Penicillins and Cephalosporins

Acting mainly on gram +ve organisms

BETA LACTAM ANTIBIOTICS

• Beta lactam ring + thiazolidine ring

• Penicillins: 6 amino penicillanic acid nucleus

• Cephalosporins = 7 CSA (cephalosporanic acid)

• Beta lactam ring constant

• Penicillins

• Cephalosporins

• Carbapenems, Monobactams

• Good therapeutic index

• PENICILLINS: Mechanism of action

• Bind to cytoplasmic membrane binding proteins(PBP) (Penicillin binding protein)

• Inhibit transpeptidation reactions in cross linkage of peptidoglycans required for cell wall synthesis

• Also activate autolytic enzymes to cause lesions inn the cell wall/membrane

INTERACTIONS

• PENICILLIN or CEPHALOSPORINS

• Not combined with aminoglycosides in a

syringe- in vitro – pharmaceutical interaction –

• Penicillin/ Penicillin/cepha/macrolides macrolides inactivate inactivate - aminoglycosides / tetracyclines /

chloramphenicol

• Synergism with aminoglycosides

• Probenecid inhibits tubular secretion

Narrow spectrum

• Penicillin G (Benzyl penicillin)

• G = GOLD = GOLD standard

• Penicillin V (potassium/sodium phenoxyethyl/phenoxymethyl penicillins)

• (V = Vesco/Vescor = Eat = oral penicillin)

Unitage - Penicillin

• 1 million units = 10 lac units = 1 mega unit

• Usually 1.2-2.4 million units = 1.2-2.4 mega

units = Means 12 to 24 lac units

• 1 UNIT = 0.6 mcg so 1 MU= 0.6 GRAMS

HIGH THERAPEUTIC INDEX

• Hypersensitivity 1-10%

• Anaphylaxis 1-4:10,000

• Superinfection

• Jarish-Herxheimer reaction

Na Penicillin G (Crystalline Peni)

• The first penicillin (called natural penicillin)

NARROW SPECTRUM

• (staph,Strept, pneumo, viridans, pyogens,C.diphtheriae, B.anthracis, Clostridium tetani,welchii, listeria) (Neisseria meningitidis,gonorrhea,H influenzae,Treponems-spirochetes)

• Acid labile –not oral (IM/SC- painful) ONLY IV

• SHORT DURATION (0.5-5 MU q 6-12h)

• Poor Penetration – CNS/fluids/cavities

• Bacterial resistance -Anaphylaxis

Pen G Repository preparations

To increase the duration of action – IM

• Procaine benzyl penicillin- 12 hrs – 0.5-1 MU IM q12-24h

• Procaine benzyl penicillin fortified (PPF)- 24 h

• Benzathine penicillin: longest: 3-4 weeks (t1/2: 2 w)

• 0.6-2.4 MU IM q2-4 WEEKS

• Strept, pneumococcal- respiratory, ENT, skin, soft

tissue infections

• Diphtheria, Anthrax, Gas gangrene, Tetanus, Listeria

• Gonorrhea, meningitis, syphilis

• Meningitis

Prophylactic uses

• Prevention of POST-STREPTOCOCCAL DISEASES

• Acute rheumatic fever, Bacterial endocarditis - by preventing

streptococcal sore throat – Benzathine Pen – Once a month

• Syphilis, Gonorrhea

• Pneumococcal meningitis, H influenzae meningitis,

meningococcal meningitis, tetanus

• Patients with prosthetic heart valves -undergoing

procedures – dental or orthopedic

• AGRANULOCYTOSIS

Pen G adverse effects

• Hypersensitivity 1-10%

• Anaphylaxis 1-4:10,000

• Superinfection

• Jarish-Herxheimer reaction

Semi-synthetic penicillins

1. Acid resistant penicillins – Pen V

2. Extended spectrum penicillins - [Amino, carbeni, ureido, amdino]

3. Penicillinase resistant penicillins - [Methicillin, cloxacillin]

Combinations

Ampicillin (1 g) + Sulbactam (500) – IM/IV

Amoxicillin (250) + Clavulanic acid (125) PO

Ampicillin / Amoxicillin + Genta / Amika / Tobramycin

SYNERGISM (but don’t mix in syringe)

Ampicillin /amoxicillin + Probenecid

Probenecid ➡ decreases tubular secretion ➡decreases renal clearance ➡ Better levels

Amdinopenicillins

• Mecillinam, pivmecillinam

• RESISTANT E. coli, Klebsiella, Shigella,

Salmonella

• NO ACTION AGAINST pseudomonas, proteus

• NOT ACTIVE AGAINST GRAM POSITIVE

• MECILLINAM: ONLY IM/IV

• ESTERS: PIVMECILLINAM: ORAL

• UTI, Typhoid fever, deeper infections

PENICILLINASE-RESISTANT PENICILLINS

Antistaphylococcal penicillins(narrow spectrum)

1. ONLY IM/IV: METHICILLIN: – hematuria, albuminuria,

acute interstitial nephritis – TOXIC NOT USED

2. ORAL, PARENTERAL: Oxacillin, Cloxacillin 250-500 mg

PO q6h – 1 h before meals (dicloxacillin, flucloxacillin)

3. NEWER: Nafcillin, Quinacillin (oral + parenteral)- secreted

in bile – use for cholecystitis

Osteomyelitis, septicemia, endocarditis, CNS, pnemonia,

skin and soft tissue infections, cholecystitis

Adverse effects - Penicillins

• Hypersensitivity : 5-7% - urticaria,serum sickness

Maculo papular skin eruption (ampi), anaphylaxis (rare)

