Antimicrobial 1.1

• Beta-lactam compounds


  • Penicillins
  • Cephalosporins
  • Monobactams
  • Carbapenems
  • Beta-lactamase inhibitors
• Penicillin


  Has a thiazolidine ring attached to a beta-lactam ring that carries a secondary amino group
• Structural integrity of 6-aminopenicillanic acid nucleus


  Essential for the biologic activity
• Hydrolysis of beta-lactam ring by bacterial beta-lactamase

  1. Produces penicilloic acid

  2. Lacks antibacterial activity
• Natural Penicillins


  • Greatest activity against Gram (+) organisms, Gram (-) cocci, and non-beta-lactamase producing anaerobes
  • Little activity against Gram (-) rods
  • Susceptible to hydrolysis by beta-lactamase
• Antistaphylococcal penicillins


  • Resistant to staphylococcal beta-lactamase
  • Active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and Gram (-) cocci and rods
• Extended-spectrum penicillins


  • Improved activity against Gram (-) rods
  • Susceptible to hydrolysis by beta-lactamase
• Penicillin Units


  Crystalline sodium penicillin G = 1600 units per mg
• Minimum Inhibitory Concentration (MIC)


  Minimum concentration needed to inhibit and kill the bacteria
• Mechanism of Action


  1. Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis

  2. Halts peptidoglycan synthesis and the cell dies

  3. Autolysis are involved in addition to the disruption of cross linking of the cell wall

  4. Kills bacterial cells only when they are actively growing and synthesizing cell walls
• Mechanisms of Resistance


  • Inactivation of antibiotic by beta-lactamase
  • Modification of target PBP (penicillin binding protein)
  • Impaired penetration of drug to target PBP
  • Antibiotic reflux
• Poor penetration alone


  Usually not sufficient to confer resistance because enough antibiotic eventually enters the cell to inhibit growth
• Pharmacokinetics


  • GI absorption of nafcillin is erratic and not suitable for oral admin
  • Dicloxacillin, ampicillin, & amoxicillin are acid-stable and relatively well absorbed orally
  • Absorption of most oral penicillin (EXCEPT FOR AMOXICILLIN) is impaired by food
  • IV admin of penicillin G is preferred to the IM administration
  • Widely distributed in body fluids and tissues with a few exceptions
  • Polar molecules
  • Benzathine & Procaine penicillins are formulated to delay absorption
  • Excreted into sputum and breast milk
  • Penetration into the eye, prostate, and CNS is poor
  • Penicillin is rapidly excreted by kidneys, small amounts are excreted by other routes
  • Nafcillin is excreted primarily by biliary excretion
  • Oxacillin, Dicloxacillin, & Cloxacillin are eliminated by both the kidney and biliary excretion
• Oral penicillins (except amoxicillin)


  Should be given 1-2 hours before or after a meal to minimize binding to food proteins and acid inactivation
• Clinical Uses of Penicillin

  • Penicillin G for infections caused by streptococci, meningococci, some enterococci, penicillin-susceptible pneumococci, non-beta-lactamase producing staphylococci, Treponema pallidum, some Clostridium spp., Actinomyces and certain other Gram (+) rods, non-beta-lactamase producing Gram (-) anaerobic bacteria
  • Penicillin V for minor infections
  • Benzathine penicillin & procaine penicillin G for effective treatment of B-hemolytic streptococcal pharyngitis
  • Procaine penicillin G was once a commonly used treatment for pneumococcal pneumonia and gonorrhea
• Penicillin Resistant to staphylococcal beta-lactamase (Antistaphylococcal penicillin)

  • Indicated for infections caused by beta-lactamase-producing staphylococci
  • Resistant to Listeria monocytogenes, Enterococci, and Methicillin-resistant strains of staphylococci
  • DOC for infections caused by methicillin-susceptible and penicillin-resistant strains of staphylococci
  • Dicloxacillin for treatment of mild to moderate localized staphylococcal infections
  • Methicillin no longer used clinically due to high rates of adverse effects
  • Oxacillin & nafcillin are DOC for serious staphylococcal infections such as endocarditis
• Extended Spectrum Penicillins


  • Aminopenicillins (Ampicillin & amoxicillin) are the most active of the oral beta-lactam antibiotics against pneumococci
  • Greater activity than penicillin against Gram (-) bacteria due to enhanced ability to penetrate the gram (-) outer membrane
  • Amoxicillin is better absorbed orally
  • Ampicillin is useful for treating serious infections caused by anaerobes, enterococci, L. Monocytogenes, E. Coli, & Salmonella
  • Carboxypenicillins, Carbenicillin, & Ticarcillin were developed to broaden the spectrum of penicillins against Gram (-) pathogens including Pseudomonas aeruginosa
  • Piperacillin is available only as co-formulation with beta-lactamase inhibitor tazobactam
  • Ampicillin, amoxicillin, piperacillin, Ticarcillin are available in combination with beta-lactamase inhibitors to extend their activity to include beta-lactamase producing strains of S. Aureus as well as some beta-lactamase producing Gram (-)
• Adverse Reactions


  • Hypersensitivity reactions including anaphylactic shock (very rare)
  • Oral lesions, fever, interstitial nephritis, eosinophilia, hemolytic anemia & other hematologic disturbances, and vasculitis
  • In patients with renal failures, penicillin in high doses can cause seizures
  • Nafcillin can cause neutropenia & interstitial nephritis
  • Oxacillin can cause hepatitis
  • Methicillin can cause interstitial nephritis
  • Ampicillin can cause pseudomembranous colitis
  • Ampicillin & amoxicillin can cause skin rashes when prescribed in the setting of viral illnesses, particularly noted during acute Epstein-Barr virus infection
  • Piperacillin-tazobactam when combined with vancomycin can cause greater incidence of acute kidney injury
• Cephalosporins & Cephamycins


