Antibacterial Agents

Chapter: Antibacterial Agents
McMaster Section Editor(s): Mark Loeb
Section Editor(s) in Interna Szczeklika: Piotr Zaborowski, Jerzy Stefaniak, Miłosz Parczewski, Weronika Rymer, Agnieszka Wroczyńska
McMaster Author(s): Bahareh Ghadaki, Marek Smieja, Shariq Haider, Jaclyn Quirt
Author(s) in Interna Szczeklika: Waleria Hryniewicz
Additional Information

Pregnancy risk categories: Table 8.2-1.

PenicillinsTop

Penicillin allergy: see Special Considerations, below.

1. Penicillins: Penicillin G (INN benzylpenicillin) (IV), penicillin V (INN phenoxymethylpenicillin) (oral). Penicillin G has two formulations: penicillin G sodium and penicillin G potassium. The potassium-based preparations are preferred in patients with heart failure, and the sodium preparations are favored in patients who experience infusion-related phlebitis.

1) Mechanism of action: Penicillin G binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in bacterial death.

2) Spectrum of activity: Active against beta-hemolytic streptococci (group A, B, C, D, F, and G), Listeria monocytogenes, Neisseria meningitides, and Treponema pallidum. Activity against other important bacterial species (Enterococcus faecalis, Streptococcus pneumoniae, viridans-group streptococci, anaerobic bacteria) may vary. Penicillins are inactive against most Staphylococcus species, including Staphylococcus aureus and coagulase-negative staphylococci, due to beta-lactamase (penicillinase) production. In addition, penicillin G and V are inactive against the majority of aerobic gram-negative bacilli as well as Bacteroides species.

3) Adverse reactions: Anaphylactoid/hypersensitivity reaction. Central nervous system (CNS) effects (increased risk of myoclonus and seizures especially in patients with high drug levels and renal insufficiency). Prolonged use associated with hematologic abnormalities, including hemolytic anemia, neutropenia, thrombocytopenia, interstitial nephritis, hepatitis, and serum sickness.

4) Pregnancy risk: B.

2. Semisynthetic antistaphylococcal penicillins: Cloxacillin (oral, IV):

1) Mechanism of action: Semisynthetic antistaphylococcal penicillins bind to penicillin-binding proteins on the cell wall and interfere with bacterial cell wall synthesis resulting in bacterial death.

2) Spectrum of activity: The drug of choice for penicillinase-producing staphylococci (ie, methicillin-susceptible S aureus [MSSA]). Also active against beta-hemolytic streptococci and S pneumoniae. Inactive against methicillin-resistant S aureus (MRSA), Enterococcus spp, L monocytogenes, aerobic gram-negative bacilli, penicillin-resistant pneumococci, and all anaerobes.

3) Adverse reactions: Anaphylactoid/hypersensitivity reaction, CNS effects (increased risk of myoclonus and seizures may occur especially in patients with high drug levels and renal insufficiency), hematologic effects (neutropenia, thrombocytopenia), hepatitis, interstitial nephritis.

4) Pregnancy risk: B.

3. Aminopenicillins: Ampicillin (IV), amoxicillin (oral):

1) Mechanism of action: Aminopenicillins bind to penicillin-binding proteins on the cell wall and interfere with bacterial cell wall synthesis resulting in cell wall death.

2) Spectrum of activity: Compared to penicillins, aminopenicillins have a similar spectrum of activity but with additional aerobic gram-negative coverage including strains of Haemophilus that do not produce beta-lactamase and some Enterobacteriaceae. Ampicillin is the drug of choice in the treatment of L monocytogenes and E faecalis infections. It is also active against beta-hemolytic streptococci, S pneumoniae, Borrelia burgdorferi, and most gram-positive anaerobes with the exception of Clostridium difficile. The prevalence of resistant strains among Escherichia coli, Proteus mirabilis, Salmonella spp, and Shigella spp is variable. Resistance to commonly isolated gram-negative bacilli include all Klebsiella spp, the Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) and AmpC chromosomal-induced cephalosporinases (SPICE organisms: Serratia, Proteus [indole-positive], Citrobacter, Enterobacter), as well as nonfermenting gram-negative bacilli (Pseudomonas spp, Acinetobacter spp, and Stenotrophomonas spp).

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. Rash noted in 65% to 100% of patients with Epstein-Barr Virus (EBV) infection. Hematologic effects (neutropenia, thrombocytopenia).

4) Pregnancy risk: B.

4. Carboxypenicillins: Ticarcillin (IV):

1) Mechanism of action: Carboxypenicillins bind to penicillin-binding proteins on the cell wall and interfere with bacterial cell wall synthesis resulting in cell wall death. They are able to penetrate the outer cell membrane of selected gram-negative bacteria.

2) Spectrum of activity: A penicillin derivative with extended activity against aerobic gram-negative bacilli compared to aminopenicillins. The most important feature of carboxypenicillins is their activity against Pseudomonas aeruginosa. Compared with ampicillin, ticarcillin has increased activity against indole-positive Proteus spp (Proteus vulgaris and Proteus rettgeri) and Morganella morganii. Otherwise ampicillin is the preferred drug of choice for other Enterobacteriaceae in addition to aerobic gram-positive bacteria, as it is a more active drug. Gram-positive and gram-negative anaerobic coverage is variable.

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. CNS effects similar to penicillin, including seizures when high drug doses are used. Hematologic effects, including bleeding related to platelet dysfunction and neutropenia. Hepatitis.

4) Pregnancy risk: B.

5. Ureidopenicillins: Piperacillin (IV):

1) Mechanism of action: Ureidopenicillins bind to penicillin-binding proteins on the cell wall and interfere with bacterial cell wall synthesis resulting in cell wall death. They are able to penetrate the outer cell membrane of selected gram-negative bacteria.

2) Spectrum of activity: Piperacillin is available alone or more commonly combined with tazobactam (see piperacillin/tazobactam, below). It is a penicillin derivative with extended activity against aerobic gram-negative bacilli, similar to ticarcillin, with activity against P aeruginosa. Piperacillin has variable activity to the Enterobacteriaceae family owing to the production of beta-lactamases. Gram-positive bacterial coverage is similar to that of ampicillin; however, ampicillin remains the drug of choice secondary to increased activity. Gram-positive and gram-negative anaerobic coverage is variable.

