3. Cefuroxime Zinacef, Zinnat 4. Cefonicid Monocid 5. Cefotetan Cefotan 6. Cefamandole Mandol 7. Cefprozil Cefzil 8. Loracarbef Lorabid 9. Cefmetazole Zefazone 10. Ceforanide

Cephalosporins
C. Third Generation 1. Cefotaxime Claforan 2. Cefoperazone Cefobid 3. Moxolactam Moxam 4. Ceftizoxime Cefizox 5. Ceftriaxone Rocephin 6. Ceftazidime Fortum 7. Cefotiam Ceradolan 8. Cefixime Suprax 9. Cefetamet Globocef 10. Cefpodoxime Vantin 11. Ceftibuten Cedax 12. Cefdinir Omnicef

CEPHALOSPORINS
Fourth Generation 1. Cefepime Cefpimax 2. Cefpirome Cefrom
II BASIS FOR CLASSIFICATION Antimicrobial Spectrum Pharmacokinetic Properties

7 amino-cephalosporanic acid parent compound Substitutions at R1 & R2 produce named compounds - contains an R2 that makes the compound stable in dilute acid and highly penicillinase resistant - MW 400-450 - Soluble to water and relatively stable to ph and temperature changes - Mechanisms of Action and Resistance similar to penicillins

GENERAL PROPERTIES OF CEPHALOSPORINS

GENERAL PROPERTIES OF CEPHALOSPORINS

Antimicrobial Spectrum - generally broader spectrum than Penicillins - generally more effective than Penicillins against B-lactamase-producing microbes (except enterococci, Methicillin-resistant Staph. Aureus and Staph epidermidis)

CEPHALOSPORINS
FIRST GENERATION Good actvity vs gm (+) & modest vs gm (-) microbes Penetration to the CSF is inadequate Oral drugs used for the treatment of UTI, for minor staphylococcal lesions, or for minor polymicrobial infections such as cellulitis or soft tissue abscess.

CEPHALOSPORINS
FIRST GENERATION not used in serious systemic infections Cefazolin penetrates well into most tissuesthe drug of choice for surgical prophylaxis Cefazolin only first generation parenteral cephalosphorin

CEPHALOSPORINS
SECOND GENERATION Better activity vs anaerobes first gen drugs actv but with extended gm (-) coverage Cefamandole, cefuroxime, cefonicid, ceforanide & cefaclor H. influenzae

CEPHALOSPORINS
SECOND GENERATION Cefoxitin, cefmetazole and cefotetan B. fragilis and some serratia strains Oral dosage for adults is 10-15 mg/kg/d in two to four divided doses; Children 20-40 mg/kg/day up to a maximum of 1 g /day.

CEPHALOSPORINS
SECOND GENERATION Oral second generations are active vs betalactamase-producing H. influenzae or Branhamela catarrhalis and have been primarily used to treat sinusitis, otitis, or lower respiratory tract infections

CEPHALOSPORINS
SECOND GENERATION Cefoxitin, Cefotetan or Cefmetazole mixed anaerobic infections as peritonitis or diverticulitis Cefuroxime crosses the BBB & for community-acquired pneumonia

THIRD GENERATION
less active than the first generation vs gm (+) cocci but most active against gram (-) including B-lactamase- producing strains Cefoperazone, Ceftazidime more active against Pseudomonas Cefoperazone, Cefotaxime active against anaerobes

THIRD GENERATION
Ceftizoxime, Moxolactam B. fragilis Cross BBB except Cefoperazone, Cefixime, Ceftibuten and Cefpodoxime proxetil Excretion Cefoperazone and Ceftriaxone: bile; Probenecid does not affect renal excretion

THIRD GENERATION
Ceftriaxone, 125 mg inj., Cefixime, single 400 mg - N. gonorrhea Cefoperazone 25- 100 mg/kg/d injected q 8-12 hrs. Cefixime 200 mg orally twice a day or 400 mg OD Cefpodoxime proxetil & Ceftibuten 200 mg 2x/day

THIRD GENERATION
Meningitis caused by pneumococci, meningococci, H. influenza & susceptible enteric gm (-) rods but not by L. monocytogenes; used in combn with aminoglycosides for Rx of meningitis caused by P. aeruginosa

CEPHALOSPORINS
FOURTH GENERATION - More resistant to hydrolysis by chromosomal beta lactamases (eg. Those produced by enterobacter) Good activity against P. aeruginosa, enterobacteriaceae, Staph aureus, S. pneumoniae

CEPHALOSPORINS
FOURTH GENERATION Highly active against Haemophilus & Neisseria Penetrates well into CSF Cleared by kidneys T - 2 hrs. Good activity against most penicillin resistant strains of streptococci

ADVERSE EFFECTS of Cephalosporins

1. Allergy 2. Toxicity: > Renal toxicity interstitial nephritis and even tubular necrosis > Cephalosporin that contains a methyl thiotetrazole group (Cefamandole, Moxolactam, Cefmetazole, Cefoteta, Cefoperazone) cause disulfiram like reactions, hypoprothrombinemia and bleeding disorders Antidote: Vit. K 10 mg 2x/ week

ADVERSE EFFECTS of Cephalosporins

Toxicity: (Cont) > Moxolactam interferes with platelet function, severe bleeding 3. Superinfection

MONOBACTAMS
Monocyclin beta lactam ring Resistant to beta-lactamases and active against gram negative rods including Pseudomonas and Serratia No activity against gram positive bacteria or anaerobes

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 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: (It has an unusual spectrum being active
only against Gram-negative aerobic rods)

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.

