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BETA LACTAM ANTIBIOTICS – PENICILLIN
Dr. Jibachha Sah
M.V.Sc (Veterinary Pharmacology)
Lecturer, College of Veterinary Science,
NPI, Bhojad, Chitwan, Nepal
SEVENTH SEMESTER ! B.V.Sc & A.H.
Course Title: Veterinary Pharmacology &
Toxicology(Chemotherapy)
Course Code: VPT-413
Lecture notes
CONTENTS
1. HISTORY
2. UNITS OF PENICILLIN
3.MECHANISM OF ACTION
4. MICROBIAL RESISTANCE
5.CLASSIFICATION OF PENICILLIN
6. MICROBIAL SUSCEPTIBILTY
7.PHARMACOKINETICS
8.PENICILLINS
9.TOXICITY
10.SUMMARY
History
01
●In 1928, Alexander Fleming observed that a Penicillium mold
contaminating a petri dish culture of staphylococci colonies was
surrounded by a clear zone free of growth. Fleming cultured the
contaminating mold on a special medium and demonstrated that
the culture broth contained a potent antibacterial substance that
was effective against a variety of gram-positive organisms and
was relatively nontoxic to animals. He named the substance
penicillin.
● In 1940, penicillin was isolated in the form of a brown, impure
powder and was the most powerful chemo-therapeutic agent
known at that time. Since then, more than 40 penicillin have been
identified. Some occur naturally; others are biosynthesized.
●In 1945, Cephalosporium acremonium was isolated from raw sewage.
The first cephalosporin, cephalosporin C, was derived from this fungus.
All other cephalosporins are semisynthetic antibiotic derivatives of
cephalosporin C. The first cephalosporin was available for clinical use in
1964.
● Although penicillins and cephalosporins are still the most commonly
used β-lactam antibiotics, much progress has been made in the
development of new β-lactams during recent years. Most notably, these
include the β-lactamase inhibitors (e.g., clavulanic acid), the
carbapenems (e.g., imipenem), and the monobactams (e.g.,
aztreonam).
UNITS OF PENICILLIN
●The international unit (IU) for penicillin has been identified as the amount of activity present in 0.6 mg
of the international pure crystalline standard sodium salt of penicillin G; 1 mg contains 1667 Oxford
units. The dose of more recent β-lactam antibiotics is expressed in milligrams per unit of body weight
rather than in international units.
● The essential penicillin molecule contains a fused ring system, the β-lactam thiazolidine.
● The physical and chemical properties, especially solubilities, of penicillins are related to the structure
of the acyl side chain and the cations used to form salts.
● Hydrolysis is the main cause of penicillin degradation and can take place in the syringe when penicil-
lin is mixed with another drug. Some penicillins are rapidly hydrolyzed by gastric acid, making them
unsuitable for oral administration. Aqueous solutions of the alkaline sodium salts of sulfonamides
inactivate penicillin.
● Penicillin is incompatible with heavy metal ions, oxidizing agents, and strong concentrations of
alcohol.
Most bacteria can be broadly classified as Gram positive or Gram
negative.
●Gram positive bacteria have cell walls composed of thick layers
of peptidoglycan.
● Gram positive cells stain purple when subjected to a Gram
stain procedure.
● Gram negative bacteria have cell walls with a thin layer of
peptidoglycan. The cell wall also includes an outer membrane
with lipopolysaccharide (LPS) molecules attached.
● Gram negative bacteria stain pink when subjected to a Gram
stain procedure.
● While both Gram positive and Gram negative bacteria produce
exotoxins, only Gram negative bacteria produce endotoxins.
MECHANISM OF ACTION
● Beta-lactam antibiotics exert their bactericidal effects by preventing bacterial cell wall synthesis and
disrupting bacterial cell wall integrity.
● Beta-lactams bind to a series of enzymes, known as penicillin-binding proteins, which are involved in
the final stages of cell wall synthesis.
● The β-lactam ring is a structural analog to the final peptide bridge (D-alanine-D-alanine) that cross-
links the peptidoglycan chains that compose the bacterial cell wall.
● Penicillin-binding proteins vary between bacterial species. The affinity of various β-lactam antibiotics
for the different penicillin-binding proteins, explain differences in spectra of activity of β-lactam antibiotics
that are not caused by the presence/absence of β-lactamases.
●Gram-negative bacteria can have up to seven different penicillin-binding proteins on their cell membranes,
each of which is involved in different catalytic reaction. The binding of a β-lactam antibiotic to a penicillin-
binding protein leads to the formation of defective cell walls that osmotically unstable.
● Cell death usually results from lysis, which may be mediated by bacterial autolysins. The β-lactam antibiotics
demonstrate a postantibiotic effect against gram-positive cocci but not against gram-negative bacilli.
Beta-lactam antibiotics kill bacterial cells only when they
are actively growing and synthesizing cell wall
β-Lactam Mechanism of Action
Bacterial cell wall is essential for their normal growth and development
(Cell wall comprised of peptidoglycan (highly cross-linked)
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.)
A five-amino-acid peptide is linked to the NAM
sugar. This peptide terminates in D-alanyl-D-alanine.
-Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby pep
-β-Lactam antibiotics, structural analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active site of PBPs.
This inhibits the transpeptidation reaction, halting peptidoglycan synthesis, and the cell dies.
They also activate autolytic enzymes that cause bacterial cell wall lesions
MICROBIAL RESISTANCE
●Three independent factors determine the bacterial susceptibility to β-lactam antibiotics. They are
Production of β-lactamases
 Permeability of cell wall,
 Sensitivity of the penicillin-binding protein.
● The elaboration of β-lactamases, enzymes that inactivate the drugs by hydrolyzing the β-lactam ring, is the
major mechanism of drug resistance. Different bacteria produce β-lactamases that differ in physical, chemical,
and functional properties. Some β-lactamases are specific for penicillins (penicillinases), some are specific for
cephalosporins (cephalosporinases), while still others have affinity for both groups.
●There are two mechanisms of β-lactamase production. They are
Chromosomal
 Plasmid.
●Chromosomally derived β -lactamases are species and genus specific and can be induced by the
presence of any β-lactam compound.
● Plasmid-derived β-lactamases can be transferred between bacteria, increasing the number of bacteria
resistant to the antibiotic.