  • Similar to penicillins but are more stable to more bacterial beta-lactamase
  • Not active against Listeria monocytogenes
  • Only ceftaroline has some activity against enterococci
• First Generation Cephalosporins


  • Very active against Gram (+) cocci such as strep and staph
  • Not active against MRSA
  • E. Coli, Klebsiella pneumoniae, & Proteus mirabilis are sensitive to 1st gen cephalosporin
• Pharmacokinetics & Dosage of First Generation Cephalosporins

  • Oral: Cephalexin is the oral 1st gen widely used in USA, excreted mainly by glomerular filtration and tubular secretion into the urine
  • Parenteral: Cefazolin is the only 1st gen parenteral cephalosporin still in general used, can be given IV or IM
• Clinical Uses of First Generation Cephalosporins

  • Treatment of UTI and staphylococcal and streptococci infections, including cellulitis & soft tissue abscess
  • Cefazolin is the DOC for surgical prophylaxis & for many streptococcal & staphylococcal infections requiring IV therapy, used for infections due to E. Coli or Klebsiella pneumoniae but CANNOT be used to treat meningitis
• Second Generation Cephalosporins


  • Relatively active against organisms inhibited by 1st gen drugs & they have extended gram (-) coverage
  • Klebsiella is usually sensitive
  • Cefuroxime & Cefaclor are active against H. Influenzae but not against Serratia & B. Fragilis
  • Cefoxitin & Cefotetan are active against B. Fragilis and some Serratia strains but less active against H. Influenzae
  • No member is active against enterococci or Pseudomonas aeruginosa
• Pharmacokinetics & Dosage of Second Generation Cephalosporins

  • Oral: Cefuroxime axetil is the most commonly used oral cephalosporin
  • Parenteral: IV infusion, IM administration is painful and should be avoided
• Clinical Uses of Second Generation Cephalosporins

  • Active against beta-lactamase-producing H. Influenzae or Moraxella catarrhalis, used to treat sinusitis, otitis, and lower respiratory tract infections
  • Cefoxitin & Cefotetan are used in peritonitis, diverticulitis, & pelvic inflammatory disease
  • Cefuroxime is sometimes used to treat CAP because of it's active against beta-lactamase producing H. Influenzae and also in pneumococci
• Third Generation Cephalosporins


  • Has an expanded Gram (-) coverage
  • Some can cross the BBB
  • Active against Citrobacter, S. Marcescens, & Providencia
  • Effective against beta-lactamase producing strains of Haemophilus and Neisseria
  • Ceftazidime is the only agent with useful activity against Pseudomonas aeruginosa
  • Cefixime is NO longer recommended for the treatment of uncomplicated urethritis and cervicitis
  • IM ceftriaxone + azithromycin is the regimen of choice for treating most gonococcal infections
• Clinical Uses of Third Generation Cephalosporins

  • Ceftriaxone is used for...
• Used to treat


  • Sinusitis
  • Otitis
  • Lower respiratory tract infections
• Cefoxitin & Cefotetan


  • Used in peritonitis, diverticulitis, & pelvic inflammatory disease
• Cefuroxime


  • Sometimes used to treat CAP because of it's active against B-lactamase producing H. Influenzae and also in pneumococci
• Third Generation Cephalosporins


  • Cefoperazone
  • Cefotaxime
  • Ceftazidime
  • Ceftizoxime
  • Ceftriaxone
  • Cefixime
  • Cefpodoxime proxetil
  • Cefdinir
  • Cefditoren pivoxil
  • Ceftibuten
  • Moxalactam
• Third Generation Cephalosporins


  • Has an expanded Gram (-) coverage
  • Some can cross the BBB
  • Active against Citrobacter, S. Marcescens, & Providencia
  • Effective against B-lactamase producing strains of Haemophilus and Neisseria
  • Ceftazidime → only agent with useful activity against Pseudomonas aeruginosa
  • Cefixime → NO longer recommended for the treatment of uncomplicated urethritis and cervicitis
  • IM ceftriaxone + azithromycin → regimen of choice for treating most gonococcal infections
• Clinical Uses of Third Generation Cephalosporins


  • Ceftriaxone & Cefotaxime → treatment of meningitis
  • Most active Cephalosporins against penicillin-non-susceptible strains of pneumococci
• Fourth Generation Cephalosporins


  • Cefepime
• Cefepime


  • Has good activity against P. Aeruginosa, Enterobacteriaceae, Methicillin-susceptible S. Aureus, S. Penumoniae
  • High active against Haemophilus & Neisseria
  • Penetrates well into CSF
  • Useful in treatment of Enterobacter infections
• Cephalosporins Active Against Methicillin-Resistant Staphylococci (MRSA)


  • Ceftaroline fosamil
• Ceftaroline fosamil


  • Treatment of skin & soft tissue infections and CAP
  • Used off-label to treat complicated infections such as bacteremia, endocarditis, and osteomyelitis
• Cephalosporins Combined with B-lactamase Inhibitors


  • Ceftolozane-tazobactam
  • Ceftazidime-avibactam
• Ceftolozane-tazobactam & ceftazidime-avibactam


  • Treatment of complicated intra-abdominal infections & UTI
• Adverse Effects of Cephalosporins

  • Allergy
  • Toxicity