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. CNS effects similar to penicillin, including seizures when high drug doses are used. Hematologic effects, including bleeding related to platelet dysfunction and neutropenia. Hepatitis.

4) Pregnancy risk: B.

CephalosporinsTop

Enterococcus spp and L monocytogenes have natural resistance to all cephalosporins.

Mechanism of action: All cephalosporins bind to penicillin-binding proteins on the cell wall and interfere with bacterial cell wall synthesis resulting in cell wall death.

1. First-generation cephalosporins: Cefazolin (IV) and cephalexin (oral):

1) Spectrum of activity: Highly active against MSSA and coagulase-negative staphylococci. Other gram-positive coverage includes beta-hemolytic streptococci, S pneumoniae, and viridans-group streptococci. Aerobic gram-negative coverage is limited due to the production of beta-lactamase–producing bacteria; however, these antibiotics can be susceptible to E coli, Klebsiella spp, and P mirabilis. Resistance is seen to ESBL- and AmpC-producing bacteria, aerobic gram-negative nonfermenters (Pseudomonas spp, Acinetobacter spp, and Stenotrophomonas spp), and most anaerobic bacteria.

2) Adverse reactions: Hypersensitivity reactions. Hematologic effects, such as neutropenia and thrombocytopenia. Transient elevations in transaminases or serum alkaline phosphatase have been noted.

3) Pregnancy risk: B.

2. Second-generation cephalosporins: This generation of cephalosporins can be divided into two groups: one with activity against H influenzae and the other, cephamycins, with activity against Bacteroides. The antistaphylococcal activity of second-generation cephalosporins is inferior to that of first-generation cephalosporins.

1) Cefaclor (oral), cefprozil (oral):

a) Spectrum of activity: Compared to first-generation cephalosporins, cefaclor and cefprozil have better activity against most streptococci, such as S pneumoniae and beta-hemolytic streptococci. Aerobic gram-negative coverage is similar to first-generation cephalosporins with the addition of H influenzae and M catarrhalis. Cefprozil appears to be more active against gram-negative bacteria compared to cefaclor. Resistance is seen to ESBL- and AmpC-producing bacteria, aerobic gram-negative nonfermenters (Pseudomonas spp, Acinetobacter spp, and Stenotrophomonas spp), and most anaerobic bacteria.

b) Adverse reactions: Hypersensitivity reactions including serum sickness, particularly in young children receiving cefaclor. Cefaclor and cefprozil have the same side chain as ampicillin, thus cross-allergenicity may occur.

c) Pregnancy risk: B.

2) Cefuroxime (IV and oral [cefuroxime axetil]):

a) Spectrum of activity: This agent is active against most streptococci, such as penicillin-sensitive S pneumoniae strains and beta-hemolytic streptococci. Cefuroxime has good coverage against H influenzae and M catarrhalis (including strains producing beta-lactamases). Unique among second-generation cephalosporins is cefuroxime’s activity against B burgdorferi, the causative agent in Lyme disease. Activity against the Enterobacteriaceae is variable and includes E coli, Klebsiella spp, and P mirabilis. Resistance is similar to that of cefaclor and cefprozil.

b) Adverse effects: Hypersensitivity reactions.

c) Pregnancy risk: B.

3) Cephamycin group: Cefoxitin (IV):

a) Spectrum of activity: The activity of cefoxitin against gram-positive bacteria is similar to that of other second-generation cephalosporins. Aerobic gram-negative coverage is enhanced with activity against the Enterobacteriaceae including ESBL- but not AmpC-producing strains. Unlike the first-generation cephalosporins, cephamycins are active against many gram-positive and gram-negative anaerobes, including some strains of Bacteroides. Unique to cephamycins is the activity against rapidly growing mycobacteria (Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum).

b) Adverse reactions: Hypersensitivity reactions.

c) Pregnancy risk: B.

3. Third-generation cephalosporins: In general, compared to first-generation cephalosporins, third-generation cephalosporins have a broader range of activity against gram-negative bacteria and decreased activity against staphylococci.

1) Cefotaxime (IV) and ceftriaxone (IV):

a) Spectrum of activity: These antibiotics are highly active against the Enterobacteriaceae (E coli, P mirabilis, indole-positive Proteus, Klebsiella spp, Providencia spp, Enterobacter spp, Serratia spp, and Citrobacter spp); however, they are susceptible to inactivation by ESBLs and AmpC chromosomal-induced cephalosporinases. Enhanced activity is seen against Salmonella, Shigella, and Yersinia species, as well as against Vibrio spp, H influenzae, N meningitides, and Neisseria gonorrhoeae. Excellent gram-positive coverage is seen against S pneumoniae, beta-hemolytic streptococci, and viridans-group streptococci. In addition, both antibiotics have activity against MSSA, but cefazolin and semisynthetic antistaphylococcal penicillins remain the drugs of choice for treatment of bacteremia. Ceftriaxone remains the drug of choice for Lyme disease with CNS involvement. For neurosyphilis, ceftriaxone can be considered as an alternative therapy for those with mild nonanaphylactic allergy to penicillin. These antibiotics are inactive against gram-negative nonfermenters (Pseudomonas spp, Acinetobacter spp, and Stenotrophomonas spp) and to most anaerobic bacteria.

b) Adverse reactions: Hypersensitivity reactions. Pseudocholelithiasis secondary to sludge in the gallbladder and hyperbilirubinemia seen with ceftriaxone only. Hematologic effects (anemia, thrombocytopenia, neutropenia).

c) Pregnancy risk: B.

