1=Chemotheraphy Pharmacy

CHEMOTHERAP
Y
General Principles of
Antimicrobial Therapy
07/13/2024 1
Topics to be discussed
1: Introduction to antimicrobial drugs

2: Antibacterial drugs
3: Antifungal drugs
4: Antiviral drugs
5: Clinical use of antimicrobial agents
6: Antiprotozoals drugs
7: Antihelminthic drugs
8: Anticancer drugs
2
2
1: Introduction
to Antimicrobial Drugs
3
Learning Objectives
By the end of this chapter you should be able to:

Define terms related to antimicrobial drugs
Explain about selective toxicity
Classify antimicrobial drugs based on there MOA
Describe the time dependent & conc dependent PD of antibiotics
Discuss about mechanisms by which microbes develop resistance
to antimicrobial drugs
4 4
Outline
Definitions
Selective toxicity
Major targets of antimicrobial agents
Antimicrobial pharmacodynamics
Super-infections
Antimicrobial resistance
5 5
• Definitions
Antibiotic agents:
Chemicals that are produced by one microbe & have the ability to harm other microbes
Antimicrobial agents:
Any agent, natural or synthetic, that has the ability to kill or suppress microorganisms
Chemotherapeutic agents:
· Any agent, natural or synthetic, that has the ability to kill
or suppress microorganisms or cancer cells
6 6
• Selective toxicity
Selective toxicity: it means that a chemical produces injury

to one kind of living matter without harming another form of
life even though the two may exist in intimate contact
They may be related to each other as parasite & host or may
be two tissues in one organism
By taking advantage of the biological diversity, it is possible
to develop chemicals that are lethal for an undesired species
& harmless for other species
7 7
Selective toxicity …
Drugs & other chemicals used for selective toxic purposes are
selective for one of 2 reasons
The chemical is equally toxic to both forms (desired & undesired) but is
accumulated mainly by undesired cells
The chemical reacts fairly specifically with a cytological or a biochemical feature

that is absent from or does not play an important role in the desired form
8 8
Antimicrobial therapy takes advantage of the biochemical

differences that exist b/n MOs & human beings
Example:
The fact that bacteria contain cell walls & humans do not has been utilized in
developing selective toxic antibiotics, such as penicillin & cephalosporins, that
kill bacteria but are relatively nontoxic to mammalian cells
9 9
In most instances, the selective toxicity is relative rather

than absolute, requiring that the conc of the drug be
carefully controlled to attack the microorganism while still
being tolerated by the host
10 10
Major targets of antimicrobial agents
Different antibiotics have different modes of action, owing

to the nature of their structure & degree of affinity to
certain target sites within bacterial cells
Inhibitors of cell wall synthesis
A drug that targets cell walls can selectively kill or inhibit
bacterial organisms
Examples: penicllins, cephalosporins, bacitracin &
vancomycin
11 11
Major targets of antimicrobial agents…
· Inhibitors of cell membrane function

B/c this structure is found in both eukaryotic & prokaryotic cells, the action of
this class of antibiotic are often poorly selective & can often be toxic for
systemic use in the mammalian host
Most clinical usage is therefore limited to topical applications
Examples: polymixin B & colistin
12 12
· Inhibitors of protein synthesis

Several types of antibacterial agents target bacterial protein synthesis by
binding to either the 30S or 50S subunits of the ribosomes
Examples: Aminoglycosides, macrolides, lincosamides, streptogramins,

chloramphenicol, tetracyclines
13 13
· Inhibitors of nucleic acid synthesis

Some antibiotics work by binding to components involved in the process of
DNA or RNA synthesis, which causes interference of the normal cellular
processes which will ultimately compromise bacterial multiplication &
survival
Examples: quinolones, metronidazole, & rifampin
14 14
· Inhibitors of other metabolic processes

Other antibiotics act on selected cellular processes essential for the survival
of the bacterial pathogens
Example: Both sulfonamides & trimethoprim disrupt the folic acid pathway,
which is a necessary step for bacteria to produce precursors important for
DNA synthesis
15 15
Anti bacterials pharmacodynamics
Bacteriostatic Vs Bactericidal activity

