Penicillins

Beta-lactam antibiotics contain a beta-lactam ring as a part of their chemical structure. Drugs in this class include penicillin G and V, penicillinase-sensitive and penicillinase-resistant penicillins, cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with "cef-" or "ceph-." Cephalosporins, carbapenems, and aztreonam Aztreonam The carbapenems and aztreonam are both members of the bactericidal beta-lactam family of antibiotics (similar to penicillins). They work by preventing bacteria from producing their cell wall, ultimately leading to bacterial cell death. Carbapenems and Aztreonam. Beta-lactam antibiotics block bacterial transpeptidase (penicillin-binding protein) and, therefore, inactivate peptidoglycan crosslinking in the cell wall. All beta-lactam antibiotics are bactericidal. Common mechanisms of resistance include beta-lactamase production or mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the penicillin-binding protein gene. The common side effects include hypersensitivity reactions, GI upset, and hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Chemistry

Penicillins are members of the beta-lactam family of drugs and consist of:

  • A beta-lactam ring: a 4-membered ring containing 2 carbons (α and β carbons), a nitrogen, and a carbonyl group (a carbon double-bonded to oxygen)
    • The beta-lactam group in the compound is responsible for antibacterial activity.
    • Can be hydrolyzed (i.e., broken down) by beta-lactamases, which are produced by certain resistant bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
    • If the beta-lactam ring is broken, the drug loses its antibacterial properties.
    • All beta-lactams contain a beta-lactam ring.
  • Thiazolidine ring: a 5-membered ring containing both sulfur and nitrogen
  • Side chain: 
    • Bound to the α-carbon in the beta-lactam ring
    • Differentiates penicillins from each other
    • Responsible for their unique pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics and spectra of activity
    • Certain structures can sterically inhibit the hydrolysis of the beta-lactam ring by beta-lactamases. 
    • Certain compounds can be more readily taken up by gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview than others.
Structure of beta-lactams

Structure of beta-lactams:
All beta-lactam antibiotics contain the same core 4-membered “beta-lactam” ring (highlighted in red). This ring is responsible for the antibacterial properties of the drug because it is the region that binds to and inhibits the penicillin-binding proteins (PBPs). The PBPs catalyze cell wall formation by generating crosslinks between the peptide chains in the peptidoglycan molecules; PBPs form these crosslinks between acyl-D-Ala-D-Ala peptides, which have a structure similar to the beta-lactam ring.

Image by Lecturio. License: CC BY-NC-SA 4.0
Penicillin chemical structure

Penicillins

Image: “Strukturen verschiedener Penicillinen” by Roland Mattern. License: Public Domain

Mechanism of Action and Resistance

All beta-lactams, including penicillins, exert their effects by inhibiting bacterial cell wall synthesis.

Background: understanding cell walls

  • Bacterial cell walls contain peptidoglycan chains (large, thick layers in gram-positive organisms and relatively smaller/thinner layers in gram-negative organisms).
  • Peptidoglycan chains are composed of:
    • A sugar backbone with 2 alternating sugars: 
      • N-acetylmuramic acid (NAM) 
      • N-acetylglucosamine acid (NAG)
    • Short peptide side chains branching off the NAM sugars
  • The short peptides form crosslinked bridges between adjacent peptidoglycan chains and create a fishnet structure:
    • Crosslinked bridges are necessary for the peptidoglycan (and thus cell wall) structure.
    • Penicillin-binding proteins (PBPs) are enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that create these crosslinked bridges. 
Structure of bacterial cell walls

Structure of bacterial cell walls

Image by Lecturio. License: CC BY-NC-SA 4.0

Mechanism of action

All beta-lactams work by irreversibly inhibiting PBPs → beta-lactam antibiotics inhibit cell wall synthesis

Presence of a beta-lactam antibiotic, irreversibly binding and inhibiting pbp

Presence of a beta-lactam antibiotic, which irreversibly binds to and inhibits the PBP, preventing it from forming new crosslinks:
The beta-lactam antibiotic effectively inhibits further cell wall synthesis, ultimately leading to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death.