● Gram-positive bacteria generally produce chromosomally derived β-lactamases. Those produced by
gram-negative bacteria are chromosomally derived or plasmid mediated. The chromosomally derived β-
lactamases produced by gram-negative bacteria are primarily cephalosporinases while the plasmid-
mediated ones are generally broader spectrum.
●Gram-negative bacteria secrete small amounts of β-lactamases into their periplasmic space, allowing for
optimal location of the enzyme to degrade the β-lactam upon entry into the organism. Newer agents have
increasing resistance to β-lactamases. For example, the cephamycins (cefoxitin and cefotetan) are apparently
stable to chromosomally mediated β-lactamases, which may give them their excellent activity against
anaerobic gram-negative rods.
● Gram-negative bacteria can produce a cell wall with a modified outer membrane that is no longer permeable
to β-lactam antibiotics. This mechanism can enhance the resistance produced by the elaboration of β-
lactamases; But it is not sufficient to markedly increase resistance by itself.
● Bacteria have an intrinsic resistance to β-lactams because of reduced sensitivity of the penicillin-binding
proteins and failure of the drugs to inhibit the operative pathways of cell wall formation.
GROUPS OF PENCILLINS
●Natural Penicillins
E.g., Penicillin G, Penicillin V
● Broad spectrum aminopenicillins
E.g., Amoxicillin, Ampicillin, Hetacillin
● Penicillinase-resistant penicillins have a ring structure attached to the carbonyl carbon of the mide side chain.
Substituents on the ring protect the lactam ring from β- lactamases.
E.g., Cloxacillin, Dicloxacillin, Methicillin, Nafcillin, Oxacillin.
● Extended-spectrum penicillins have either a carboxylic acid group or a basic group at the α-position at R, which
gives these drugs a wider spectrum of activity than the other three groups of penicillins.
E.g., Azlocillin, Carbenicillin, Mezlocillin, Piperacillin, Ticarcillin
MICROBIAL SUSCEPTIBILTY
●The natural penicillins are active against many Streptococci spp. and non-penicillinase-
producing Staphylococci spp. They are active against some gram-positive and gram-negative bacilli,
including Corynebacterium, Listeria monocytogenes, Pasteurella multocida, and Haemophilus influenzae.
● Natural penicillins are active against many gram-positive and gram-negative anaerobic bacteria,
including Fusobacterium, streptococcus and some strains of Clostridium.
● Natural penicillins are also active against most spirochetes, including Leptospira and Borrelia
burgdorferi. Natural penicillins are inactive against Pseudomonas, mostEnterobacteriaceae, and penicillinase
producing Staphylococcus spp.
Aminopenicillins
●Aminopenicillins are generally active against the microbes that are susceptible to natural penicillins. They are
also active against some Enterobacteriaceae, including strains of E. coli, Proteus mirabilis, and Salmonella.
● Aminopenicillins are inactive against Pseudomonas, Bacteroides fragilis, and penicillinase-
producing Staphylococcus spp.
Penicillinase-resistant penicillins
● The penicillinase-resistant penicillins are active against many penicillinase-producing Staphylococcus spp.
which are resistant to the natural penicillins and the aminopenicillins.
● Penicillinase-resistant penicillins also have some activity against other gram-positive and gram-negative
bacteria and spirochetes. However, they are generally less effective than the other penicillins.
Extended-spectrum penicillins
●Extended-spectrum penicillins have the most activity against gram-negative aerobic and anaerobic bacteria of
all of the penicillin groups. The drugs are active against many strains of Enterobacteriaceae and some strains
of Pseudomonas.
● Carbenicillin and ticarcillin are active against some strains of E. coli, Morganella morganii, Proteus spp.,
and Salmonella. In addition to these organisms, mezlocillin and piperacillin are active against some strains
of Enterobacter, Citrobacter, Klebsiella, and Serratia.
● The extended-spectrum penicillins have some activity against gram-positive aerobic and anaerobic bacteria
but are generally less effective against these organisms than are the natural penicillins and aminopenicillins.
● Extended-spectrum penicillins are generally more active against Bacteroides fragilis than are other
available penicillins.
PHARMACOKINETICS
●Most penicillins are rapidly absorbed when injected in aqueous suspension by the
IM or SC route. Maximum blood concentrations result in 15-30 minutes. IM
injection is the most common route of administration. It is necessary to orally
administer 5 times the amount of penicillin G necessary for IM injections to
produce comparable blood concentrations, because of inactivation by the gastric
acid and enteric bacteria.
●Absorption of penicillin occurs during the first few hours after intramammary
infusion. Blood concentrations are consistently higher when penicillin is infused in
infected quarters than when infused into normal quarters. Serum plays a significant
role in transfer of penicillin from treated to untreated quarters. There is systemic
absorption of sodium benzylpenicillin and procaine benzylpenicillin administered
intrauterine to horses and cattle, respectively.
●Sodium or potassium penicillin suspended in an inert oil prolongs absorption of penicillin from the
site of infection for approximately 18 hours. Incorporation of the poorly soluble procaine penicillin in
oil prolongs absorption for 24 or more hours. Addition of 2% aluminum monostearate to a
suspension of penicillin in oil produces a gel with a high degree of water repellency, which markedly
slows absorption of procaine penicillin suspended in the medium. Although the use of an oil vehicle
helps to prolong the duration of therapeutic blood concentrations, undesirable physical properties
limit widespread use.
●Horses may show unfavorable acute and chronic tissue reactions to the parenteral administration of
an antibiotic in an oil vehicle.
●Procaine penicillin G is a buffered aqueous suspension available for IM injection. Absorption of
penicillin from this preparation is prolonged. Absorption of procaine may become problematic in
drug-testing programs used in racing horses. A small amount of sodium or potassium penicillin G
may be added to establish a therapeutic concentration immediately following IM injection. Benzathine
penicillin G is a repository salt of penicillin. Absorption of this compound may be prolonged for 7 or
more days.
●Diffusion of penicillin into the tissues and fluids occurs as long as the unbound plasma concentration
exceeds that of the tissues and fluids. High concentrations of penicillins are generally reached in
kidneys, liver, and lung.
●Penicillins do not penetrate the CNS to any great extent. Penicillin will diffuse across the placenta,
into the fetal circulation. Tissue residues of penicillin in slaughtered animals are considered a public
health hazard because of potential hypersensitivity reactions in people.