Bacteriostatic agents:
Act primarily by arresting bacterial multiplication

Inhibitory drug conc are much lower than bactericidal drug conc
Bactericidal agents:
Those that act primarily by killing bacteria
NB: Bacteriostatic & bactericidal agents are equivalent for the

Tx of most infectious diseases in immunocompetent hosts
16 16
Cont…..
• Bactericidal drugs act most effectively on rapidly dividing
organisms.
• Thus a bacteriostatic drug, by reducing multiplication, may
protect the organism from the killing effect of a bactericidal
drug.
• Bacteriostatic and cidal drug not given jointly
17
Bacteriostatic vs. Bactericidal Examples
•Bacteriostatic • Bactericidal
Chloramphenicol Pencillins & Cephalosporins
Clindamycin Isoniazid, Metronidazole, Polymyxins
Macrolides Rifampin, Vancomycin,
Sulfonamides Aminoglycosides
Tetracyclines Bacitracin, Quinolones
Trimethoprim
Minimal inhibitory concentration (MIC):

is the Lowest concentration of antimicrobial drug capable of
inhibiting growth of an organism in a defined growth medium.
18 18
Antimicrobial Pharmacodynamics…
Conc-dependent vs. Time-dependent killing
· Bactericidal drugs can be divided into 2 groups:
Conc-dependent killing:
E.g. aminoglycosides, fluoroquinolones
Show a significant ↑ in the rate of bacterial killing as the
concentration of antibiotic increases from 4-64 fold the
MIC of the drug for the infecting organism
These drugs exhibit a ”post-antibiotic effect” (PAE):
persistent suppression of bacterial growth after limited
19 19
Conc- dependent killing (Cont…)

Proposed MZMs for the PAE include:
Slow recovery of bacteria after non-lethal damage to cell structures
Persistence of the antibiotic at its binding site or within the periplasmic space
A need for bacteria to synthesize new proteins before growth can continue
Giving drugs that exhibit this conc-dependent killing by a once-a-day bolus
infusion achieves high peak levels, favoring rapid killing of the infecting pathogen
20 20
· Time-dependent killing:
E.g. β-lactams & vancomycin
Bactericidal activity continues as long as the plasma conc is ˃ the MBC
Efficacy for these antibiotics is maximized by the percentage of time that
blood conc of a drug remain above the MIC
21 21
• Super-infections
Antibacterial drugs are designed to kill bacteria, but no drug

kills all bacteria
Killing of normal flora removes the inhibitory effect of the
normal flora
Which produce antibacterial substances & compete for essential
nutrients
This allows for uninhibited growth of potentially pathogenic
bacteria & fungi
22 22
Super-infections…
The more broad-spectrum the antibiotic & the more

prolonged the therapy, the greater is the change in the
normal micro-flora, & the greater the chance that a single
drug-resistant microorganism will proliferate & cause
infection
The most specific & narrow spectrum antimicrobial
drug should be selected to treat infections whenever
possible
23 23
Super-infections…
Common organisms in superinfection include:

C. difficile
MDR G-(-) rods
MRSA
Candida or other fungi
24 24
Drug Resistance
 Is un responsiveness of microorganism against to antimicrobial
agent.
• It is the major problem threatening the continued success of
antimicrobial drugs
• Overuse & inappropriate use of antibiotics in pts has fueled a
major ↑ in prevalence of MDR pathogens
 Mechanism by which resistance is acquired
 Mutation, Decreased drug entry. e.g TTC
 Biochemical alteration leading to antimicrobial resistance
include:
 Destruction of the drug by the organism e.g, B-lactamase
inactivate penicillin.
 Development of altered drug receptor. E.g
Aminoglycosides, penicillin, erythromycin
 Dev’t of alternate metabolic pathway, e.g sulphonamide
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Delaying the Emergency of resistance
1. Antimicrobial should only employed when actually required.

