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Beta-Lactam Antibiotics

• Beta-lactam antibiotics interfere with bacterial cell wall synthesis, specifically cross-linking, by binding to transpeptidases.

Beta-Lactam Mechanism of Action

• Beta-lactams structurally mimic D-Ala-D-Ala, a component used in bacterial cell wall synthesis.
• Beta-lactams bind to the transpeptidase active site, inhibiting the enzyme.
• Inhibition of transpeptidase disrupts the cross-linking of cell walls, leading to cell lysis and death in bacteria.

Mechanisms of Antibiotics

• Antibiotics work through various mechanisms, including inhibiting cell wall synthesis, protein synthesis, and nucleic acid synthesis or function.
• Antibiotics that inhibit cell wall synthesis or function: Beta-lactams, Penicillins, Cephalosporins, Carbapenems, Monobactams, Vancomycin, Daptomycin, and Polypeptides
• Antibiotics that inhibit protein synthesis (50S subunit): Macrolides, Clindamycin, Linezolid, Streptogramins, and chloramphenicol.
• Antibiotics that inhibit protein synthesis (30S subunit): Aminoglycosides, Tetracyclines, and Tigecycline
• Antibiotics that inhibit nucleic acid synthesis or function: Quinolones (inhibit DNA gyrase and/or topoisomerase IV), Trimethoprim / Sulfamethoxazole (inhibit Folate synthesis), and Metronidazole/Nitrofurantoin (create free radicals)

Beta-Lactams

• Beta-lactams contain an internal amide with the amine in the beta-position relative to the carboxylic acid.
• All beta-lactams have similar mechanisms of action and general properties.
• Beta-lactam antibiotics represent the largest group of known antibiotics, accounting for about 60% of the total.
• The nitrogen atom in the beta-lactam ring is neutral due to the delocalization of lone pair electrons and resonance with the carbonyl group.
• The beta-lactam ring is responsible for the activity, allergenicity, and stability of these antibiotics.
• Beta-lactams are stable for 7-14 days at 4°C, 1-2 days at room temperature, and up to 5 years in dry form

Stability of Beta-Lactams

• The beta-lactam ring is inherently unstable due to its highly strained 4-membered structure.
• Instability rises in the presence of beta-lactamase enzymes, acids, and bases.
• Beta-lactamase enzymes, produced by resistant microorganisms like Staphylococcus aureus, Haemophilus influenzae, and Neisseria gonorrhoeae, can break down the beta-lactam ring.

Common Characteristics of Penicillins

• Penicillins are acids with a pKa around 2.5-3.
• They are crystalline and should be protected from moisture for stability over years if stored dry.
• Penicillins have an unpleasant taste.
• They are usually used as sodium or potassium salts due to the fact that free acids are not suitable for formulation.
• Penicillins are generally considered safe during pregnancy and lactation.
• A precaution is to watch out for anaphylactic shock and diarrhea, as penicillins pass into breast milk.
• Protein binding capabilities vary between 20% and 90%, influencing the amount of free drug in the bloodstream.
• Immunological reactions, such as anaphylactic shock, can occur in less than 0.1% of the population.
• Rashes affected 5-7% of people.
• These reactions result from the beta-lactam ring reacting with a terminal amine on a lysine in a polypeptide, forming an allergen so antibodies are formed the first time the patient is exposed to the antibiotic.
• Subsequent exposures can cause severe reactions.
• Impure preparations may cause more severe reactions due to residual proteins so adrenaline is the first line of treatment to stabilize blood pressure and relieve broncho-constriction.

Drug Interactions

• Drug interactions have been reported, including those with oral contraceptives and antigout medications like probenecid.
• Probenecid can compete with penicillins for tubular sites for excretion, potentially leading to higher and toxic blood levels of penicillins.

Penicillins

• This was the first group of antibiotics discovered.
• Natural penicillins include Penicillin G and Penicillin V.
• Semi-synthetic penicillins are divided based on their properties: Penicillinase-resistant, Broad-spectrum, and Mega-spectrum

Penicillin G

• Source: Penicillium chrysogenum
• Penicillin G is used in units, where one USP unit equals the antibiotic activity present in 0.6 µg
• Mixture of compounds, including Penicillin G, K, V, O, and S, are produced in the medium however it and can be obtained exclusively by adding phenyl acetic acid.