●Penicillin G, penicillin V, nafcillin, ticarcillin, and the aminopenicillins are metabolized to some extent
by hydrolysis of the β-lactam ring. The metabolites are microbiologically inactive.
●Penicillins and their metabolites are excreted in the urine by tubular secretion. Most of the drug is
excreted in the urine within 1 hour of IM injection of sodium or potassium penicillin in an aqueous
solution.
●Probenecid competitively inhibits renal tubular secretion of penicillins. Penicillin is also eliminated in
milk.
PENICILLINS
COMPOUNDS OF PENICILLIN
● Natural penicillins
● Aminopenicillins
● Penicillinase-resistant penicillins
● Extended-spectrum penicillins
NATURAL PENICILLINS
● Penicillin G and penicillin V are currently used clinically. The phenoxy-methyl group in penicillin V imparts
more acid stability, allowing for oral administration, but less antibacterial activity.
● Penicillin G is commercially available as a benzathine, procaine, potassium, or sodium salt. Penicillin V is
available as a potassium salt. The potassium and sodium salts of the drugs are soluble in water while the
benzathine and procaine salts are less soluble in water. Penicillin G can be injected IV, IM, or SC.
●Procaine penicillin G should not be administered IV, because procaine can adversely affect the cardiac
conduction system. Oral administration of penicillin V is more applicable to humans and small animals
than to food-producing animals.
● Penicillin is usually not administered orally to herbivores because it suppresses bacterial metabolism
in the digestive tract. The exception are those herbivores that are very young or animals that require
suppression of bacterial fermentation to prevent bloat.
● Penicillin is administered via both intramammary and systemic routes to treat bovine mastitis. Milk
contaminated with antibiotics may cause public health problems as well as inhibit the cheese-making
process.
● Penicillin in milk and milk products may sensitize susceptible humans, with subsequent penicillin
therapy more likely to produce an allergic reaction. Recommended withdrawal times must be adhered to.
The type of vehicle used in intramammary infusion preparation is a factor that also determines time
required for elimination of antibiotics via the milk.
● In general, penicillin in fat-soluble ointments or mineral oil vehicles persists longer in the bovine udder
than penicillin administered in an aqueous vehicle. In contrast, aqueous vehicles favor rapid release of
antibiotics to attain maximum therapeutic concentrations. This information is provided on the label.
AMINOPENICILINS
●Ampicillin and amoxicillin have been used in the treatment of a variety of diseases in domestic
animals
● Half-life of all aminopenicillins is approximately 60-90 minutes. Tissue drug concentrations may be
higher than serum concentrations. Following oral administration, ampicillin is more quickly absorbed
when mixed with water or glucose solutions than when added to milk or milk replacer.
● Amoxicillin differs from ampicillin by the addition of a parahydroxy group. It has greater resistance
to gastric acid and is more completely absorbed than ampicillin.
● Hetacillin is prepared by a reaction of ampicillin with acetone. When administered as an aqueous
solution, it is rapidly converted back to ampicillin and acetone. Thus the spectrum of activity is
identical to that of ampicillin.
PENICILLASE RESISTANT PENICILLIN
●Methicillin sodium is a water-soluble penicillinase-resistant penicillin that produces therapeutic
concentrations in the CNS. Methicillin is primarily used as an antistaphyloccocal drug. However,
methicillin is a powerful inducer of penicillinase, and staphylococci may develop resistance by
nonpenicillinase mechanisms.
●Methicillin is given by the IV or IM route and is usually well tolerated. Occasionally some pain may be
observed following IM injection.
●Oxacillin, cloxacillin, dicloxacillin, and nafacillin resist acid hydrolysis and can be
administered orally.
EXTENDED SPECTRUM PENICILLINS
●Carbenicillin and other members of this group have the major advantage that they are effective
against Pseudomonas, Proteus, and other gram-negative bacteria resistant to other penicillins.
●Carbenicillin has a broad range of antibacterial activity that has been related to the carboxyl group
substituted on the α-carbon of the benzyl side chain.
●Carbenicillin is acid labile and must be administered parenterally. Carbenicillin indanyl, the indanyl
ester of Carbenicillin, is acid stable and suitable for oral administration. It is rapidly absorbed from the
small intestine and peak plasma concentrations are achieved within 1 hour of oral administration.
●Carbenicillin is primarily eliminated by the renal tubules, with approximately 80% of the dose
appearing in the urine within 9 hours. Peak serum Carbenicillin concentrations achieved following oral
administrations are low and many infections are not treatable with this drug unless confined to the
lower urinary tract.
●Ticarcillin and mezlocillin are not absorbed orally and must be administered IV or IM.
TOXICITY
●Penicillins are very safe drugs, with relative few adverse effects reported. Acute allergic reactions
are the most common untoward effect in people. Acute anaphylaxis, collapse, hypersalivation,
shaking, vomiting, urticaria, fever, eosinophilia, neutropenia, agranulocytosis, thrombocytopenia,
leukopenia, anemia, and lymphadenopathy can occur in sensitized animals.
●Coomb's-positive hemolytic anemia has been reported in horses following penicillin
administration.
The IV administration of hypertonic solutions of sodium benzylpenicillin has resulted in ataxia and
convulsions in cats and dogs. Procaine can also cause anaphylaxis and CNS disorders. Guinea
pigs, chinchillas, birds, snakes, and turtles are sensitive to procaine penicillin.
●Anorexia, vomiting, and diarrhea can occur when penicillins are given orally. Changes in the
intestinal flora induced by penicillin administration can also lead to diarrhea.
●Extended-spectrum penicillins have been associated with coagulopathies in humans. The
incidence of this is unknown in veterinary patients.
DOSAGE: The dosage for cattle, sheep, swine, and horses is 3000 units per pound of body weight, or 1.0 mL
for each 100 pounds of bodyweight, once daily. Treatment should not exceed 7 days in non-lactating dairy and
beef cattle, sheep, and swine, or 5 days in lactating dairy cattle
INDICATIONS: Penicillin G Procaine is indicated for the treatment of:
1. Cattle and sheep - bacterial pneumonia (shipping fever) caused by Pasteurella multocida.
2. Swine - erysipelas caused by Erysipelothrix rhusiopathiae.
3. Horses - strangles caused by Streptococcus equi.
Commercially available penicillin
SUMMARY
1.To what classification of drug does penicillin belong?