MONOBACTAMS
Aztreonam resembles aminoglycosides in spectrum of activity Given 1-2 g IV every 8 hrs. T1/2 1-2 hrs.

BETA LACTAMASE INHIBITORS

Resemble B-lactam molecules but themselves have very weak antibacterial action Bind to Beta-lactamase, inactivate them and prevent the destruction Synergistic with other beta-lactams

BETA LACTAMASE INHIBITORS

Available only in fixed combinations with specific penicillins A. Clavulanic Acid combined with Amoxicillin (Augmentin) - combined with Ticarcillin (Timentin) B. Sulbactam Pivoxil and Ampicillin (Unasyn) C. Tazobactam and Piperacillin (Tazocin)

 Carbepenems are a new class of drugs which are structurallv similar to the penicillins. These drugs were developed to deal with beta-lactamase producing Gram-negative organisms, which were resistant to broad spectrum and extended spectrum penicillins. Carbapenems are derived from Streptomyces species and one example is the semisynthetic imipenem which acts in the same way as the other beta-lactams. The most extensively studied drug is imipenem.

Carbapenems

Imipenem:
Mechanism of action: Imipenem, like other b-lactams, binds to penicillin binding proteins. Hence it disrupts cell wall synethesis and is bactericidal. 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).

 It is resistant to most forms of b-lactamase, including that produced by staphylococcus. However, methicillin-resistant staphylococcus is usually resistant to imipenem. Susceptible organisms include: Streptococci, Enterococci. Staphylococci, Lister, Enterobacteriaceae, Pseudomonas, Bacteroides, and Clostridium.

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

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 with meropenem.

CARBAPENEMS
Imipenem gram (-) rods, gram- positive organisms and anaerobes > inactivated by dehydropeptidases in renal tubules resulting in low urinary concentrations. combined with Cilastatin (dehydropeptidase inhibitor) to reduce inactivation > penetrates body tissues and fluids well including the CSF

CARBAPENEMS
Imipenem: 0.25 0.5 g IV q 6-8 hrs. > adverse effects include nausea, vomiting, diarrhea, reactions to infusion site, excessive in renal failure seizures Meropenem slightly greater activity against gram (-) aerobes; does not require an inhibitor > penetrates CSF; 1 g q 8 hrs.

A. VANCOMYCIN
- gram (+) staph MOA binds firmly to D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide Resistance modification of the D-Ala-DAla binding site of the peptidoglycan building block in which the terminal DAla is replaced by D-lactate resulting to loss of a critical H bond that facilitates high affinity binding of vancomycin to its target and loss of activity

A. VANCOMYCIN
Poorly absorbed from the intestinal tract but oral for the Rx of antibiotic asst enterocolitis caused by C. difficile 99% excreted by glomerular filtration t: 6-10 days - not removed by dialysis

A. VANCOMYCIN
Rx for parenteral vancomycin: sepsis or endocarditis caused by meth-resistant staph plus Cefotaxime, Ceftriaxone or Rifampicin for Rx of meningitis of pen resistant strain of pneumococcus. Dose: 30 mg/kg/day in 2 -3 div doses Causes phlebitis, chills and fever, ototoxicity, nephrotoxicity, red man or red neck syndrome

B. FOSFOMYCIN
inhibits cytoplasmic enzyme enol pyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the phosphoenolpyruvate to UDP-Nacetylglucosamine 1st step in the formation of UDP-N-acetylmuramic acid, the precursor of acetylmuramic acid - Transported into the cell by glycerophosphate or glucose 6 phosphate transport systems

B. FOSFOMYCIN
Resistance is due to inadequate transport of drug into the cell Active against both Gram (+) and Gram (-) In vitro synergism with beta-lactams, animoglycosides or fluoroquinolones Available orally (2-4 g, single dose in uncomplicated UTI) and parenterally Excreted through the kidneys Safe in pregnancy

C. BACITRACIN
active against Gram (+) organisms inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall nephrotoxic poorly absorbed; limited to topical use 500 units/g ointment + polymyxin B or Neomycin

D. CYCLOSERINE
widely distributed into tissues excreted through the urine 0.5 1 g / d in 2-3 divided doses causes dose related CNS toxicity, headaches, tremors, acute psychosis, convulsions

POST-TEST
1. PARENT COMPOUND OF CEPHALOSPHORIN 2. PARENT COMPOUND OF PENICILLIN 3-6: composition of the beta lactam structure of the beta lactam antibiotics 7. ENZYME PRODUCED BY BACTERIA THAT HYDROLYSIS PENICILLIN

8. ANTIBIOTIC OF CHOICE AGAINST STAPH INFECTION 9. 2ND GENERATION CEPHALOSPHORIN THAT CAN ENTER THE BBB 10. ORAL FORM OF PENICILLIN