Essential Structural Components of Penicillin G

• Has an Amide, with the amine in the beta-position relative to the carboxylic acid.
• Contains a B-lactam ring in the cis-orentation.
• Also contains a Bicyclic system and a Carboxylic acid.

Pharmaceutical Forms of Penicillin G

• Water-soluble salts of Penicillin G are used for IV, IV infusion, or IM administration with a rapid onset and short duration (t1/2 = 1/2 hour).
• Potassium salts should be preferred in hypertensive patients
• Sodium salts should be preferred in patients with renal insufficiency.
• Procaine Penicillin G (Wycillin®) consists of Procaine (local anesthetic) and Penicillin G in a 1:1 ratio at a water Solubility of 1:250 ml.
• It is used as an IM suspension with a duration of action lasting up to one week.
• Benzathine Penicillin G (Bicillin®) contains Benzathine and Penicillin G in a 1:2 ratio at a water solubility of 1:5000 ml.
• Also used as an IM suspension with a duration of action lasting 3-4 weeks.
• Metabolism of Benzathine yields pen.G + Oxalic acid (toxic metabolite) and must be used with a urine alkalinser to prevent crystallisation of calcium oxalate formed.

Pharmacokinetics of Penicillin G

• Administered via IM or IV route.
• It should never be administered orally
• Penetrates to CSF in case of Meningitis
• Distributes to almost all body tissues and fluid
• Concurrent administration of probenecid will lead the kidney to excrete it before Pen G which leads to increased blood level concentration of Pen G five times.

Mechanism of Action

• Leads to inhibition of transpeptidation leading to the loss of murine layers during cell division.
• Inhibits stage III of cell wall synthesis and thus prevents cross-linking of peptidoglycan.
• It is less effective against Gram-negative bacteria due to the presence of the outer mucopolysaccharide membrane.

Antimicrobial Spectrum

• Is narrow spectrum and effective against a limited number of microorganisms, mostly Gram-positive, such as Staph. aureus, soft tissue infections, and Osteomyelitis
• Penicillin G is effective agains against Streptococci like Sterpt. viridans, Sterpt. Pneumonia, and Strept. pyogenes
• Also effective against Enterococci, Corynbacterium diphtheria (Diphtheria), and Clostridium tetani (Tetanus).
• It also has some activity against some Gram-negative bacteria, such as Neisseria meningitides (Meningitis), N. gonorrheae (Gonorrhea), and Treponema pallidum (Syphilis).
• The blood-brain barrier (BBB) is normal and allows most beta-lactam agents (eg: penicillin G) to penetrate poorly. However, in the presence of meningeal inflammation, CSF penetration is enhanced likely as a result of separation of intercellular tight junctions, raising the level of Pen G in the CSF.
• In case of allergy or penicillin-resistant strain, third-generation cephalosporins are the beta-lactams of choice in the empiric treatment of meningitis (ceftriaxone or cefotaxime are used).

Properties of Penicillin G

• Active against Gram-positive bacteria (e.g., staphylococci, meningitis, and gonorrhoea) and limited activity against Gram-negative cocci.
• Non-toxic and narrow spectrum
• Taken orally, Penicillin G is ineffective, since it breaks down in the acid conditions of the stomach.
• Sensitive to all known beta-lactamases, enzymes produced by penicillin-resistant bacteria that catalyze the degradation of penicillins.
• Allergic reactions are suffered by some individuals.
• Production happens from P. chrysogenum by the addition of phenoxyacetic acid instead of phenyl-acetic acid.
• Beta-lactamases are enzymes produced by penicillin resistant bacteria whch catalyze the degradation of penicillins.

Penicillin V

• Beta-lactamases are enzymes produced by penicillin resistant bacteria whch catalyze the degradation of penicillins.
• Production happens from P. chrysogenum by the addition of phenoxyacetic acid instead of phenyl-acetic acid.

Properties of Penicillin V

• Relatively acid stable and given orally due to the electron withdrawing group that makes the side chain carbonyl less electronegative, which prevents it from attacking the lactam carbonyl.
• Moderate blood level concentration so it is not the good choice for treating N.gonorrheae and Strept. pneumonia infections.