2) Cefixime (oral):

a) Spectrum of activity: The spectrum of activity of cefixime is not quite as wide as that of the third-generation cephalosporins listed above. While it retains reasonable activity against beta-hemolytic streptococci and viridans-group streptococci, variable activity exists for S pneumoniae and resistance is seen towards the staphylococcal bacteria. Among the Enterobacteriaceae, E coli, Klebsiella spp, Proteus spp, Salmonella spp, Shigella spp, and Yersinia spp remain susceptible. Coverage of Neisseria species includes N gonorrhea only, although increasing resistance has been noted. Cefixime is inactive against gram-negative nonfermenters and most anaerobes.

b) Adverse reactions: Hypersensitivity reactions.

c) Pregnancy risk: B.

3) Ceftazidime (IV):

a) Spectrum of activity: Similar activity to that of ceftriaxone and cefotaxime for the gram-negative bacteria Enterobacteriaceae. Ceftazidime is also particularly active against the gram-negative nonfermenters, including Pseudomonas, Acinetobacter, Burkholderia, and Stenotrophomonas species. Markedly lower activity against gram-positive cocci compared to ceftriaxone and cefotaxime is noted. Resistance is seen towards ESBL- and AmpC-producing gram-negative bacteria and anaerobes.

b) Adverse reactions: Hypersensitivity reactions. Side chains of ceftazidime and aztreonam are identical, resulting in cross-allergenicity. CNS effects, such as seizures, have been associated with high ceftazidime levels in patients with renal insufficiency.

c) Pregnancy risk: B.

4. Fourth-generation cephalosporins: Cefepime (IV):

1) Spectrum of activity: Cefepime has similar activity to ceftriaxone and cefotaxime with respect to S pneumoniae and MSSA. In addition, while similar activity also exists against the Enterobacteriaceae and H influenzae, activity of this agent against Pseudomonas spp and gram-negative bacilli producing AmpC beta-lactamases is high, although there is regional variability with respect to Pseudomonas susceptibility. Cefepime is inadequate in the case of ESBL-producing strains, as variable susceptibility has been noted. Cefepime has poor to no activity against other gram-negative nonfermenters, Burkholderia, Acinetobacter, and Stenotrophomonas species, as well as anaerobes.

2) Adverse reactions: Hypersensitivity reactions. CNS effects with risk of encephalopathy, myoclonus, seizures, and nonconvulsive status epilepticus.

3) Pregnancy risk: B.

5. Fifth-generation cephalosporins:

1) Ceftaroline (IV):

a) Mechanism of action: Avid binding to penicillin-binding protein 2a, which results in activity against MRSA.

b) Spectrum of activity: Active against most gram-positive bacteria with notable activity against MRSA and coagulase-negative staphylococci. In vitro activity is seen against vancomycin-intermediate S aureus (VISA), hetero-VISA, and vancomycin-resistant S aureus (VRSA). Activity against aerobic gram-negative bacilli is similar to that of ceftriaxone and cefotaxime. In addition, ceftaroline has activity against Streptococcus pneumoniae that is intermediate or resistant to penicillin or ceftriaxone. Ceftaroline is inactivated by ESBL and AmpC and is inactive against Pseudomonas spp, Acinetobacter spp, enterococci, and most anaerobes.

c) Adverse reactions: Hypersensitivity reactions. Positive direct Coombs test without clinical hemolysis.

d) Pregnancy risk: B. 

2) Ceftobiprole (IV):

a) Mechanism of action: Avid binding to penicillin-binding protein 2a, which results in activity against MRSA. It can also bind penicillin-binding protein 2x in penicillin-resistant S pneumonia.

b) Spectrum of activity: An advanced generation cephalosporin with activity against some aerobic gram-positive and gram-negative bacteria including MRSA and enterococci. Its in-vitro activity is similar to ceftaroline. Ceftobiprole is inactivated by ESBL and AmpC.

c) Adverse reactions: Hypersensitivity reactions/anaphylaxis. Positive direct Coombs test without clinical hemolysis. Hyponatremia.

d) Pregnancy risk: B.

MonobactamsTop

Aztreonam (IV):

1) Mechanism of action: Aztreonam binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death.

2) Spectrum of activity: Only gram-negative bacteria are susceptible to aztreonam. Most notable activity is against Pseudomonas spp; however, antipseudomonal beta-lactams are more active. This antibiotic is also active against a wide range of the Enterobacteriaceae (E coli, Proteus spp, Klebsiella spp, Providencia spp, Enterobacter spp, Serratia spp, Citrobacter spp, Salmonella spp, and Shigella spp), although they are susceptible to inactivation by ESBLs and AmpC chromosomal-induced cephalosporinases.

3) Adverse reactions: Hypersensitivity reactions. Clinical cross-allergenicity with other beta-lactams has not been demonstrated except for ceftazidime, where in vitro cross-allergenicity exists due to their identical side chains.

4) Pregnancy risk: B.

CarbapenemsTop

Ertapenem, meropenem, imipenem, doripenem (IV):

1) Mechanism of action: Carbapenems bind to penicillin-binding proteins on the cell wall and interfere with bacterial cell wall synthesis resulting in cell wall death.

2) Spectrum of activity: These agents have the broadest spectrum of activity of all antibiotics and cover multiple gram-positive, gram-negative (beta-lactamase–producing H influenzae and the Enterobacteriaceae) and anaerobic bacteria (including Bacteroides). Carbapenems are the drug of choice for ESBL- or AmpC-producing gram-negative bacteria. Notable differences between carbapenems include ertapenem resistance in Pseudomonas and Acinetobacter species, meropenem susceptibility in Burkholderia species, and imipenem susceptibility in Nocardia species. Carbapenems are generally inactive against S maltophilia, Enterococcus faecium, and MRSA. Imipenem has the highest activity against E faecalis.

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. CNS toxicity including seizures, with imipenem associated with the highest risk. Doripenem should not be used for treatment of pneumonia given its higher mortality rates compared to other carbapenems, such as imipenem.

4) Pregnancy risk: B.

BETA-LACTAMASE INHIBITOR COMBINATIONSTop

Amoxicillin/clavulanic acid and piperacillin/tazobactam are more commonly used in routine practice than ticarcillin/clavulanic acid and ampicillin/sulbactam.

1. Amoxicillin +clavulanic acid (oral):

1) Mechanism of action: Amoxicillin binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death. Clavulanic acid acts as a beta-lactamase inhibitor.