NAM: N-acetylmuramic acid
NAG: N-acetylglucosamine
Image by Lecturio. License: CC BY-NC-SA 4.0

Bactericidal activity

Beta-lactams, including penicillins, exert a bactericidal (rather than a bacteriostatic) effect. 

  • Bacterial cell wall is necessary for its survival → if lacking, cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death is initiated
  • When bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview attempt to replicate, they shed their cell walls.
  • In the presence of penicillins, however, bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview are unable to form a new cell wall.
  • Bacteria are unable to effectively divide, and the remaining cell autocatalyzes and dies.
Bacteria attempting to divide in the presence of penicillin

Bacterium attempting to divide in the presence of penicillin:
The bacterium sheds its wall and becomes a spheroplast. The spheroplast is unable to survive and autocatalyzes (dies).

Image by Lecturio. License: CC BY-NC-SA 4.0

Mechanisms of resistance

Bacteria use 3 primary mechanisms to resist penicillins:

  • Beta-lactamase resistance (penicillins are inactivated): 
    • Beta-lactamase is an enzyme that cleaves the beta-lactam ring and inactivates the antibiotic.
    • In the case of penicillin resistance, the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are often called penicillinases.
    • Can be produced by both gram-positive and gram-negative organisms
    • Usually secreted
    • May be secreted only in the presence of a beta-lactam antibiotic
    • Most common type of resistance
    • Most gram-negative bacilli possess a beta-lactamase gene.
  • PBP-mediated resistance (↓ penicillin binding to PBPs): 
    • Mutations in PBPs → ↓ affinity of penicillins to PBPs 
    • Despite the mutations, the PBPs are still able to produce a cell wall.
  • Porin-mediated resistance (↓ penicillin uptake): 
    • Penicillins enter bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview through channels called porins in the cell walls.
    • Bacteria can ↓ production of porins → ↓ antibiotic levels within the cell → antibiotic resistance
    • Common mechanism of resistance in Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa

Penicillinase-resistant medications

  • Some drugs can help overcome penicillinase by acting as penicillinase inhibitors.
  • Penicillinase-resistant medications are often combined with penicillinase-sensitive penicillins to enhance activity.
  • Penicillinase inhibitors include:
    • Clavulanic acid 
    • Sulbactam
    • Tazobactam

Classification

Penicillins can be classified as natural penicillins, antistaphylococcal penicillins, and broad-spectrum penicillins. Penicillins can also be classified as penicillinase-sensitive or penicillinase-resistant compounds.

Penicillinase-sensitive penicillins

  • Natural penicillins: chemicals that are naturally produced:
    • Penicillin G
    • Penicillin V
  • Broad-spectrum penicillins: much better activity against gram-negative bacilli:
    • 2nd generation (aminopenicillins):
      • Ampicillin (IV/oral)
      • Amoxicillin (oral)
    • 3rd-generation drugs (carbenicillin and ticarcillin) are not available in the U.S.
    • 4th generation (also known as antipseudomonal penicillins):
      • Piperacillin
      • Mezlocillin

Penicillinase-resistant penicillins

Penicillinase-resistant penicillins have a large R group next to the beta-lactam ring, which prevents the degradation of drugs by penicillinase. Penicillinase-resistant penicillins are effective against methicillin-susceptible staphylococci; thus, they are commonly referred to as antistaphylococcal penicillins.