(A) Penicillin is a member of a group of drugs known as β-lactams because of their
characteristic four-membered lactam ring.
2. Define β-lactamase.
(A)β-lactamase is a bacterial enzyme that hydrolyzes the amide bond of the β- lactam
ring. It is also known as penicillinase.
3. What are penicillin-binding proteins (PBPs)?
(A)Penicillin-binding proteins are enzymes that are involved in the synthesis of the cell
wall and in the maintenance of the morphologic structure of bacteria.
4. What are transpeptidases?
(A) Transpeptidases are bacterial enzymes responsible for cross-linking
peptidoglycan chains, which is the final step in bacterial cell wall synthesis.
5.What is the major mechanism by which penicillins kill bacteria?
(A)Penicillins bind to PBPs and inhibit the transpeptidase step, which results in
bacterial cells lysis.
6. What additional mechanism is involved?
(A) Penicillins also release autolysins, which are bacterial degradative enzymes that
are involved in the normal remodeling of the bacterial cell wall.
7. Which type of organisms are not susceptible to penicillins?
(A)Organisms that are not actively growing or do not have a cell wall.
8. How are the penicillins classified?
(A)Penicillins, some of the most common and important antibiotics, can be classified as
follows:
(i)Natural penicillins
(ii)Antistaphylococcal penicillins
(iii)Antipseudomonal penicillin
(iv)Extended –spectrum penicillin
9. Natural penicillin
(i) Penicilin G- Oral,IV,M
History:
●Cephalosporin compounds were first isolated from cultures of Acremonium strictum from a sewer in
Sardinia in 1948 by Italian scientist Giuseppe Brotzu which was previously known as "Cephalosporium".
● He noticed these cultures produced substances that were effective against Salmonella typhi, the
cause of typhoid fever, which had β-lactamase.
STRUCTURE OF CEPHALOSPORIN
● These are a group of semisynthetic antibiotics derived from cephalosporin- C obtained from a fungus
cephalosporium. They are chemically related to penicillins
Mechanism of action
●All cephalosporins are bactericidal.
● Cephalosporins have three different mechanisms of action2. They are:
● Binding to specific penicillin-binding proteins.
● Inhibition of cell wall synthesis.
● Activation of autolytic (self-destructive) enzymes in the bacterial cell wall
First-Generation Cephalosporins
●First-generation cephalosporins come in oral and intravenous forms. They are active against
Viridans streptococci, group A hemolytic streptococci, Staphylococcus aureus, E. coli, Klebsiella
and Proteus bacteria.
Second-generation cephalosporins treat the following:
●Sinusitis
● Otitis media (ear infection)
● Mixed anaerobic infections including peritonitis and diverticulitis
● Prophylaxis after colorectal surgery
Third-Generation Cephalosporins
Ceftriaxone which has numerous uses including:
●Lower respiratory tract infections
● Skin and soft tissue infections
● Uncomplicated gonorrhea
● Urinary tract infections
● Otitis media
● Pelvic inflammatory disease
● Surgical prophylaxis
● Bacteria septicemia (blood infection)
● Meningitis
● Bone infections
● Joint infections
● Intra-abdominal infections
Fourth-Generation Cephalosporin
Cefepime is more active against Enterobacter and Citrobacterr bacteria.
Clinical uses for cefepime:
●Moderate to severe pneumonia
● Severe urinary tract infection
● Skin and soft tissue infections
● Complicated intra-abdominal infections
CLINICAL USES AND TOXICITY
Clinical uses
Limited in Veterinary practice because of cost
●Cefazolin –Surgical Prophylaxis
● Cefalexin –dermatitis, ECM(Early chick mortality
● Ceftiofur –Shipping fever, urinary tract infection
● Ceftriaxone, Cefataxime – Meningitis
● Cefoperazone, Cefsulodine, Ceftazidime –Pseudomonal infection
Distribution:
●Cephalosporins are distributed into most body fluids and tissues, including kidneys, lungs, joints, bone, soft
tissues, and the biliary tract, but in general, the volume of distribution is <0.3 L/kg.
Absorption:
●Only a few cephalosporins are acid stable and thus effective when administered PO (eg, cephalexin,
cephradine, cefadroxil, cefpodoxime, and cefachlor). They are usually well absorbed, and bioavailability
values are 75%–90%.
Side effects of Cephalosporin
●The approved cephalosporins are relatively nontoxic.
● IM injections can be painful, and repeated IV administration may lead to local phlebitis. Nausea,
vomiting, and diarrhea may occasionally be seen.
● For dogs and cats and other cephalosporin based medications include loss of appetite, vomiting,
and diarrhea.
● Allergic reactions including itching, formation of rashes, and difficulty in breathing are also
observed in pets.
PHARMACOKINETICS
●Good bioavailability after parentral administration.
● Oral –food interferes bioavailability– Cefaclor, Cephradine
● Poor BBB penetration except Cefotaxime, Ceftriaxone, Cefepine, Cefuroxime, Ceflazidine.
● Variable plasma protein binding especially Ceftriaxone, 80-95%bound, Cefadroxil - 20%bound
● Excretion –Urine
● Cefotaxime, Cephapirin,Cephalothirn –Desacteyl derative
Excretion:
Most cephalosporins, including cefpodoxime and cefovecin, are renally excreted.
Toxicity
Generally non-toxic
●Cephaloridine –Nephrotoxcity,
● I/M –Painful, Repeated I/V –Phlebitis
● Nausea, Vomition, Diarrhoea – Occasionally Superinfection
● Anti Vitamin K effect – Cefamandole, Cefoperazone, Moxalactam
● Hypersensitivity –Acute Pernicillin allergy – Cross reactions may occur.
OTHER Β LACTAM ANTIBIOTIC
Beta lactamase inhibitors
Clavulanic acid- Amoxycillin
Clavulanic acid- Ticarcillin
Sulbactam- Ampicillin:
Piperacillin- tazobactam:
CARBAPENEM
Carbapenems are derivatives of Streptomyces spp.They are highly active against a wide variety of gram
positive and gram negative bacteria and are resistant to many beta lactamases.
MONOBACTAM
Synthetic- Aztreonam:
It is a synthetic analogue isolated from Streptomyces
spp.