2) Spectrum of activity: The combination of amoxicillin and clavulanic acid retains the antimicrobial activity of amoxicillin with the addition of selected beta-lactamase–producing bacteria that are susceptible to the inhibition of clavulanic acid as well as broader anaerobic coverage. Gram-positive coverage includes MSSA, beta-hemolytic streptococci, S pneumoniae, E faecalis, and viridans-group streptococci. Gram-negative beta-lactamase–producing strains of H influenzae and Moraxella catarrhalis are susceptible to amoxicillin/clavulanic acid. Amoxicillin/clavulanic acid is the drug of choice for animal and human bites as it has excellent activity against Pasteurella spp, Capnocytophaga spp, and other oral pathogens. This antibiotic retains high activity against the vast majority of clinically important gram-positive and gram-negative anaerobic bacteria with the exception of C difficile. Similar to amoxicillin, resistance is common against the Enterobacteriaceae producing ESBL and AmpC beta-lactamase–producing strains as well as nonfermenting gram-negative bacilli.

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. Incidence of diarrhea higher than with amoxicillin alone and primarily attributed to the clavulanic acid component. Rash in patients with EBV-mediated infectious mononucleosis. Hepatotoxicity linked to clavulanic acid, usually resulting in a cholestatic reaction.

4) Pregnancy risk: B.

2. Piperacillin + tazobactam (IV):

1) Mechanism of action: Piperacillin binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death. Tazobactam acts as a beta-lactamase inhibitor.

2) Spectrum of activity: The activity of this combination is similar to ampicillin/clavulanic acid with additional coverage against nonfermenting gram-negative bacilli (Pseudomonas spp and Acinetobacter spp). Stenotrophomonas maltophilia is resistant.

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. Use with caution in patients with a history of seizure disorder, as high drug levels may increase the risk of seizures. Serious skin reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Hematologic effects, including bleeding related to platelet dysfunction and neutropenia.

4) Pregnancy risk: B.

3. Ticarcillin + clavulanic acid (IV):

1) Mechanism of action: Ticarcillin binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death. Clavulanic acid acts as a beta-lactamase inhibitor.

2) Spectrum of activity: Similar to that of piperacillin/tazobactam with the addition of S maltophilia coverage.

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. CNS effects similar to penicillin, including seizures when high drug doses are used. Hematologic effects, including bleeding related to platelet dysfunction and neutropenia. Hepatitis.

4) Pregnancy risk: B.

4. Ampicillin + sulbactam:

1) Mechanism of action: Ampicillin binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death. Sulbactam acts as a beta-lactamase inhibitor.

2) Spectrum of activity: The addition of the beta-lactamase inhibitor sulbactam expands the spectrum of ampicillin to include MSSA, beta-lactamase producing H influenzae and M catarrhalis, some Enterobacteriaceae including Klebsiella species, and added anaerobic coverage including Bacteroides species. Importantly, ampicillin/sulbactam has activity against many strains of Acinetobacter baumannii.

3) Adverse reactions: Hypersensitivity/anaphylactoid reactions. Hepatic effects, such as hepatitis and cholestatic jaundice, have been noted. Rash in patients with EBV-mediated infectious mononucleosis.

d) Pregnancy risk: B.

5. Ceftolozane + tazobactam (IV):

1) Mechanism of action: Ceftolozane binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death. Tazobactam acts as a beta-lactamase inhibitor.

2) Spectrum of activity: A novel cephalosporin whose main activity is against aerobic gram-negative bacteria, including ESBL-producing strains and AmpC producers. A unique spectrum exists for multidrug-resistant P aeruginosa. Although activity does exist for streptococcal species, this antibiotic is generally inactive to staphylococcal and enterococcal species. Anaerobic coverage includes Bacteroides species.

3) Adverse reactions: Hypersensitivity reactions.

4) Pregnancy risk: B.

6. Ceftazidime + avibactam (IV):

1) Mechanism of action: Ceftazidime binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death. Avibactam acts as a beta-lactamase inhibitor and protects ceftazidime from degradation.

2) Spectrum of activity: A novel cephalosporin whose main activity is against aerobic gram-negative bacteria, including Pseudomonas spp, ESBL-producing strains and AmpC producers, and some carbapenemase-producing Enterobacteriaceae (CPE) such as Klebsiella pneumoniae carbapenemases and OXA-type carbapenemases. Ceftazidime-avibactam does not have activity against Acinetobacter species or CPE that produce metallo-beta-lactamases. It is less active against anaerobes compared with other beta-lactam/beta-lactamase combinations.

3) Adverse reactions: Hypersensitivity reactions. Neurotoxicity (asterixis, coma, encephalopathy, myoclonus, seizures).

4) Pregnancy risk: B.

7. Meropenem-vaborbactam (IV):

1) Mechanism of action: Meropenem binds to penicillin-binding proteins on the cell wall and interferes with bacterial cell wall synthesis resulting in cell wall death. Vaborbactam acts as a beta-lactamase inhibitor and protects meropenem from degradation.

2) Spectrum of activity: The main role of this antibiotic is its use against K pneumoniae carbapenemase-producing Enterobacteriaceae. It is not active against class B or D carbapenemases (ie, metallo-beta-lactamases and OXA-type enzymes).

3) Adverse reactions: Hypersensitivity reactions. Neurotoxicity (seizures, myoclonus).

4) Pregnancy risk: No data available.

Macrolides and AzalidesTop

Discussed agents include macrolides erythromycin and clarithromycin (oral); azalides azithromycin (oral and IV); the ketolide telithromycin (oral); and spiramycin.

1) Mechanism of action: These agents bind to the 50S subunit of bacterial ribosomes leading to inhibition of protein synthesis.