Clinical Used of Penicillin V

• Prophylactic is taken against sub-acute endocarditis and in rheumatic fever, in sickle cell babies against pneumococcal infections, and in mouth infections
• Also is used for treatment of tonsillitis and sore throat

Semisynthetic Penicillins

• Semisynthetic Penicillins
• Semi-synthetic penicillins aim to increase the spectrum by improving cell wall permeability (adding polar groups), decrease penicillinase susceptibility (steric hindrance by bulky group close to the B-lactam ring), and/or increase acid liability (electron withdrawing groups at the side chain).
• In 1959, 6-aminopenicillanic acid (6-APA) was obtained by action of acylase enzyme on Pen G and chemical hydrolysis.

Structure-Activity Relationship (SAR)

• Position 1: If the sulfur is oxidized to the sulfone/sulfoxide, it gives better acid stability but becomes less active.
• Position 2: Any change lowers activity
• Position 3: The carboxylic acid must be present -- if it is changed to an alcohol/ester, it is inactivates
• Position 4: Must have a nitrogen
• Position 5: No substitutions allowed
• Position 6: If an electron withdrawing group (NO2, Cl, Fl ..), then the amide oxygen will be less nucleophillic, giving the compound better acid stability
• If a bulky group (ph, diph,...) is added close to the ring, it makes the drug better resistant to B-lactamases
• If a polar group (NH2, COOH, OH) is added, its spectrum becomes broader, since it can pass through the porin in the Gram negative bacterial cell walls.
• Position 7: Must have the carbonyl

Classes of Semisynthetic Penicillins

• Penicillinase – Resistant Penicillins (PRP)
• Broad Spectrum Penicillins (BSP)
• Mega – Spectrum Penicillins (MSP)

Penicillinase-Resistant Penicillins (PRP)

• Methicillin are Dimethoxy groups that increase resistance of the drug to penicillinase. (OCH3) group increases the acid sensitivity as an electron releasing group.
• Nafcillin is penicillinase stable, acid stable, more lipophilic, and penetrates CSF
• Isoxazolyl Penicillins, such as Oxacillin, Cloxacillin = Prostaphlin, Dicloxacillin, and Flucloxacillin = Fluxapen, are resistant to ẞ-lactamas enzymes adn gastic acidity while also being active agains Staphylococcal infections
• Isoxazolyl Penicillins have the following toxicities: Hypersensitivity, GIT side effects, Hepatotoxicity, Neurotoxicity, and Neutropenia
• Cloxacillin (Prostaphlin): Administer Oral and parenteral ; Cloxacillin + Ampicillin = Hi Flucil, Ampiclox, Rivaclox
• Dicloxacillin: Administer Orally only and is most potent due to higher lipid solubility; Dicloxacillin + Ampicillin = Cloxapen, Dipebacid
• Flucloxacillin (Fluapen): Administered orally only - Flucloxacillin + Ampicillin = Ampiflux
• Penicillinase-Resistant penicillins can be used for treatment of infection caused by penicillinase producing Staph. aureus or for to treat respiratory and urinary tracts, skin, bone and joint infections due to Staph. aureus penicillinase producing strains
• Has the toxicity, Hypersensitivity reactions and Nephropathy in a large i.v dose. Nafcillin can cause reversible neutropenia (abnormally low number of neutrophil granulocytes) and platelets dysfunction leading to abnormal bleeding time.
• Nafcillin is also very irritant at injection site (causes phlebitis).

Broad Spectrum Penicillins (BSP)

• These are penicillinase sensitive, and the zwitter ion forms at PH = 7 which increases the penetration of the Gram negative bacterial cell walls.
• These are acid stable
• Aminopenicillin G (Epicicillin): Used for infections caused by Gram-negative bacteria: E. coli (which causes UTI), Proteus mirabilis (which causes UTI),Brucella spp., Haemophilus influenzae (infections of the upper respiratory tract (URT)), and Gardnerella vaginalis (which causes bacterial infection and vaginitis).
• Has toxicitiy, Less bound to plasma proteins, Rapidly excret excreted through kidney, 35- 50% only absorbed, actively transported in the intestine as phenylalanine, and Should be taken 1 hr before meals or 2 hr after meal.
• Ampicillin side effects included in 2 forms of diarrhea, mild and severe, it can decrease hormones levels in contraceptive pills, ampillicin rash, and pseudomembraneous colitis (PMC)
• On treatment of ampicillin, suppression of the normal intestinal flora occurs and is leading to super infection of clostridium difficle.
• The treatment of this adverse reaction is Lactobacillius with Cholestyramine to absorb the toxin while vancomycin and metronidazole organisme re establishes.