It is stable to most betalactamases.

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Betalactamin antibiotics-Dr.Jibachha Sah

  • 1. BETA LACTAM ANTIBIOTICS – PENICILLIN Dr. Jibachha Sah M.V.Sc (Veterinary Pharmacology) Lecturer, College of Veterinary Science, NPI, Bhojad, Chitwan, Nepal SEVENTH SEMESTER ! B.V.Sc & A.H. Course Title: Veterinary Pharmacology & Toxicology(Chemotherapy) Course Code: VPT-413 Lecture notes
  • 2. CONTENTS 1. HISTORY 2. UNITS OF PENICILLIN 3.MECHANISM OF ACTION 4. MICROBIAL RESISTANCE 5.CLASSIFICATION OF PENICILLIN 6. MICROBIAL SUSCEPTIBILTY 7.PHARMACOKINETICS 8.PENICILLINS 9.TOXICITY 10.SUMMARY
  • 3. History 01 ●In 1928, Alexander Fleming observed that a Penicillium mold contaminating a petri dish culture of staphylococci colonies was surrounded by a clear zone free of growth. Fleming cultured the contaminating mold on a special medium and demonstrated that the culture broth contained a potent antibacterial substance that was effective against a variety of gram-positive organisms and was relatively nontoxic to animals. He named the substance penicillin. ● In 1940, penicillin was isolated in the form of a brown, impure powder and was the most powerful chemo-therapeutic agent known at that time. Since then, more than 40 penicillin have been identified. Some occur naturally; others are biosynthesized.
  • 4. ●In 1945, Cephalosporium acremonium was isolated from raw sewage. The first cephalosporin, cephalosporin C, was derived from this fungus. All other cephalosporins are semisynthetic antibiotic derivatives of cephalosporin C. The first cephalosporin was available for clinical use in 1964. ● Although penicillins and cephalosporins are still the most commonly used β-lactam antibiotics, much progress has been made in the development of new β-lactams during recent years. Most notably, these include the β-lactamase inhibitors (e.g., clavulanic acid), the carbapenems (e.g., imipenem), and the monobactams (e.g., aztreonam).
  • 5. UNITS OF PENICILLIN ●The international unit (IU) for penicillin has been identified as the amount of activity present in 0.6 mg of the international pure crystalline standard sodium salt of penicillin G; 1 mg contains 1667 Oxford units. The dose of more recent β-lactam antibiotics is expressed in milligrams per unit of body weight rather than in international units. ● The essential penicillin molecule contains a fused ring system, the β-lactam thiazolidine. ● The physical and chemical properties, especially solubilities, of penicillins are related to the structure of the acyl side chain and the cations used to form salts. ● Hydrolysis is the main cause of penicillin degradation and can take place in the syringe when penicil- lin is mixed with another drug. Some penicillins are rapidly hydrolyzed by gastric acid, making them unsuitable for oral administration. Aqueous solutions of the alkaline sodium salts of sulfonamides inactivate penicillin. ● Penicillin is incompatible with heavy metal ions, oxidizing agents, and strong concentrations of alcohol.
  • 6. Most bacteria can be broadly classified as Gram positive or Gram negative. ●Gram positive bacteria have cell walls composed of thick layers of peptidoglycan. ● Gram positive cells stain purple when subjected to a Gram stain procedure. ● Gram negative bacteria have cell walls with a thin layer of peptidoglycan. The cell wall also includes an outer membrane with lipopolysaccharide (LPS) molecules attached. ● Gram negative bacteria stain pink when subjected to a Gram stain procedure. ● While both Gram positive and Gram negative bacteria produce exotoxins, only Gram negative bacteria produce endotoxins.
  • 7. MECHANISM OF ACTION ● Beta-lactam antibiotics exert their bactericidal effects by preventing bacterial cell wall synthesis and disrupting bacterial cell wall integrity. ● Beta-lactams bind to a series of enzymes, known as penicillin-binding proteins, which are involved in the final stages of cell wall synthesis. ● The β-lactam ring is a structural analog to the final peptide bridge (D-alanine-D-alanine) that cross- links the peptidoglycan chains that compose the bacterial cell wall. ● Penicillin-binding proteins vary between bacterial species. The affinity of various β-lactam antibiotics for the different penicillin-binding proteins, explain differences in spectra of activity of β-lactam antibiotics that are not caused by the presence/absence of β-lactamases.
  • 8. ●Gram-negative bacteria can have up to seven different penicillin-binding proteins on their cell membranes, each of which is involved in different catalytic reaction. The binding of a β-lactam antibiotic to a penicillin- binding protein leads to the formation of defective cell walls that osmotically unstable. ● Cell death usually results from lysis, which may be mediated by bacterial autolysins. The β-lactam antibiotics demonstrate a postantibiotic effect against gram-positive cocci but not against gram-negative bacilli.
  • 9. Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall
  • 10. β-Lactam Mechanism of Action Bacterial cell wall is essential for their normal growth and development (Cell wall comprised of peptidoglycan (highly cross-linked) 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.) A five-amino-acid peptide is linked to the NAM sugar. This peptide terminates in D-alanyl-D-alanine.
  • 11. -Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby pep -β-Lactam antibiotics, structural analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active site of PBPs. This inhibits the transpeptidation reaction, halting peptidoglycan synthesis, and the cell dies. They also activate autolytic enzymes that cause bacterial cell wall lesions
  • 12. MICROBIAL RESISTANCE ●Three independent factors determine the bacterial susceptibility to β-lactam antibiotics. They are Production of β-lactamases  Permeability of cell wall,  Sensitivity of the penicillin-binding protein. ● The elaboration of β-lactamases, enzymes that inactivate the drugs by hydrolyzing the β-lactam ring, is the major mechanism of drug resistance. Different bacteria produce β-lactamases that differ in physical, chemical, and functional properties. Some β-lactamases are specific for penicillins (penicillinases), some are specific for cephalosporins (cephalosporinases), while still others have affinity for both groups.