  • Dicloxacillin
  • Cloxacillin
  • Oxacillin
  • Nafcillin
  • Methicillin (rarely used due to resistance and the risk of interstitial nephritis)

Penicillin-penicillinase inhibitor combinations

  • Ampicillin-sulbactam (Unasyn)
  • Amoxicillin-clavulanate (Augmentin)
  • Piperacillin-tazobactam (Zosyn)

Pharmacokinetics

Distribution

  • All penicillins are distributed in:
    • Pleural cavity/ lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs
    • Pericardial fluid
    • Peritoneal fluid/ ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
    • Synovial fluid
    • Urine
    • Bile (especially mezlocillin)
  • Poor penetration across the blood-brain barrier (exception: during inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation in meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis)

Protein binding

  • Varies based on the drug
  • Penicillinase-resistant penicillins (nafcillin, oxacillin, cloxacillin): > 90% is protein bound.
  • Penicillin V: > 80% is protein bound.
  • Amoxicillin, ampicillin, and piperacillin: 15%–20% is protein bound.

Half-life

  • Relatively short for all penicillins (generally < 1 hour)
  • Parenteral agents are typically administered every 4 hours.
  • Exception: Piperacillin has a longer half-life when administered at higher doses.

Metabolism

  • Penicillinase-resistant penicillins (nafcillin, oxacillin, cloxacillin) undergo hepatic metabolism.
  • Most others are not extensively metabolized.

Excretion

  • Most are excreted primarily in the urine:
    • Most are excreted unchanged.
    • Ampicillin and piperacillin require dose adjustments in patients with renal insufficiency.
  • Some are excreted primarily in the bile/feces, including:
    • Penicillinase-resistant penicillins (nafcillin, oxacillin, and cloxacillin)
    • Mezlocillin