(1-4:10,000) (possibly fatal), angioedema -(lips , tongue, periorbital)

• Cross-allergenicity penicillins +/- cepha

• Acute Interstitial nephritis: Methicillin

• GI, diarrhea, maculopapular rash: Ampicillin

• Superinfection: Opportunistic fungi/bacteria: pseudomembranous enterocolitis, diarrhea

• Jarish-Herxheimer Reaction, Seizures, epilepsy

• Bleeding [ Carbenicillin, Ticarcillin, Pen G]

• Eosinophilia

Beta lactamase inhibitors

Clavulanic acid (oral)

Sulbactam,Tazobactam (Parenteral)

• Destroy/inactivate beta lactamase

enzyme: class II-V

• Penicillin destroys the organism

• Suicidal inhibitors:

• Inhibit the enzyme, themselves get inactivated

• Progressive inhibition:

• Initially slow ➡ later covalent (stronger) binding and inhibitions

Beta lactamase inhibitors – combinations

 • AMOXICILLIN 250 mg + CLAVULANATE 125 mg

• (ORAL)

• AMPICILLIN 1 g + SULBACTAM 500 mg

Beta lactamase inhibitors – combinations

• PARENTERAL q 6-8 h

• PIPERACILLIN 4 g + TAZOBACTAM 500 mg

• Intravenous infusion q 8h

• TICARCILLIN + CLAVULANIC ACID: PARENTERAL

Beta lactamase inhibitors – spectrum and uses

• Staph aureus, H. influenzae

• N. gonorrhea, E.coli

• Proteus, Klebsiella, salmonella, shigella

• Peritonitis, pelvic, urinary, respiratory

infections

• Gonorrhea, burns, septicemia, hospital,

postoperative, CNS infections

Penicillins overview

Semisynthetic Penicillins

Acid resistant Penicillins: Penicillin V (K, Na

phenoxyethyl, phenoxymethyl)

Extended spectrum penicillins:

Aminopenicillins: Ampi,amoxi, talampi, bacam, pivampi

Carboxypenicillins: Carbenicillin, Ticarcillin

Ureidopenicillins: Piperacillin, azlo, mezlo

Amdinocillins: Mecillinam, Pivmecillinam

Penicillinase-resistant penicillins:

Parenteral: Methicillin

Parenteral + Oral: Cloxacillin, dicloxacillin

Newer: Nafcillin, quinacillin

CEPHALOSPORINS

-Beta-lactam antibiotics

-Contain 7-CSA nucleus

-used as Alternatives to penicillins

-classified Generation I-IV, V

-useful against beta-lactamase producing organisms, but

NONE is useful against MRSA

-Not useful against

- MRSA, Enterococci, Listeria, Atypicals –mycoplasma,

chlamydia, Clostridium difficile

Combinations

• PROBENECID: increases plasma levels

• (inhibits tubular secretion)

• Aminoglycosides – synergism

• but Do not mix in a syringe/infusion bottle

CEPHA- indications..

1. Gram positive---

Strept, penicillinase-producing staph., pneumo (Resp,

skin-soft tissue, bone, meningitis, surg prophylaxis),

Diphtheria, anthrax, tetanus, gas gangrene, food

poisoning ---- (Generation-I)

(Cephalothin, cefazolin- surgical infections);

cephalexin, cefadroxil (oral)

2. Gram-negative (bacillary dysentery, meningitis,

gonorrhea, typhoid fever - Ceftriaxone),aerobic-

anerobic infections. 

3. Surgical prophylaxis

4. Skin-soft tissue-bone, RTI, CAP, UTI, burns

5. Deeper infections (Abdominal, pelvic, obstetric,

gynecological, central nervous system-

meningitis)

6. Gram negative septicemia

7. Post-operative and Nosocomial infections

8. Neutropenia, immune-compromised hosts

CEPHA- SPECIFIC EXAMPLES -CEFTRIAXONE (Generation-III, parenteral)

-125 mg iv single dose- GONORRHEA –PPNG

-Resistant TYPHOID - 4 g iv qd x 2 days  2 g qd

-Meningitis, pseudomonas, indications of III gen

-secreted in bile, safer in renal failure

-longest t ½ - 6-8 hours -CEPHALOTHIN, CEFAZOLIN: Surgical prophylaxis

-ceftaZIDIME - Pseudomonas

-ceftiZOXIME- anaerobes

LADEM – not covered by cepha

• Listeria monocytogenes

• Atypicals – chlamydia, mycoplasma

• Difficile (Clostridium difficile)

• Enterococci (streptococcus fecalis)

• MRSA (except newer 5th generation)

CEPHA - Adverse Effects

-Hypersensitivity – 2% - rashes, drug fever, serum

sickness (cefaclor)

-Nausea, vomiting -Pain (IM), thrombophlebitis (repeated

IV)

-cross-allergenicity allergenicity between between cepha

-partial cross-allergenicity with penicillins

-INTERSTITIAL NEPHRITIS, renal damage

(cephaloridine-most toxic)

(cefoperazone, ceftriaxone - excreted thru’ bile into feces)

Diarrhea - Superinfections –

pseudomembranous

enterocolitis…….Clostridium difficile

-Hypoprothrombinemia, bleeding

-Hemolysis in G6PD deficiency, bleeding

-DISULFIRAM-like reaction – cefotetan, cefoperazone,

cefamandole, cefaclor