  • 13. ●There are two mechanisms of β-lactamase production. They are Chromosomal  Plasmid. ●Chromosomally derived β -lactamases are species and genus specific and can be induced by the presence of any β-lactam compound. ● Plasmid-derived β-lactamases can be transferred between bacteria, increasing the number of bacteria resistant to the antibiotic. ● Gram-positive bacteria generally produce chromosomally derived β-lactamases. Those produced by gram-negative bacteria are chromosomally derived or plasmid mediated. The chromosomally derived β- lactamases produced by gram-negative bacteria are primarily cephalosporinases while the plasmid- mediated ones are generally broader spectrum.
  • 14. ●Gram-negative bacteria secrete small amounts of β-lactamases into their periplasmic space, allowing for optimal location of the enzyme to degrade the β-lactam upon entry into the organism. Newer agents have increasing resistance to β-lactamases. For example, the cephamycins (cefoxitin and cefotetan) are apparently stable to chromosomally mediated β-lactamases, which may give them their excellent activity against anaerobic gram-negative rods. ● Gram-negative bacteria can produce a cell wall with a modified outer membrane that is no longer permeable to β-lactam antibiotics. This mechanism can enhance the resistance produced by the elaboration of β- lactamases; But it is not sufficient to markedly increase resistance by itself. ● Bacteria have an intrinsic resistance to β-lactams because of reduced sensitivity of the penicillin-binding proteins and failure of the drugs to inhibit the operative pathways of cell wall formation.
  • 15. GROUPS OF PENCILLINS ●Natural Penicillins E.g., Penicillin G, Penicillin V ● Broad spectrum aminopenicillins E.g., Amoxicillin, Ampicillin, Hetacillin ● Penicillinase-resistant penicillins have a ring structure attached to the carbonyl carbon of the mide side chain. Substituents on the ring protect the lactam ring from β- lactamases. E.g., Cloxacillin, Dicloxacillin, Methicillin, Nafcillin, Oxacillin. ● Extended-spectrum penicillins have either a carboxylic acid group or a basic group at the α-position at R, which gives these drugs a wider spectrum of activity than the other three groups of penicillins. E.g., Azlocillin, Carbenicillin, Mezlocillin, Piperacillin, Ticarcillin
  • 16. MICROBIAL SUSCEPTIBILTY ●The natural penicillins are active against many Streptococci spp. and non-penicillinase- producing Staphylococci spp. They are active against some gram-positive and gram-negative bacilli, including Corynebacterium, Listeria monocytogenes, Pasteurella multocida, and Haemophilus influenzae. ● Natural penicillins are active against many gram-positive and gram-negative anaerobic bacteria, including Fusobacterium, streptococcus and some strains of Clostridium. ● Natural penicillins are also active against most spirochetes, including Leptospira and Borrelia burgdorferi. Natural penicillins are inactive against Pseudomonas, mostEnterobacteriaceae, and penicillinase producing Staphylococcus spp.
  • 17. Aminopenicillins ●Aminopenicillins are generally active against the microbes that are susceptible to natural penicillins. They are also active against some Enterobacteriaceae, including strains of E. coli, Proteus mirabilis, and Salmonella. ● Aminopenicillins are inactive against Pseudomonas, Bacteroides fragilis, and penicillinase- producing Staphylococcus spp. Penicillinase-resistant penicillins ● The penicillinase-resistant penicillins are active against many penicillinase-producing Staphylococcus spp. which are resistant to the natural penicillins and the aminopenicillins. ● Penicillinase-resistant penicillins also have some activity against other gram-positive and gram-negative bacteria and spirochetes. However, they are generally less effective than the other penicillins.
  • 18. Extended-spectrum penicillins ●Extended-spectrum penicillins have the most activity against gram-negative aerobic and anaerobic bacteria of all of the penicillin groups. The drugs are active against many strains of Enterobacteriaceae and some strains of Pseudomonas. ● Carbenicillin and ticarcillin are active against some strains of E. coli, Morganella morganii, Proteus spp., and Salmonella. In addition to these organisms, mezlocillin and piperacillin are active against some strains of Enterobacter, Citrobacter, Klebsiella, and Serratia. ● The extended-spectrum penicillins have some activity against gram-positive aerobic and anaerobic bacteria but are generally less effective against these organisms than are the natural penicillins and aminopenicillins. ● Extended-spectrum penicillins are generally more active against Bacteroides fragilis than are other available penicillins.
  • 19. PHARMACOKINETICS ●Most penicillins are rapidly absorbed when injected in aqueous suspension by the IM or SC route. Maximum blood concentrations result in 15-30 minutes. IM injection is the most common route of administration. It is necessary to orally administer 5 times the amount of penicillin G necessary for IM injections to produce comparable blood concentrations, because of inactivation by the gastric acid and enteric bacteria. ●Absorption of penicillin occurs during the first few hours after intramammary infusion. Blood concentrations are consistently higher when penicillin is infused in infected quarters than when infused into normal quarters. Serum plays a significant role in transfer of penicillin from treated to untreated quarters. There is systemic absorption of sodium benzylpenicillin and procaine benzylpenicillin administered intrauterine to horses and cattle, respectively.
  • 20. ●Sodium or potassium penicillin suspended in an inert oil prolongs absorption of penicillin from the site of infection for approximately 18 hours. Incorporation of the poorly soluble procaine penicillin in oil prolongs absorption for 24 or more hours. Addition of 2% aluminum monostearate to a suspension of penicillin in oil produces a gel with a high degree of water repellency, which markedly slows absorption of procaine penicillin suspended in the medium. Although the use of an oil vehicle helps to prolong the duration of therapeutic blood concentrations, undesirable physical properties limit widespread use. ●Horses may show unfavorable acute and chronic tissue reactions to the parenteral administration of an antibiotic in an oil vehicle. ●Procaine penicillin G is a buffered aqueous suspension available for IM injection. Absorption of penicillin from this preparation is prolonged. Absorption of procaine may become problematic in drug-testing programs used in racing horses. A small amount of sodium or potassium penicillin G may be added to establish a therapeutic concentration immediately following IM injection. Benzathine penicillin G is a repository salt of penicillin. Absorption of this compound may be prolonged for 7 or more days.