Indications

Table: Spectrum of activity and clinical uses of penicillins
Drug (route of administration) Spectrum of activity Clinical uses
Penicillin G (IV/IM) and penicillin V (oral) Narrow:
  • Gram-positive cocci:
    • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pyogenes
    • S. pneumoniae
    • S. agalactiae (GBS)
  • Gram-positive bacilli:
    • Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes Infections monocytogenes
    • Actinomyces Actinomyces Actinomyces is an anaerobic, gram-positive, branching, filamentous rod. Actinomyces israelii is the most common species involved in human disease. The organism is commonly found as part of the normal flora in the oral cavity, gastrointestinal tract, and reproductive tract. Actinomyces/Actinomycosis Israelii
  • Gram-negative cocci:
    • Neisserria meningitidis
    • N. gonorrhoeae
  • Spirochetes:
    • Treponema Treponema Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema pallidum
    • Leptospira Leptospira Leptospira is a spiral or question mark-shaped, gram-negative spirochete with hook-shaped ends. The disease, leptospirosis, is a zoonosis, infecting animals. Rodents are the most important reservoir. Bacteria shed in the urine of rodents and other animals can be transmitted to humans via contaminated water. Leptospira/Leptospirosis spp.
  • Streptococcal pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis (i.e., strep throat)
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis
  • Toxic shock syndrome Toxic Shock Syndrome Toxic shock syndrome (TSS) is an acute, multi-systemic disease caused by the toxin-producing bacteria, Staphylococcus aureus and Streptococcus pyogenes. Staphylococcal TSS is more common and associated with tampons and nasal packing. Toxic Shock Syndrome caused by Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus spp.
  • Rheumatic fever Rheumatic fever Acute rheumatic fever (ARF) is an autoimmune inflammatory process that usually follows Streptococcal pharyngitis. Acute rheumatic fever usually occurs 2-4 weeks after an untreated infection and affects the heart, skin, joints, and nervous system. Rheumatic Fever prophylaxis
  • Bacterial meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis caused by L. monocytogenes or N. meningitidis
  • Gonorrhea Gonorrhea Gonorrhea is a sexually transmitted infection (STI) caused by the gram-negative bacteria Neisseria gonorrhoeae (N. gonorrhoeae). Gonorrhea may be asymptomatic but commonly manifests as cervicitis or urethritis with less common presentations such as proctitis, conjunctivitis, or pharyngitis. Gonorrhea
  • S. agalactiae (GBS) infections in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis (penicillin G)
  • Leptospirosis Leptospirosis Leptospira is a spiral or question mark-shaped, gram-negative spirochete with hook-shaped ends. The major clinical species is Leptospira interrogans, which causes a mild flu-like illness in a majority of cases. The manifestations are biphasic, with Leptospira found in the blood initially. Leptospira/Leptospirosis
  • Anthrax Anthrax Anthrax is an infection caused by the bacterium Bacillus anthracis, which usually targets the skin, lungs, or intestines. Anthrax is a zoonotic disease and is usually transmitted to humans from animals or through animal products. Symptoms depend on which organ system is affected. Anthrax
  • Botulism Botulism Botulism is a rare, neuroparalytic syndrome caused by Clostridium botulinum (C. botulinum). A fatal neurotoxin (botulinum toxin) is released causing varying degrees of muscle paralysis and distinct clinical syndromes. The most common types of botulism are foodborne and infant. Botulism (adjunct)
  • Diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria (adjunct)
  • Tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus (adjunct)
Cloxacillin and dicloxacillin Narrow:
Gram-positive cocci:
  • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus spp. (excluding MRSA)
  • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus spp.
  • Skin and soft tissue infections
    • Impetigo Impetigo Impetigo is a highly contagious superficial bacterial infection typically caused by Staphylococcus aureus (most common) and Streptococcus pyogenes. Impetigo most commonly presents in children aged 2 to 5 years with lesions that evolve from papules to vesicles to pustules, which eventually break down to form characteristic "honey-colored" crusts. Impetigo
    • Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis
    • Mastitis Mastitis Mastitis is inflammation of the breast tissue with or without infection. The most common form of mastitis is associated with lactation in the first few weeks after birth. Non-lactational mastitis includes periductal mastitis and idiopathic granulomatous mastitis (IGM). Mastitis
  • Otitis externa Otitis externa Otitis externa (also known as external otitis or swimmer's ear) is an infection of the external auditory canal that is most often caused by acute bacterial infection and is frequently associated with hot, humid weather and water exposure. Patients commonly present with ear pain, pruritus, discharge, and hearing loss. Otitis Externa
  • Septic arthritis Septic arthritis Septic arthritis is an infection of the joint due to direct inoculation, contiguous extension, or hematogenous spread of infectious organisms into the joint space. This process causes an acute, inflammatory, monoarticular arthritis. Septic Arthritis
  • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia due to susceptible bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
Ampicillin (IV/oral) and amoxicillin (oral) Wider:
  • Gram-positive bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview:
    • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus spp.
    • L. monocytogenes
  • Gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview:
    • Helicobacter Helicobacter Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation. Helicobacter pylori
    • Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae
    • Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli
    • Proteus Proteus Proteus spp. are gram-negative, facultatively anaerobic bacilli. Different types of infection result from Proteus, but the urinary tract is the most common site. The majority of cases are caused by Proteus mirabilis (P. mirabilis). The bacteria are part of the normal intestinal flora and are also found in the environment. Enterobacteriaceae: Proteus mirabilis
    • Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella spp.
    • Shigella Shigella Shigella is a genus of gram-negative, non-lactose-fermenting facultative intracellular bacilli. Infection spreads most commonly via person-to-person contact or through contaminated food and water. Humans are the only known reservoir. Shigella spp.
  • Activity is enhanced with the use of clavulanate.
  • ENT infections:
    • Pharyngitis
    • Tonsillitis Tonsillitis Tonsillitis is inflammation of the pharynx or pharyngeal tonsils, and therefore is also called pharyngitis. An infectious etiology in the setting of tonsillitis is referred to as infectious pharyngitis, which is caused by viruses (most common), bacteria, or fungi. Tonsillitis
    • Otitis media
    • Rhinosinusitis
  • GI infections:
    • H. pylori eradication
    • Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella
    • Complementary with aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides for enterococcal infections
  • Community-acquired pneumonia
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis prophylaxis
  • Bacterial meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
  • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
  • Genitourinary infections:
    • Urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections (not 1st line)
    • Intra-amniotic infections
    • Postpartum endometritis Endometritis Endometritis is an inflammation of the endometrium, the inner layer of the uterus. The most common subtype is postpartum endometritis, resulting from the ascension of normal vaginal flora to the previously aseptic uterus. Endometritis
    • Tubo-ovarian abscess
Piperacillin (only available as piperacillin/tazobactam in the US) Widest:
  • Gram-positive bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview:
    • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus spp.
    • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus spp. (excluding MRSA)
  • Gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview:
    • P. aeruginosa
    • Many Enterobacteriaceae
  • Paired with the penicillinase inhibitor tazobactam to enhance activity.
  • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
  • Neutropenic fever Neutropenic fever Neutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Neutropenic Fever in high-risk patients
  • Intra-abdominal/pelvic infections:
    • Appendicitis Appendicitis Appendicitis is the acute inflammation of the vermiform appendix and the most common abdominal surgical emergency globally. The condition has a lifetime risk of 8%. Characteristic features include periumbilical abdominal pain that migrates to the right lower quadrant, fever, anorexia, nausea, and vomiting. Appendicitis
    • Pelvic inflammatory disease Pelvic inflammatory disease Pelvic inflammatory disease (PID) is defined as a polymicrobial infection of the upper female reproductive system. The disease can affect the uterus, fallopian tubes, ovaries, and adjacent structures. Pelvic inflammatory disease is closely linked with sexually transmitted diseases, most commonly caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Gardnerella vaginalis. Pelvic Inflammatory Disease
    • Postpartum endometritis Endometritis Endometritis is an inflammation of the endometrium, the inner layer of the uterus. The most common subtype is postpartum endometritis, resulting from the ascension of normal vaginal flora to the previously aseptic uterus. Endometritis
  • Skin and soft tissue infections:
    • Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis
    • Abscesses
    • Ischemic/diabetic foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot infections
Mezlocillin Wide: good gram-negative coverage Biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the "corners" of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract infections (e.g., biliary cholangitis)
GBS: group B Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus

Adverse Effects and Contraindications

Adverse effects

The most common effects are related to allergic reactions.

  • IgE-mediated allergic reactions:
    • Present with pruritis, urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives), angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, and/or anaphylaxis
    • Symptoms typically appear within 4 hours of administration (often within minutes).
  • Serum sickness:
    • A late allergic reaction due to circulating immune complexes
    • Characterized by fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives), adenopathy, arthritis, and occasionally glomerulonephritis
  • Dermatologic reactions:
    • Morbilliform rash: a maculopapular eruption due to a hypersensitivity reaction
    • Erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme: target lesions developing with acute onset
    • Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome: a desquamating skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin condition involving mucosal surfaces
  • Neurologic reactions:
    • Encephalopathy
    • Penicillin neurotoxicity: 
      • Decreased level of consciousness (e.g., somnolence, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma)
      • Generalized hyperreflexia
      • Myoclonus
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • GI and hepatic reactions:
    • Diarrhea (especially with ampicillin and amoxicillin)
    • Clostridioides difficile colitis 
    • Suppression of gut flora leading to vitamin K deficiency
    • Hypersensitivity hepatitis (especially with oxacillin and nafcillin)
  • Renal reactions:
    • Glomerulonephritis (occurring in association with allergic reactions)
    • Allergic interstitial nephritis (especially with nafcillin and methicillin)
    • AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury (associated with the concomitant use of piperacillin-tazobactam and vancomycin)
  • Hematologic reactions:
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia due to immune-mediated destruction of polymorphonuclear (PMN) leukocytes
    • Hemolytic anemia
    • Immune thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, especially with ticarcillin
    • Suppression of gut flora leading to vitamin K deficiency

