antibacterial agents

1. ANTIBACTERIAL AGENTS
kelvin

2. Introduction
• The ability to direct therapy specifically at a disease-causing
infectious agent is unique to the management of infectious
diseases.
• Its initial success depends on exploiting differences between
our own makeup and metabolism and that of the
microorganism in question.
• The mode of action of antimicrobials on bacteria and viruses
is the focus of this chapter.
• The continued success of antibacterial and antiviral agents
depends on whether the organisms to which the agent was
originally directed develop resistance.

3. GENERAL CONSIDERATIONS
• Clinically effective antimicrobial agents all exhibit selective
toxicity toward the parasite rather than the host, a
characteristic that differentiates them from the disinfectants
• In most cases, selective toxicity is explained by action on
microbial processes or structures that differ from those of
mammalian cells.
• For example, some agents act on bacterial cell wall
synthesis, and others on functions of the 70 S bacterial
ribosome but not the 80 S eukaryotic ribosome.

4. Definitions
•Antibiotic—antimicrobials of microbial origin, most of which
are produced by fungi or by bacteria of the genus
Streptomyces.
•Antimicrobial—any substance with sufficient antimicrobial
activity that it can be used in the treatment of infectious
diseases.
•Bactericidal—an antimicrobial that not only inhibits growth
but is lethal to bacteria.
•Bacteriostatic—an antimicrobial that inhibits growth but
does not kill the organisms

5. Definitions
• Chemotherapeutic—a broad term that encompasses
antibiotics, antimicrobials, and drugs used in the treatment
of cancer.
• In the context of infectious diseases, it implies the agent is not an
antibiotic.
•Minimal inhibitory concentration (MIC)—a laboratory term
that defines the lowest concentration ( g/mL) able to inhibit
growth of the microorganism.
•Resistant—organisms that are not inhibited by clinically
achievable concentrations of a antimicrobial agent

6. Definitions
• Sensitive—term applied to microorganisms indicating that
they will be inhibited by concentrations of the antimicrobic
that can be achieved clinically.
• Spectrum—an expression of the categories of
microorganisms against which an antimicrobial is typically
active
• A narrow-spectrum agent has activity against only a few organisms.
• A broad-spectrum agent has activity against organisms of diverse
types (eg, Gram-positive and Gram-negative bacteria).
• Susceptible—term applied to microorganisms indicating
that they will be inhibited by concentrations of the
antimicrobic that can be achieved clinically.

7. General considerations
• Some antimicrobial agents, such as penicillin, are
essentially nontoxic to the host, unless hypersensitivity has
developed.
• For others, such as the aminoglycosides, the effective
therapeutic dose is relatively close to the toxic dose; as a
result, control of dosage and blood level must be much more
precise
• Ideally, selective toxicity is based on the ability of an
antimicrobial agent to attack a target present in bacteria but
not humans

8. Sources of Antimicrobial Agents
• Antibiotics are synthesized by molds or bacteria
• Production in quantity is by industrial fermentation
• Chemicals with antibacterial activity are discovered by chance
or as the result of screening programs
• Naturally occurring antimicrobics can be chemically modified

9. Spectrum of Action
• Spectrum is the range of bacteria against which the agent is
typically active
• Some antibacterial antimicrobics are known as narrow-
spectrum agents; for example, benzyl penicillin is highly
active against many Gram-positive and Gram-negative cocci
but has little activity against enteric Gram-negative bacilli
• Broad-spectrum agents inhibit both Gram-positive and Gram
negative species

10. Selected antibacterial antimicrobials
• Antimicrobics That Act on Cell Wall Synthesis
• Cross-linking of peptidoglycan is the target of β-lactams and
glycopeptides

11. β-Lactam Antimicrobials
• The β -lactam antimicrobics comprise the penicillins,
cephalosporins, carbapenems and monobactams.
• A β-lactam ring is part of the structure of all β -lactam
antimicrobics
• Their name derives from the presence of a β -lactam ring in their
structure; this ring is essential for antibacterial activity.
• Penicillin, the first member of this class, was derived from molds
of the genus Penicillium, and later natural β -lactams were
derived from both molds and bacteria of the genus
Streptomyces.