  • 21. ●Diffusion of penicillin into the tissues and fluids occurs as long as the unbound plasma concentration exceeds that of the tissues and fluids. High concentrations of penicillins are generally reached in kidneys, liver, and lung. ●Penicillins do not penetrate the CNS to any great extent. Penicillin will diffuse across the placenta, into the fetal circulation. Tissue residues of penicillin in slaughtered animals are considered a public health hazard because of potential hypersensitivity reactions in people. ●Penicillin G, penicillin V, nafcillin, ticarcillin, and the aminopenicillins are metabolized to some extent by hydrolysis of the β-lactam ring. The metabolites are microbiologically inactive. ●Penicillins and their metabolites are excreted in the urine by tubular secretion. Most of the drug is excreted in the urine within 1 hour of IM injection of sodium or potassium penicillin in an aqueous solution. ●Probenecid competitively inhibits renal tubular secretion of penicillins. Penicillin is also eliminated in milk.
  • 22. PENICILLINS COMPOUNDS OF PENICILLIN ● Natural penicillins ● Aminopenicillins ● Penicillinase-resistant penicillins ● Extended-spectrum penicillins NATURAL PENICILLINS ● Penicillin G and penicillin V are currently used clinically. The phenoxy-methyl group in penicillin V imparts more acid stability, allowing for oral administration, but less antibacterial activity. ● Penicillin G is commercially available as a benzathine, procaine, potassium, or sodium salt. Penicillin V is available as a potassium salt. The potassium and sodium salts of the drugs are soluble in water while the benzathine and procaine salts are less soluble in water. Penicillin G can be injected IV, IM, or SC.
  • 23. ●Procaine penicillin G should not be administered IV, because procaine can adversely affect the cardiac conduction system. Oral administration of penicillin V is more applicable to humans and small animals than to food-producing animals. ● Penicillin is usually not administered orally to herbivores because it suppresses bacterial metabolism in the digestive tract. The exception are those herbivores that are very young or animals that require suppression of bacterial fermentation to prevent bloat. ● Penicillin is administered via both intramammary and systemic routes to treat bovine mastitis. Milk contaminated with antibiotics may cause public health problems as well as inhibit the cheese-making process. ● Penicillin in milk and milk products may sensitize susceptible humans, with subsequent penicillin therapy more likely to produce an allergic reaction. Recommended withdrawal times must be adhered to. The type of vehicle used in intramammary infusion preparation is a factor that also determines time required for elimination of antibiotics via the milk. ● In general, penicillin in fat-soluble ointments or mineral oil vehicles persists longer in the bovine udder than penicillin administered in an aqueous vehicle. In contrast, aqueous vehicles favor rapid release of antibiotics to attain maximum therapeutic concentrations. This information is provided on the label.
  • 24. AMINOPENICILINS ●Ampicillin and amoxicillin have been used in the treatment of a variety of diseases in domestic animals ● Half-life of all aminopenicillins is approximately 60-90 minutes. Tissue drug concentrations may be higher than serum concentrations. Following oral administration, ampicillin is more quickly absorbed when mixed with water or glucose solutions than when added to milk or milk replacer. ● Amoxicillin differs from ampicillin by the addition of a parahydroxy group. It has greater resistance to gastric acid and is more completely absorbed than ampicillin. ● Hetacillin is prepared by a reaction of ampicillin with acetone. When administered as an aqueous solution, it is rapidly converted back to ampicillin and acetone. Thus the spectrum of activity is identical to that of ampicillin.
  • 25. PENICILLASE RESISTANT PENICILLIN ●Methicillin sodium is a water-soluble penicillinase-resistant penicillin that produces therapeutic concentrations in the CNS. Methicillin is primarily used as an antistaphyloccocal drug. However, methicillin is a powerful inducer of penicillinase, and staphylococci may develop resistance by nonpenicillinase mechanisms. ●Methicillin is given by the IV or IM route and is usually well tolerated. Occasionally some pain may be observed following IM injection. ●Oxacillin, cloxacillin, dicloxacillin, and nafacillin resist acid hydrolysis and can be administered orally.
  • 26. EXTENDED SPECTRUM PENICILLINS ●Carbenicillin and other members of this group have the major advantage that they are effective against Pseudomonas, Proteus, and other gram-negative bacteria resistant to other penicillins. ●Carbenicillin has a broad range of antibacterial activity that has been related to the carboxyl group substituted on the α-carbon of the benzyl side chain. ●Carbenicillin is acid labile and must be administered parenterally. Carbenicillin indanyl, the indanyl ester of Carbenicillin, is acid stable and suitable for oral administration. It is rapidly absorbed from the small intestine and peak plasma concentrations are achieved within 1 hour of oral administration. ●Carbenicillin is primarily eliminated by the renal tubules, with approximately 80% of the dose appearing in the urine within 9 hours. Peak serum Carbenicillin concentrations achieved following oral administrations are low and many infections are not treatable with this drug unless confined to the lower urinary tract. ●Ticarcillin and mezlocillin are not absorbed orally and must be administered IV or IM.
  • 27. TOXICITY ●Penicillins are very safe drugs, with relative few adverse effects reported. Acute allergic reactions are the most common untoward effect in people. Acute anaphylaxis, collapse, hypersalivation, shaking, vomiting, urticaria, fever, eosinophilia, neutropenia, agranulocytosis, thrombocytopenia, leukopenia, anemia, and lymphadenopathy can occur in sensitized animals. ●Coomb's-positive hemolytic anemia has been reported in horses following penicillin administration. The IV administration of hypertonic solutions of sodium benzylpenicillin has resulted in ataxia and convulsions in cats and dogs. Procaine can also cause anaphylaxis and CNS disorders. Guinea pigs, chinchillas, birds, snakes, and turtles are sensitive to procaine penicillin. ●Anorexia, vomiting, and diarrhea can occur when penicillins are given orally. Changes in the intestinal flora induced by penicillin administration can also lead to diarrhea. ●Extended-spectrum penicillins have been associated with coagulopathies in humans. The incidence of this is unknown in veterinary patients.
  • 28. DOSAGE: The dosage for cattle, sheep, swine, and horses is 3000 units per pound of body weight, or 1.0 mL for each 100 pounds of bodyweight, once daily. Treatment should not exceed 7 days in non-lactating dairy and beef cattle, sheep, and swine, or 5 days in lactating dairy cattle INDICATIONS: Penicillin G Procaine is indicated for the treatment of: 1. Cattle and sheep - bacterial pneumonia (shipping fever) caused by Pasteurella multocida. 2. Swine - erysipelas caused by Erysipelothrix rhusiopathiae. 3. Horses - strangles caused by Streptococcus equi.