Ampicillin Combinations

• Unasyn is composed of: ampicillin: sulbactam sodium salt (2:1) also known as (Ampictam, Sabect, Unictam, Ampictam, Ultracillin, Synerpen)
• Sulbactam binds irreversibly to penicillinase active site leading to deactivation of the enzyme and is an inactive penicillin analogue
• unasyn is usually used as IV or IM form, Unasyn prepared as sodium salt so caution of hypertension
• effective against E. coli and H. influenza
• It it more absorbed than ampicillin and undergo hydroklysis to esterase enzymes in plasma to release ampicillin
• Bacampicillin: It is more absorbed than ampicillin and undergoes hydrolysis with esterase enzymes in plasma to release ampicillin in high yield

Amoxycillin

• Trade names: Amoxil- E mox- Hymox- Ospamox- Glomox- Remox- Julphamox
• Advantages: It is Acid stable, but penicillinase sensitive, more abosred than ampicillin by tyrosine active transport (75% abosrbed), High absorption from GIT decrease incidence of diarrhea and PMC, food will not interfere with absorption, and has a a longer t1/2 due retain in polar body fluids (long acting).
• Spectrum: More potent against salmonella typhi, Helicabacter Pylori (gastric/duenal ulcer) combination with clarithromycin+omeprazole and less active agains shigella.
• Excretion: In the urine
• Amoxycillin + clavulanate potassium (250mg/125mg, 500/125, and 875/125)
• Is sodium free, and is safe for htn patients, that clavulanate is a β-lactam penicillin analog inactivate βlactamases by blocking the active sites of these enzymes
• Spectrum: Used for treating Lower respiratory tract infections (pneumonia), Ear Infections, Sinus Infections, Skin Infections,Urinary tract infection (UTI such as bladder infections or kidney infections).

Mega Spectrum Penicillins

• Includes Extended Spectrum Penicillins and Antipseudomonal Penicillins These can be separated into α Carboxy Penicillins,and Ureidopenicillins

α Carboxy Penicillins

• Carbenicillin is effective against Psudomonas
• Charcteristics: Acid and penicillinase sensitive, resistant to ampicillin, and effective against gram -ve bacilli due to COOH group and its effect of better penetration

Combination

• Gentamycin combines with Psudomonal

• Coliform infections where the two drugs can never be combined in and IV

• Carindacillin (Geocillin) one of few ABx effective orally as an indenyl ester prodrug absorbed orally and hydrolysed against p.aeruginosa

  • Thienyl is a Ticarcillin

• Acdantages of Ticarcillin: Not given rorally. but i.v or i.m and offers higher levels than given longer and its now replacing carbenicillin use Timention consists of ticarcillin + clavunate

• Ureidopenicillins contain (NH-CO-NH).

• These ABX are very polar high penetration and potency

• They are not absorbed orally but penicillins can be sensitive and reserved for hospitl use.

Ureidopenicillins

• They are too polar to be absorbed orally however adminstered parentrally
• penicillinase sentisitve and therefore serve as the first live.

Advantages

• Have low Mic so low therapeutic
• Low toxic affect
• DOC for Pseduonomous aeuginosa
• They are the main ABX treatin, a combination agains genta

Pseduononomas arenginosa

• Used to expand agains gram bacteria include E. coil Pa. Mirabilis and H.flu Kelsiella Pneuoniae Bactreoeides Faligis Entrobacter

• Piperacillins the main comopund contains. Nh CO making them megasafe for the gram negative becteria

  • MIC = 4 micro grams a ml

• Can have a synergistic affect when combined

Toxicity:

• Hyerpsentitivty
• Nuero toxicity in massive doses
• Distubance Reversivle neutropenia
• Elcectrolyte and acid base disturbance

Beta-Lactam Monobactam

• Beta-lactam Monobactams consist of a lone β-lactam ring and not fused to another ring.
• They work only against aerobic Gram negative bacteria (e.g., Neisseria, Pseudomonas).
• They do not have coss Hypersentitivity reactions with penicillin and are resistant to some beta-lactamases.
• Aztreonam (Azactam- Cayston) can administered via I.M., I.V., or Inhalation depending on the location and severity of the patient.
• Has an Active ability aagains Gram-negative bacteria, including Pseudomonas aeruginosa
• Aztreonam side effects range from mild to severe.
• There is no activity against Gram-positive bacteria or anaerobes
• Side effects: -Injection site reactions.
  • Gastrointestinal side effects, including diarrhea, nausea, and vomiting.