12. β-Lactam Antimicrobials
• It is possible to synthesize β -lactams, but most are derived
from semisynthetic processes involving the chemical
modification of the products of fermentation
• Interfere with peptidoglycan cross-linking by binding to
transpeptidases called PBPs
• Penicillins, cephalosporins, monobactams, and
carbapenems differ in terms of the structures fused to the β-
Lactam ring
• β -Lactam antimicrobics kill growing bacteria killed by lysing
weakened cell walls

13. β-Lactam Antimicrobics
• Penicillins
• Penicillins differ primarily in their spectrum of activity against
Gram negative bacteria and resistance to staphylococcal
penicillinase.
• This penicillinase is one of a family of bacterial enzymes
called β -lactamases that inactivate β -lactam antimicrobics
• Penicillin G is active primarily against Gram-positive
organisms, Gram-negative cocci, and some spirochetes,
including the spirochete of syphilis.

14. β-Lactam Antimicrobics
• Penicillins
• Penicillin G is the least toxic and least expensive of all the
penicillins. Its modification as penicillin V confers acid stability, so it
can be given orally.
• Resistance to staphylococcal and Gram-negative -
lactamases determines spectrum
• Penetration of outer membrane is often limited

15. β-Lactam Antimicrobics
• The penicillinase-resistant penicillins (methicillin, nafcillin,
oxacillin) also have narrow spectra, but are active against
penicillinase-producing S. aureus
• The broader spectrum penicillins owe their expanded activity
to the ability to traverse the outer membrane of some Gram-
negative bacteria.
• Some, such as ampicillin, have excellent activity against a
range of Gram-negative pathogens but not P. aeruginosa,
an important opportunistic pathogen.
• Broad-spectrum penicillins penetrate the outer membrane of
some Gram-negative bacteria

16. β-Lactam Antimicrobics
• Others, such as carbenicillin and ticarcillin, are active
against Pseudomonas when given in high dosage but are
less active than ampicillin against some other Gram-
negative organisms.
• The penicillins with a Gram-negative spectrum are slightly
less active than penicillin G against Gram-positive
organisms and are inactivated by staphylococcal
penicillinase.
• Some penicillins are inactivated by staphylococcal
penicillinase

17. β-Lactam Antimicrobics
• Cephalosporins
• Some penicillins are inactivated by staphylococcal
penicillinase
• Cephalosporins are penicillinase resistant
• Shifting between first- and third generation cephalosporins
gives a wider Gram-negative spectrum
• Second- and third-generation cephalosporins have less
activity against Gram-positive bacteria

18. β-Lactam Antimicrobics
• Cephalosporins
• First-generation cephalosporins inhibit Gram-positive bacteria
and a few Enterobacteriaceae
• cefazolin and cephalexin Second-generation
cephalosporins are also active against anaerobes
• cefoxitin and cefaclor
• Second generation-cephalosporins are also active against
anaerobes
• Third-generation cephalosporins have increasing potency
against Gram-negative organisms
• ceftriaxone, cefotaxime, and ceftazidime
• Ceftriaxone and cefotaxime are preferred for meningitis
• Ceftazidime is used for Pseudomonas

19. β-Lactam Antimicrobics
• Fourth-generation cephalosporins have enhanced ability to
penetrate outer membrane of Gram negative bacteria and
resistance to many Gram-negative β-Lactamases.
• Cefepime (example)
• They have activity against an even wider spectrum of
Enterobacteriaceae as well as P. aeruginosa.
• These cephalosporins retain the high affinity of third generation drugs
and activity against Neisseria and H. influenzae.

20. β-Lactam Antimicrobics
• Carbapenems
• The carbapenems (imipenem & meropenem) have the
broadest spectrum of all β-lactam antibiotics.
• This fact appears to be due to the combination of easy
• penetration of Gram-negative and Gram-positive bacterial
cells and high level of resistance to β-Lactamases
• Carbapenems are very broad spectrum
• Monobactams (Aztreonam)
• Activity is primarily against Gram-negatives

21. β-Lactam Antimicrobics
• β-Lactamase Inhibitors
• β -lactamase inhibitors are β -lactams that bind β –
lactamases and inhibit their activity
• Other β -lactams are enhanced in the presence of β -
lactamase inhibitors

22. Glycopeptide Antimicrobics
• The agents include vancomycin and teicoplanin.
• Each of these antimicrobics inhibit assembly of the linear
peptidoglycan molecule by binding directly to the terminal
amino acids of the peptide side chains.
• The effect is the same as with β -lactams, prevention of
peptidoglycan cross-linking.
• Both agents are bactericidal, but are primarily active only
against Gram-positive bacteria.