2) Spectrum of activity: Clarithromycin and azithromycin have broader activity compared to erythromycin. The macrolides are used quite extensively for respiratory tract infections. These agents have good activity against S pneumoniae, Haemophilus spp, M catarrhalis, and atypical pneumonia pathogens, including Legionella pneumophila, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Erythromycin is inactive against H influenzae. Additional activity includes aerobic gram-positive coverage including MSSA and beta-hemolytic Streptococcus (group A, B, C, G), although increasing resistance has been noted and susceptibility testing is required before using macrolides for these infections. Azithromycin is the macrolide of choice for treatment of sexually transmitted infections, including Chlamydia trachomatis, Mycoplasma genitalium, and T pallidum. Resistance has been noted for N gonorrhea. The gram-negative spectrum includes activity against E coli, Salmonella spp, Yersinia enterocolitica, Shigella spp, Campylobacter jejuni, Vibrio cholerae, and Helicobacter pylori. Unique to both azithromycin and clarithromycin is the activity against nontuberculous mycobacteria, including being first-line therapy for Mycobacterium avium complex. Telithromycin has a unique spectrum of activity in that it was designed to target macrolide-resistant respiratory pathogens including multidrug-resistant S pneumoniae. Spiramycin is predominantly used for treatment of suspected or confirmed Toxoplasma gondii infection acquired during pregnancy.

3) Adverse reactions: Hypersensitivity reactions. Hepatotoxicity and gastrointestinal adverse effects, such as nausea and diarrhea. Cardiac effects, including QT prolongation with risk of torsades de pointes. Azithromycin may increase the risk of cardiovascular death in patients with predisposing factors. Transient reversible hearing loss has been associated with azithromycin use. In the case of telithromycin, hepatic effects including severe liver injury and acute failure, and cautious use is advised in patients with underlying liver disease. Telithromycin is contraindicated in patients with myasthenia gravis.

4) Pregnancy risk: Azithromycin and erythromycin, category B. Clarithromycin and telithromycin, category C.

LincosamidesTop

Clindamycin (oral and IV):

1) Mechanism of action: Clindamycin binds to the 50S subunit of bacterial ribosomes leading to inhibition of protein synthesis.

2) Spectrum of activity: This agent is active against aerobic gram-positive cocci (MSSA, beta-hemolytic Streptococcus, viridans-group streptococci, S pneumoniae), gram-positive and gram-negative anaerobic bacteria (including Bacteroides species), and certain protozoa (Plasmodium falciparum, T gondii, Pneumocystis jiroveci). However, increasing rates of resistance have been noted for gram-positive cocci and Bacteroides species. Clindamycin is intrinsically inactive against Enterococcus and all aerobic gram-negative bacteria.

3) Adverse reactions: The most common adverse reactions include diarrhea, including the risk of C difficile infection, and hypersensitivity reactions (fever, rash, erythema multiforme, DRESS).

4) Pregnancy risk: B.

StreptograminsTop

Quinupristin/dalfopristin (IV):

1) Mechanism of action: Quinupristin/dalfopristin binds to the 50S subunit of bacterial ribosomes leading to inhibition of protein synthesis.

2) Spectrum of activity: This agent is active against multidrug-resistant strains of gram-positive cocci, including S aureus (MRSA, VISA, VRSA), penicillin-resistant S pneumoniae, and vancomycin-resistant E faecium (VRE). Quinupristin/dalfopristin is inactive against E faecalis (due to natural resistance) and all aerobic gram-negative bacilli.

3) Adverse reactions: Hypersensitivity reactions. Arthralgias and myalgias. Hyperbilirubinemia. Phlebitis has been noted when the antibiotic is infused through a peripheral line.

4) Pregnancy risk: B.

OxazolidinonesTop

1. Linezolid (oral and IV):

1) Mechanism of action: Linezolid binds to the 50S subunit of bacterial ribosomes leading to inhibition of protein synthesis.

2) Spectrum of activity: This agent is active against multidrug-resistant strains of gram-positive cocci, including S aureus (MRSA, VISA, VRSA), penicillin-resistant S pneumoniae, vancomycin-resistant E faecium and E faecalis (VRE). It is also active against beta-hemolytic streptococci and viridans-group streptococci. The unique coverage includes Nocardia and a variety of mycobacterial species.

3) Adverse reactions: Hypersensitivity reactions. Hematologic effects, such as myelosuppression, dependent on duration of therapy (>2 weeks). Lactic acidosis, peripheral and optic neuropathy with an extended therapy course >4 weeks. Because linezolid is a monoamine oxidase inhibitor, serotonin syndrome may occur with concomitant proserotonergic drug use.

4) Pregnancy risk: C.

2. Tedizolid (oral and IV):

1) Mechanism of action: Tedizolid binds to the 50S subunit of bacterial ribosomes leading to inhibition of protein synthesis.

2) Spectrum of activity: Tedizolid is similar to linezolid with respect to the spectrum of activity. Data on its efficacy for MRSA bacteremia is limited.

3) Adverse reactions: Hypersensitivity reactions. Hematologic effects, such as myelosuppression; however, it may be less myelotoxic compared with linezolid. Because tedizolid is a monoamine oxidase inhibitor, serotonin syndrome may occur with concomitant proserotonergic drug use.

4) Pregnancy risk: C.

GlycopeptidesTop

Vancomycin (IV, oral only indicated for C difficile), teicoplanin (IV):

1) Mechanism of action: These agents bind to target peptidoglycan (D-alanyl-D-alanine) terminus and inhibit cell wall synthesis.

2) Spectrum of activity: Activity is most notable against gram-positive aerobes and anaerobes, and particularly against MSSA and MRSA, enterococci, streptococci, Corynebacterium spp, and Clostridium spp. Vancomycin activity is unique in that it has activity against C difficile and is recommended as first-line therapy for severe infections. Natural resistance to glycopeptides is found in Lactobacillus spp, Leuconostoc spp, Pediococcus spp, and in Erysipelothrix rhusiopathiae. Neither antibiotic has activity against aerobic or anaerobic gram-negative bacteria.

3) Adverse reactions: Hypersensitivity reactions, not to be confused with infusion-related reaction red man syndrome (hypotension, flushing, urticaria) due to rapid (<1 hour) IV administration. Rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis). Nephrotoxicity (acute tubular necrosis and interstitial nephritis) and ototoxicity consisting of tinnitus and vertigo. Hematologic effects, such as neutropenia and thrombocytopenia, noted after prolonged therapy or associated with high drug doses and levels in the blood.