Contraindications

  • Hypersensitivity reactions
  • Serious skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin reactions (e.g., Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome)

Comparison of Antibiotic Coverage and Classification

Comparison based on mechanisms of action

Antibiotics can be classified in several ways. One way is to classify them based on their mechanism of action:

Table: Antibiotics classified by primary mechanism of action
Mechanism Classes of antibiotics
Bacterial cell wall synthesis inhibitors
  • Penicillins
  • Cephalosporins
  • Penems
  • Miscellaneous
Bacterial protein synthesis inhibitors
  • Tetracyclines Tetracyclines Tetracyclines are a class of broad-spectrum antibiotics indicated for a wide variety of bacterial infections. These medications bind the 30S ribosomal subunit to inhibit protein synthesis of bacteria. Tetracyclines cover gram-positive and gram-negative organisms, as well as atypical bacteria such as chlamydia, mycoplasma, spirochetes, and even protozoa. Tetracyclines
  • Macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides
  • Ketolide
  • Lincosamides Lincosamides The lincosamides, lincomycin and clindamycin, are inhibitors of bacterial protein synthesis. Drugs in this class share the same binding site as that of macrolides and amphenicols; however, they differ in chemical structure. Lincosamides target the 50S ribosomal subunit and interfere with transpeptidation. Lincosamides
  • Streptogramins
  • Linezolid
Agents acting against DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and/or folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12
  • Sulfonamides
  • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim
  • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones
Antimycobacterial agents Antimycobacterial Agents Antimycobacterial agents represent a diverse group of compounds that have activity against mycobacterial infections, including tuberculosis, leprosy and Mycobacterium avium complex (MAC) disease. The 1st-line agents for tuberculosis are rifampin, isoniazid, pyrazinamide, and ethambutol. Antimycobacterial Agents
  • Anti- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis agents
  • Antileprosy agents
  • Atypical mycobacterial agents

Comparison based on coverage

Different antibiotics have varying degrees of activity against different bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview. The table below outlines the antibiotics that are active against 3 important classes of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, including gram-positive cocci, gram-negative bacilli, and anaerobes.

Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. Letourneau, A.R. (2019). Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects. In Bloom, A. (Ed.), UpToDate. Retrieved May 20, 2021, from https://www.uptodate.com/contents/beta-lactam-antibiotics-mechanisms-of-action-and-resistance-and-adverse-effects
  2. Letourneau, A.R. (2019). Penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins. In Bloom, A. (Ed.), UpToDate. Retrieved July 8, 2021, from https://www.uptodate.com/contents/penicillin-antistaphylococcal-penicillins-and-broad-spectrum-penicillins 
  3. Letourneau, A.R. Cephalosporins. UpToDate. Retrieved May 20, 2021, from https://www.uptodate.com/contents/cephalosporins
  4. Penicillin G Benzathine. Medscape. Retrieved May 20, 2021, from https://reference.medscape.com/drug/bicillin-la-permapen-penicillin-g-benzathine-999573
  5. Abraham, E.P. (1987). Cephalosporins 1945-1986. In: The Cephalosporin Antibiotics. Williams, J.D. (Ed.). Adis Press.
  6. Bodey, G.P. (1990). Penicillins, monobactams and carbapenems. Tex Heart Inst J. 17(4), 315-329.
  7. Deck, D.H., Winston, L.G. (2012). Beta-lactam & other cell wall- & membrane-active antibiotics (Chapter 43). In: Basic and Clinical Pharmacology. 12e. Katzung, B.G., Masters, S.B., Trevor, A.J. (Editors). McGraw-Hill/Lange.
  8. Hauser, A.R. (2013). Antibiotic basics for clinicians. The ABCs of choosing the right antibacterial agent. 2nd Ed. Lippincott Williams & Wilkins. ISBN-13: 978-1-4511-1221-4

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