23. Glycopeptide Antimicrobics
• Their main use has been against multiresistant Gram-positive
infections including those caused by strains of staphylococci
that are resistant to the penicillinase-resistant penicillins and
cephalosporins.
• Neither agent is absorbed by mouth, although both have been
used orally to treat Clostridium difficile infections of the bowel
• Glycopeptide antimicrobics bind directly to amino acid side
chains

24. Aminoglycosides
• Aminoglycosides are bactericidal
• These include: Streptomycin, gentamicin, tobramycin, amikacin and
neomycin
• Aminoglycosides must be transported into cell by oxidative
metabolism
• Not active against anaerobes
• Ribosome binding disrupts initiation complexes
• binding destabilizes the ribosomes, blocks initiation complexes, and
thus prevents elongation of polypeptide chains.
• distortion of the site of attachment of mRNA, mistranslation of codons,
and failure to produce the correct amino acid sequence in proteins.

25. Aminoglycosides
• Streptomycin binds to the 30S ribosomal subunit but newer
and more active aminoglycosides bind to multiple sites on
both 30S and 50S subunits.
• No entry into human cells
• Spectrum includes P. aeruginosa
• Broad spectrum and slow development of resistance
enhance their use and often combined with β-lactam
antimicrobics
• Renal and vestibular toxicity must be monitored

26. Tetracyclines
• Tetracyclines include tetracycline, minocycline and doxycycline.
• The tetracyclines inhibit protein synthesis by binding to the 30S
ribosomal subunit at a point that blocks attachment of aminoacyl-
tRNA to the acceptor site on the mRNA ribosome complex
• Block tRNA attachment
• Activity is bacteriostatic
• Broad spectrum includes some intracellular bacteria
• Chlamydia, rickettsia and mycoplasma
• Orally absorbed but chelated by some foods
• Dental staining limits use in children

27. Chloramphenicol
• It influences protein synthesis by binding to the 50S
ribosomal subunit and blocking the action of peptidyl
transferase, which prevents formation of the peptide bond
essential for extension of the peptide chain.
• Chloramphenicol blocks peptidyl transferase
• Its action is bacteriostatic.
• It has little effect on eukaryotic ribosomes, which explains its
selective toxicity.
• Diffusion into body fluid compartments occurs readily
• Marrow suppression and aplastic anemia are serious
toxicities and thus use is sharply restricted

28. Macrolides
• The macrolides include erythromycin, azithromycin, and
clarithromycin
• They affect protein synthesis at the ribosomal level by
binding to the 50S subunit and blocking the translocation
reaction.
• Ribosomal binding blocks translocation
• Their effect is primarily bacteriostatic.
• Macrolides, which are concentrated in phagocytes and other
cells, are effective against some intracellular pathogens
• Erythromycin is active against Gram-positives

29. Macrolides
• The Gram-negative spectrum includes Neisseria, Bordetella,
Campylobacter, and Legionella, but not the
Enterobacteriaceae.
• Erythromycin is also effective against Chlamydia and
Mycoplasma
• Azithromycin and clarithromycin have enhanced Gram-
negative spectrum
• Borrelia burgdorferi (Lyme disease) and Toxoplasma gondii

30. Clindamycin & Oxazolidinones
• Clindamycin
• Spectrum is similar to macrolides with addition of anaerobes
• Oxazolidinones (Linezolid)
• Activity against Gram-positive bacteria resistant to other agents

31. Streptogramins
• Quinupristin and dalfopristin are used in a fixed combination
known as quinupristin-dalfopristin in a synergistic ratio.
• They inhibit protein synthesis by binding to different sites on
the 50S bacterial ribosome
• quinupristin inhibits peptide chain elongation
• dalfopristin interferes with peptidyl transferase.
• Their clinical use has been limited to treatment of
vancomycin-resistant enterococci.