4) Pregnancy risk: B (oral), C (IV).

LipoglycopeptidesTop

Telavancin, oritavancin, dalbavancin (IV) are all new antibiotics.

1) Mechanism of action: Inhibition of bacterial cell wall synthesis.

2) Spectrum of activity: Currently these antibiotics are only indicated for complicated skin and skin tissue infections caused by susceptible strains of gram-positive bacteria including S aureus (MRSA and MSSA), beta-hemolytic Streptococcus (A and B), and the Streptococcus anginosus group. Telavancin and oritavancin are approved for infections with E faecalis (vancomycin-susceptible isolates only). These agents have no activity against aerobic and anaerobic gram-negative bacteria.

3) Adverse reactions: Telavancin is associated with infusion-related reactions similar to vancomycin, QT prolongation, and nephrotoxicity. Oritavancin is associated with infusion-related reactions and increased risk of osteomyelitis. Dalbavancin is associated with hypersensitivity reactions, infusion-related reactions, and elevation in liver enzymes.

4) Pregnancy risk: C for all 3 drugs.

LipopeptidesTop

Daptomycin (IV):

1) Mechanism of action: Daptomycin produces irreversible alterations in the cell membrane leading to loss of ions such as potassium and eventually leading to cell death.

2) Spectrum of activity: Activity is most notable against gram-positive aerobes and particularly against resistant staphylococci (MRSA, VISA, VRSA), E faecalis and E faecium including VRE, and streptococci. Daptomycin is not to be used for primary pneumonia, as it is inactivated by pulmonary surfactant. It shows no activity against aerobic and anaerobic gram-negative bacteria.

3) Adverse reactions: Hypersensitivity reactions. Risk of myopathy and increased creatinine kinase. Peripheral neuropathy. Eosinophilic pneumonia after 2 to 4 weeks of therapy.

4) Pregnancy risk: B.

FluoroquinolonesTop

Agents discussed include second-generation fluoroquinolones ciprofloxacin (oral, IV), norfloxacin (oral), and ofloxacin (oral); third-generation fluoroquinolone levofloxacin (oral, IV); and fourth-generation fluoroquinolone moxifloxacin (oral, IV).

1) Mechanism of action: Inhibition of DNA gyrase and topoisomerase IV leading to direct inhibition of DNA synthesis.

2) Spectrum of activity: The greatest activity of these agents is against aerobic gram-negative bacilli from the Enterobacteriaceae family, including ESBL and AmpC producers, H influenzae, M catarrhalis, and nonfermenters including Pseudomonas, Acinetobacter, Burkholderia, and Stenotrophomonas species. Among fluoroquinolones, ciprofloxacin has the most potent activity against gram-negative bacteria, especially against P aeruginosa. The third- and fourth-generation agents have better activity against gram-positive bacteria and respiratory pathogens compared to that of second-generation fluoroquinolones; this includes coverage against S aureus (MSSA) and S pneumoniae, as well as C pneumoniae, M pneumoniae, and L pneumophila. Enterococcus species can be susceptible to fluoroquinolones; however, these agents must only be used for urinary infections and not for systemic infections. Unique to moxifloxacin is its enhanced activity against anaerobic bacteria such as Bacteroides species, although higher rates of resistance have been noted. Fluoroquinolones also have activity against tuberculous and nontuberculous mycobacteria and are often used in combination therapy.

3) Adverse reactions: Hypersensitivity reactions. Exercise caution when using in children aged <16 years due to joint cartilage injury. Gastrointestinal effects, such as diarrhea and C difficile infection. CNS toxicity ranging from headaches and lightheadedness to seizures. These agents have neuromuscular-blocking activity and may exacerbate muscle weakness in individuals with myasthenia gravis. Increased risk of tendinopathy and retinal detachment. Cardiac effects, such as QT prolongation. Dysglycemia in patients with diabetes mellitus with moxifloxacin conferring the highest risk.

4) Pregnancy risk: C.

TetracyclinesTop

Agents discussed include the first-generation drug tetracycline (oral); second-generation tetracyclines doxycycline (oral, IV) and minocycline (oral, IV); and third-generation tetracycline tigecycline (IV).

1) Mechanism of action: These agents bind to the 30S ribosomal subunit of bacteria and inhibit protein synthesis. Doxycycline is one of the most active tetracyclines and as such is more often used than tetracycline.

2) Spectrum of activity: As for first- and second-generation tetracyclines, these agents have a broad spectrum of activity, including aerobic gram-positive and gram-negative bacteria. They are also active against MRSA. Major uses of these antibiotics, especially doxycycline, are for infections due to atypical bacteria (Chlamydia spp, Ureaplasma spp, Chlamydophila spp, M pneumoniae, L pneumophila), spirochetes (Leptospira spp, Borrelia spp, Treponema spp), and Rickettsia and Plasmodium species.

Third-generation tetracyclines have a narrow spectrum of use, as tigecycline is currently Health Canada–approved only for treatment of complicated skin and soft tissue infections and intra-abdominal infections. Tigecycline is often used for treatment of multidrug-resistant bacteria as it shows activity against VRE, MRSA, and ESBL-, AmpC-, and carbapenemase-producing bacteria. Resistance to tigecycline is frequently observed in A baumannii, Burkholderia cepacia, M morganii, Providencia spp, Proteus spp, and S maltophilia. Pseudomonas species have inherent resistance to tigecycline.

3) Adverse effects: Contraindicated in children aged <8 years due to deposition in developing teeth and bones. Hypersensitivity reactions. Erosive esophagitis, especially if taken orally at bedtime. Photosensitivity. Risk of intracranial hypertension (eg, pseudotumor cerebri). Increased blood urea nitrogen due to the catabolic effect; therefore, use with caution in patients with renal impairment. Hepatotoxicity more common with tetracycline than with doxycycline.

4) Pregnancy risk: D.

Aminoglycosides Top

Amikacin, gentamicin, tobramycin, streptomycin, spectinomycin (IV, IM, inhaled):

1) Mechanism of action: These agents bind to the 30S ribosomal subunit of bacteria and inhibit protein synthesis.