  • 30. SUMMARY 1.To what classification of drug does penicillin belong? (A) Penicillin is a member of a group of drugs known as β-lactams because of their characteristic four-membered lactam ring. 2. Define β-lactamase. (A)β-lactamase is a bacterial enzyme that hydrolyzes the amide bond of the β- lactam ring. It is also known as penicillinase. 3. What are penicillin-binding proteins (PBPs)? (A)Penicillin-binding proteins are enzymes that are involved in the synthesis of the cell wall and in the maintenance of the morphologic structure of bacteria. 4. What are transpeptidases? (A) Transpeptidases are bacterial enzymes responsible for cross-linking peptidoglycan chains, which is the final step in bacterial cell wall synthesis.
  • 31. 5.What is the major mechanism by which penicillins kill bacteria? (A)Penicillins bind to PBPs and inhibit the transpeptidase step, which results in bacterial cells lysis. 6. What additional mechanism is involved? (A) Penicillins also release autolysins, which are bacterial degradative enzymes that are involved in the normal remodeling of the bacterial cell wall. 7. Which type of organisms are not susceptible to penicillins? (A)Organisms that are not actively growing or do not have a cell wall. 8. How are the penicillins classified? (A)Penicillins, some of the most common and important antibiotics, can be classified as follows: (i)Natural penicillins (ii)Antistaphylococcal penicillins (iii)Antipseudomonal penicillin (iv)Extended –spectrum penicillin 9. Natural penicillin (i) Penicilin G- Oral,IV,M
  • 32.
  • 33. History: ●Cephalosporin compounds were first isolated from cultures of Acremonium strictum from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu which was previously known as "Cephalosporium". ● He noticed these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever, which had β-lactamase.
  • 34. STRUCTURE OF CEPHALOSPORIN ● These are a group of semisynthetic antibiotics derived from cephalosporin- C obtained from a fungus cephalosporium. They are chemically related to penicillins Mechanism of action ●All cephalosporins are bactericidal. ● Cephalosporins have three different mechanisms of action2. They are: ● Binding to specific penicillin-binding proteins. ● Inhibition of cell wall synthesis. ● Activation of autolytic (self-destructive) enzymes in the bacterial cell wall
  • 35.
  • 36. First-Generation Cephalosporins ●First-generation cephalosporins come in oral and intravenous forms. They are active against Viridans streptococci, group A hemolytic streptococci, Staphylococcus aureus, E. coli, Klebsiella and Proteus bacteria. Second-generation cephalosporins treat the following: ●Sinusitis ● Otitis media (ear infection) ● Mixed anaerobic infections including peritonitis and diverticulitis ● Prophylaxis after colorectal surgery
  • 37. Third-Generation Cephalosporins Ceftriaxone which has numerous uses including: ●Lower respiratory tract infections ● Skin and soft tissue infections ● Uncomplicated gonorrhea ● Urinary tract infections ● Otitis media ● Pelvic inflammatory disease ● Surgical prophylaxis ● Bacteria septicemia (blood infection) ● Meningitis ● Bone infections ● Joint infections ● Intra-abdominal infections
  • 38. Fourth-Generation Cephalosporin Cefepime is more active against Enterobacter and Citrobacterr bacteria. Clinical uses for cefepime: ●Moderate to severe pneumonia ● Severe urinary tract infection ● Skin and soft tissue infections ● Complicated intra-abdominal infections
  • 39. CLINICAL USES AND TOXICITY Clinical uses Limited in Veterinary practice because of cost ●Cefazolin –Surgical Prophylaxis ● Cefalexin –dermatitis, ECM(Early chick mortality ● Ceftiofur –Shipping fever, urinary tract infection ● Ceftriaxone, Cefataxime – Meningitis ● Cefoperazone, Cefsulodine, Ceftazidime –Pseudomonal infection
  • 40. Distribution: ●Cephalosporins are distributed into most body fluids and tissues, including kidneys, lungs, joints, bone, soft tissues, and the biliary tract, but in general, the volume of distribution is <0.3 L/kg. Absorption: ●Only a few cephalosporins are acid stable and thus effective when administered PO (eg, cephalexin, cephradine, cefadroxil, cefpodoxime, and cefachlor). They are usually well absorbed, and bioavailability values are 75%–90%.
  • 41. Side effects of Cephalosporin ●The approved cephalosporins are relatively nontoxic. ● IM injections can be painful, and repeated IV administration may lead to local phlebitis. Nausea, vomiting, and diarrhea may occasionally be seen. ● For dogs and cats and other cephalosporin based medications include loss of appetite, vomiting, and diarrhea. ● Allergic reactions including itching, formation of rashes, and difficulty in breathing are also observed in pets.
  • 42. PHARMACOKINETICS ●Good bioavailability after parentral administration. ● Oral –food interferes bioavailability– Cefaclor, Cephradine ● Poor BBB penetration except Cefotaxime, Ceftriaxone, Cefepine, Cefuroxime, Ceflazidine. ● Variable plasma protein binding especially Ceftriaxone, 80-95%bound, Cefadroxil - 20%bound ● Excretion –Urine ● Cefotaxime, Cephapirin,Cephalothirn –Desacteyl derative
  • 43. Excretion: Most cephalosporins, including cefpodoxime and cefovecin, are renally excreted.
  • 44. Toxicity Generally non-toxic ●Cephaloridine –Nephrotoxcity, ● I/M –Painful, Repeated I/V –Phlebitis ● Nausea, Vomition, Diarrhoea – Occasionally Superinfection ● Anti Vitamin K effect – Cefamandole, Cefoperazone, Moxalactam ● Hypersensitivity –Acute Pernicillin allergy – Cross reactions may occur.
  • 45. OTHER Β LACTAM ANTIBIOTIC Beta lactamase inhibitors Clavulanic acid- Amoxycillin Clavulanic acid- Ticarcillin Sulbactam- Ampicillin: Piperacillin- tazobactam:
  • 46. CARBAPENEM Carbapenems are derivatives of Streptomyces spp.They are highly active against a wide variety of gram positive and gram negative bacteria and are resistant to many beta lactamases. MONOBACTAM Synthetic- Aztreonam: It is a synthetic analogue isolated from Streptomyces spp. It is stable to most betalactamases.

Editor's Notes

  1. Commercially available penicillin