32. Inhibitors of Nucleic Acid Synthesis
• Quinolones
• The quinolones have a nucleus of two fused six-member
rings that when substituted with fluorine become
fluoroquinolones, which are now the dominant quinolones
for treatment of bacterial infections.
• Fuoroquinolones include ciprofloxacin, norfloxacin and
ofloxacin, the addition of a piperazine ring and its
methylation alter the activity and pharmacologic properties
of the individual compound.
• The primary target of all quinolones is DNA topoisomerase
(gyrase)

33. Inhibitors of Nucleic Acid Synthesis -
Quinolones
• This enzyme is responsible for nicking, supercoiling, and
sealing bacterial DNA during replication.
• Inhibition of topoisomerase blocks supercoiling
• They are bactericidal
• The enhanced activity and lower frequency of resistance
seen with the fluoroquinolones is attributed to binding at
multiple sites on the enzyme.
• Fluoroquinolones have a broad spectrum, including
Pseudomonas
• Well distributed after oral administration

34. Inhibitors of Nucleic Acid Synthesis Folate -
Inhibitors
• Agents that interfere with synthesis of folic acid by bacteria
have selective toxicity because mammalian cells are unable
to accomplish this feat and use preformed folate from
dietary sources
• Bacteria must synthesize folate that humans acquire in their diet
• Sulfonamides
• Sulfonamides are structural analogs of PABA and compete
with it for the enzyme (dihydropteroate synthetase) that
combines PABA and pteridine in the initial stage of folate
synthesis.
• This blockage has multiple effects on the bacterial cells; the
most important of these is disruption of nucleic acid
synthesis.

35. Inhibitors of Nucleic Acid Synthesis - Folate
Inhibitors
• Competition with PABA disrupts nucleic acids
• The effect is bacteriostatic, and the addition of PABA to a
medium that contains sulfonamide neutralizes the inhibitory
effect and allows growth to resume.
• Major use is urinary tract infections
• Trimethoprim-Sulfamethoxazole
• Trimethoprim acts on the folate synthesis pathway but at a
point after sulfonamides
• It competitively inhibits the activity of bacterial dihydrofolate
reductase, which catalyzes the conversion of folate to its
reduced active coenzyme form.

36. Inhibitors of Nucleic Acid Synthesis - Folate
Inhibitors
• Trimethoprim-Sulfamethoxazole
• When combined with sulfamethoxazole, a sulfonamide,
trimethoprim leads to a two-stage blockade of the folate
pathway, which often results in synergistic bacteriostatic or
bactericidal effects.
• This quality is exploited in therapeutic preparations that combine both
agents in a fixed proportion designed to yield optimum synergy.
• Dihydrofolate reductase inhibition is synergistic with
sulfonamides
• Activity against common bacteria and some fungi

37. Inhibitors of Nucleic Acid Synthesis -
Metronidazole
• Active against bacteria, fungi, and parasites
• The antibacterial action requires reduction of the nitro group
under anaerobic conditions
• The reduction products act on the cell at multiple points
• The most lethal of these effects is induction of breaks in DNA strands.
• Metronidazole is active against a wide range of anaerobes,
including Bacteroides fragilis

38. Inhibitors of Nucleic Acid Synthesis -
Metronidazole
• Clinically, it is useful for any infection in which anaerobes
may be involved.
• Because these infections are typically polymicrobial, a
second antimicrobial (eg, β -lactam) is usually added to
cover aerobic and facultative bacteria.

39. Inhibitors of Nucleic Acid Synthesis -
Rifampin
• Blocking of RNA synthesis occurs by binding to polymerase
• Rifampin binds to the β -subunit of DNA-dependent RNA
polymerase, which prevents the initiation of RNA synthesis.
• This agent is active against most Gram-positive bacteria and
selected Gram-negative organisms, including Neisseria and
Haemophilus
• Not active against members of the Enterobacteriaceae

40. Inhibitors of Nucleic Acid Synthesis -
Rifampin
• The most clinically useful property of rifampin is its
antimycobacterial activity, which includes Mycobacterium
tuberculosis and the other species that most commonly
infect humans.
•
• Resistance by mutation of the polymerase readily occurs

41. Antimicrobics Acting on the Outer &
Cytoplasmic Membranes
• The polypeptide antimicrobics polymyxin B and colistin
have a cationic detergent-like effect.
• They bind to the cell membranes of susceptible Gram-
negative bacteria and alter their permeability, resulting in
loss of essential cytoplasmic components and bacterial
death.
• These agents react to a lesser extent with cell membranes
of the host, resulting in nephrotoxicity and neurotoxicity.

42. Antimicrobics Acting on the Outer & Cytoplasmic
Membranes
• Their spectrum is essentially Gram-negative; they act
against P. aeruginosa and other Gram-negative rods.
• Although these antimicrobics were used for systemic
treatment in the past, their use is now limited to topical
applications.
• They have an advantage; resistance to them rarely
develops.

43. END