2) Spectrum of activity: The spectrum of antimicrobial activity of aminoglycosides includes mainly aerobic gram-negative bacteria including ESBL-, AmpC-, and carbapenemase-producing bacteria and P aeruginosa. In severe invasive infections caused by gram-negative bacilli, aminoglycosides are often used in combination with another active antibiotic from a different class, such as beta-lactams. Similarly, among gram-positive bacteria such as staphylococci, streptococci, and enterococci, the use of aminoglycosides must always be part of combination therapy with beta-lactams or glycopeptides.Evidence 1 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Harwick HJ, Kalmanson GM, Guze LB. In vitro activity of ampicillin or vancomycin combined with gentamicin or streptomycin against enterococci. Antimicrob Agents Chemother. 1973 Oct;4(4):383-7. PubMed PMID: 4791300; PubMed Central PMCID: PMC444563. Cooper MD, Keeney RE, Lyons SF, Cheatle EL. Synergistic effects of ampicillin-aminoglycoside combinations on group B streptococci. Antimicrob Agents Chemother. 1979 Mar;15(3):484-6. PubMed PMID: 380461; PubMed Central PMCID: PMC352690. Streptomycin and amikacin demonstrate favorable activity against mycobacteria. Spectinomycin is used predominately for second-line treatment against N gonorrhoeae in patients with cephalosporin allergy. Aminoglycosides are not active against Burkholderia spp, S maltophilia, and anaerobic bacteria.

Among all aminoglycosides, resistance to amikacin is least frequently seen. Tobramycin is most active against P aeruginosa. Gentamicin is most established among aminoglycosides in combination treatment of infections caused by gram-positive bacteria.

3) Adverse reactions: Primary toxicities include nephrotoxicity and ototoxicity (cochlear and vestibular toxicity). Neuromuscular blockade can occur and as such aminoglycosides are contraindicated in patients with myasthenia gravis.

4) Pregnancy risk: D.

RifamycinsTop

1. Rifampin (INN rifampicin), rifapentine, and rifabutin (oral):

1) Mechanism of action: Inhibition of bacterial DNA-dependent RNA polymerase.

2) Spectrum of activity:

a) Rifampin: The most common rifamycin used. The primary use of rifampin is in the prophylaxis or treatment of tuberculous and nontuberculous mycobacteria. It is also the drug of choice for H influenzae type b and Neisseria meningitidis prophylaxis. As treatment, rifampin is given as combination therapy. The ability for rifampin to penetrate biofilms and its activity against staphylococci make it a preferable drug for use in combination therapy for deep-seated staphylococcal infections (endocarditis and prosthetic joints). Monotherapy with rifampin outside of latent tuberculosis and H influenzae type b prophylaxis is not recommended due to the rapid emergence of resistance.

b) Rifabutin: Relative to rifampin, the main advantage of rifabutin is its reduced potential for drug interactions. It is therefore used as a substitute for rifampin in treatment of selected mycobacterial infections in patients receiving medications that exhibit significant interactions with rifampin.

c) Rifapentine: Currently approved for latent tuberculosis treatment only. An advantage of rifapentine is its long half-life, which means it can be given once a week.

3) Adverse reactions: Hypersensitivity reaction. Orange or red discoloration of body fluids. Influenza-like syndrome seen with use of high drug doses and especially with the use of rifapentine and isoniazid. Hematologic effects, such thrombocytopenia, leukopenia, or anemia, with rifabutin having the higher risk. Hepatotoxicity with increased risk in patients with underlying liver disease or with use of concomitant hepatotoxic medications. Significant drug-drug interactions due to CYP3A4 induction.

Rifabutin-specific reactions: Uveitis (rare).

Rifapentine-specific reactions: Hyperuricemia.

4) Pregnancy risk: C.

2. Rifaximin (oral):

1) Spectrum of activity: A nonabsorbable antibiotic that is indicated in the treatment of traveler’s diarrhea (E coli) and hepatic encephalopathy. It may also be used (off-label) in the treatment of C difficile diarrhea in patients not responding to first-line and second-line antimicrobial drugs.

2) Adverse reactions: Hypersensitivity reaction.

3) Pregnancy risk: C.

Other ANTIBACTERIAL Agents Top

1. Sulfamethoxazole/trimethoprim (oral, IV):

1) Mechanism of action: The combination of sulfamethoxazole/trimethoprim inhibits enzyme systems involved in the bacterial synthesis of folic acid.

2) Spectrum of activity: This agent is effective against a wide variety of aerobic gram-positive and gram-negative bacteria. Out of gram-positive bacteria, sulfamethoxazole/trimethoprim is most active against MSSA and MRSA. Its activity against beta-hemolytic streptococci is quite variable. Gram-positive bacilli coverage includes L monocytogenes and Nocardia species. Gram-negative coverage is notable for the Enterobacteriaceae family (E coli, Proteus spp, Klebsiella spp, Salmonella spp, Shigella spp, Y enterocolitica) including both ESBL and AmpC producers, and Burkholderia species. Sulfamethoxazole/trimethoprim is the drug of choice for S maltophilia and P jiroveci. Resistance is seen against P aeruginosa and most anaerobes.

3) Adverse reactions: Hypersensitivity reaction/anaphylaxis. Rash, including increased risk for Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis. Hematologic effects (agranulocytosis, anemia, thrombocytopenia). Renal effects (increased creatinine due to inhibition of tubular secretion, hyperkalemia, interstitial nephritis). Hepatic toxicity.

4) Pregnancy risk: D.

2. Nitrofurantoin (oral):

1) Mechanism of action: Nitrofurantoin shows multiple actions, including inhibition of ribosomal translation, bacterial DNA damage, and interference with the Krebs cycle.

2) Spectrum of activity: Nitrofurantoin is used exclusively in the treatment of lower urinary tract infections. The spectrum of activity includes gram-positive bacteria (predominantly Staphylococcus saprophyticus and enterococci, including VRE) and gram-negative bacilli from the Enterobacteriaceae family (including ESBL and AmpC producers). Nitrofurantoin is not active against P aeruginosa or anaerobes.

3) Adverse reactions: Hypersensitivity reaction, including DRESS syndrome. Contraindicated in patients with renal dysfunction and creatinine clearance <60 mL/min. Due to the risk of hemolytic anemia, use with caution in patients with glucose-6-phosphate dehydrogenase deficiency. Hepatic and pulmonary toxicity with interstitial pneumonitis after prolonged therapy. Neurologic effects, such as peripheral neuropathy and optic neuritis.

4) Pregnancy risk: B. Due to the risk of hemolytic anemia, nitrofurantoin is contraindicated at term (38-42 weeks’ gestation) and in neonates <1 month of age.

3. Fosfomycin (oral, IV):

1) Mechanism of action: Inhibition of cell wall synthesis.

2) Spectrum of activity: The oral formulation of fosfomycin is currently available in Canada. It is approved for treatment of uncomplicated lower tract urinary infections secondary to E coli and E faecalis. Its coverage includes resistant organisms, such as VRE (E faecalis only), and ESBL- and carbapenemase-producing gram-negative bacilli.

3) Adverse reactions: Hypersensitivity reactions.

4) Pregnancy risk: B.

4. Imidazole derivatives: Metronidazole, tinidazole (oral, IV):

1) Mechanism of action: These agents are cytotoxic to anaerobic bacteria.

2) Spectrum of activity: Metronidazole is more commonly used than tinidazole. The primary spectrum of activity includes gram-positive and gram-negative anaerobic bacteria, although they are more active against gram-negative bacteria such as Bacteroides spp and Fusobacterium spp. Among gram-positive anaerobic bacilli, the majority of Actinomyces spp, Propionibacterium spp, and Lactobacillus spp are resistant. Metronidazole is the drug of choice for treatment of nonsevere C difficile diarrhea. These agents are also active against many protozoa (Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica).

3) Adverse reactions: Hypersensitivity reactions. A disulfiram-like reaction when metronidazole is administered systemically to patients drinking ethanol. CNS effects, such as peripheral neuropathy, aseptic meningitis, and optic neuropathy, have been reported with prolonged drug use.

4) Pregnancy risk: B.

5. Fidaxomicin (oral):

1) Mechanism of action: Fidaxomicin inhibits RNA polymerase, resulting in inhibition of protein synthesis and cell death.

2) Spectrum of activity: Currently indicated for treatment of C difficile infections in adults.

3) Adverse reaction: Hypersensitivity reaction. Due to cross-reactivity with macrolides, it should be used with caution in patients with a history of macrolide allergy.

4) Pregnancy risk: B.

6. Mupirocin (topical):

1) Mechanism of action: Mupirocin binds to bacterial RNA synthetase resulting in inhibition of protein synthesis.

2) Spectrum of activity: A topical antibiotic used to eradicate nasal carriage of S aureus including MRSA strains and treat uncomplicated skin infections (eg, impetigo).

3) Adverse reactions: Hypersensitivity reaction.

4) Pregnancy risk: B.

7. Colistin (polymyxin E; IV, inhaled):

1) Mechanism of action: Colistin acts as a detergent and damages the bacterial cell membrane.

2) Spectrum of activity: Colistin has a narrow spectrum of activity and is primarily used for infections with multidrug-resistant bacteria, such as P aeruginosa, Acinetobacter spp, S maltophilia, and carbapenemase-producing E coli and Klebsiella spp. Some aerobic gram-negative bacilli are intrinsically resistant (Serratia spp, Proteus spp, Providencia spp, and Morganella spp). Other resistant organisms include all gram-positive bacteria and most anaerobes.

3) Adverse reactions: The most important adverse effect of colistin is nephrotoxicity resulting in acute tubular necrosis. CNS toxicity with dizziness, paresthesia, slurred speech, and vertigo may occur. Use of inhaled colistin may result in bronchoconstriction.

4) Pregnancy risk: C.

Special ConsiderationsTop

Penicillin Allergy

Penicillin allergy is the most common patient-reported drug allergy, with 5% to 10% of patients identifying themselves as allergic. In large studies it has been found that ~90% of these patients will have negative penicillin allergy skin tests and will tolerate penicillin.

For self-identified penicillin-allergic patients, it is suggested they be referred to an allergist for assessment and diagnosis, ideally when they are not acutely ill. Penicillin skin testing is useful in the prediction of Gell and Coombs type 1 hypersensitivity (IgE-mediated allergy). Typical symptoms of these reactions include hives, angioedema, shortness of breath, and drop in blood pressure. Approximately 1% to 3% of skin test-negative patients will react on subsequent challenge to penicillin and these reactions are typically mild.Evidence 2High Quality of Evidence (high confidence that we know true effects of the intervention). Sogn DD, Evans R 3rd, Shepherd GM, et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med. 1992 May;152(5):1025-32. PubMed PMID: 1580706. Macy E, Mangat R, Burchette RJ. Penicillin skin testing in advance of need: multiyear follow-up in 568 test result-negative subjects exposed to oral penicillins. J Allergy Clin Immunol. 2003 May;111(5):1111-5. PubMed PMID: 12743578. There is no utility of skin testing in predicting type 4 (cell-mediated) drug reactions. Red flags for these types of reactions include joint pain, fever, and desquamating or bullous rash. Penicillin should be avoided in the future if the patient has a history of these symptoms.

Penicillins and cephalosporins share a common beta-lactam ring, which often leads to avoidance of cephalosporins in penicillin-allergic patients. Data suggest that R-group chains are more important in predicting cross-reactivity of these drugs that the beta-lactam ring itself.

Clear estimates of cross reactivity are limited by lack of high-quality controlled studies and by the fact that cephalosporins manufactured before 1980 are known to have been contaminated with penicillin. In a group of studies including only patients with confirmed penicillin allergy, on skin testing the reaction rate to cephalosporins was ~3.4%; this falls to 2% if studies published before 1980 are excluded. It must be remembered that cephalosporin allergy can occur independently of penicillin allergy.

Use of cephalosporin in patients with confirmed or reported allergy to penicillin may depend on the available choices and severity of reaction and should consider the above probability.

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