2. Narrow spectrum agents should be employed whenever
possible.
3. Newer antibiotics should be reserved.
 Selection of Anti microbial agent;
 The identity of infecting organism
 Drug sensitivity of infecting organism
 Host factor( site of the infection, immunity of the host , age
sex, pregnancy, organ function)
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 Antibiotics have three general uses
 Empirical (initial) therapy
Antibiotic should cover all the likely pathogens
Either combination therapy or a single broad-
spectrum agent
 Definitive therapy
Once the infecting microorganism is identified, a
narrow-spectrum, low-toxicity agent is instituted
 Prophylactic or preventive therapy
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Factors that affect selection of antibiotics
 Microbial sensitivity
 Local Factors
 Pharmacokinetic factors
 Age
 Route of Administration
 Pregnancy
 Host Defence Mechanisms  Drug allergy
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Combining Antimicrobial Agents
 Recommended in specifically defined situations based on

pharmacological rationale.
 Selection of an appropriate combination
 Understanding of the potential for interaction between
the antimicrobial agents.
 Interactions may affect either the microorganism or the
patient.
 May enhance or impair overall antimicrobial activity.
 May have additive or super additive toxicities.
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 Indications for the Clinical Use of Combinations of
Antimicrobial Agents
 For empirical therapy of an infection in which the cause is
unknown.
 For treatment of polymicrobial infections
 To enhance antimicrobial activity (i.e. synergism) for a
specific infection
 To prevent emergence of resistance.
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Disadvantages of Combinations of Antimicrobial Agents
 Increased risk of toxicity from two or more agents

 Selection of multiple-drug-resistant microorganisms
 Eradication of normal host flora with subsequent super
infection
 Increased cost to the patient.
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Misuses of Antibiotics
 Treatment of nonresponsive infections

 Therapy of fever of unknown origin
 Improper Dosage
 Inappropriate reliance on chemotherapy alone
 Lack of adequate bacteriological information
 Post antibiotic effect(PAE): is persistent suppression of
bacterial growth after limited exposure to an antimicrobial
agent . Such agent w/c exhibit long PAE require only one
dose/day e.g Aminoglycosides & floroquinolone against G-ve
bacteria.
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Monitoring antimicrobial therapy
• Antimicrobial therapy is assessed by monitoring

clinical responses and laboratory results
– The frequency of monitoring is directly
proportional to the severity of infection
– Important clinical indicators of success are
reduction of fever and resolution of signs &
symptoms related to the affected organ system
– Various laboratory tests are used to monitor
treatment
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Cont….
• Pathogenic microorganisms include bacteria, fungi,
viruses, protozoa and helminths (worms).
Common pathogenic Gram-positive bacteria include
• Actinomyces, Clostridium,
• corynebacterium, Enterococcus,
• Lactobacillus, Listeria,
• Mycobacterium, Nocardia,
• Staphylococcus epidermidis,
• Staphyloccocus aureus,
• Streptococcus pneumonia,
• streptococcus pyogens
Common Gram-negative Bacteria include
• Escherichia coli, • Haemophilus influenzae
• Pseudomonas aeruginosa, • Helicobacter pylori(H.Pylori),
• Neisseria gonorrhoeae, • Treponema pallidum,
• Chlamydia trachomatis, • Neisseria meningitidis,
• Salmonella typhi, • Klebsiella pneumoniae,
• Enteritis Salmonella, • Legionella pneumophila,
• Enterobacteriaceae, • Vibrio cholerae.
• Moraxella catarrhalis,
• Antimicrobial agents may be classified
according to the type of organism against which
they are active
- Antibacterial drugs
- Antiviral drugs
- Antifungal drugs
- Antiprotozoal drugs
- Anthelminthic drugs
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2: Antibacterial Drugs
37
Learning Objectives
By the end of this chapter you should be able to demonstrate an

understanding of antibacterial agents with respect to:
Drug classes & the specific mechanisms
Major PK characteristics of each drug class
Primary adverse effects of each drug class
Unique characteristics of individual agents
Similarities & differences in the spectrum of activity of the drug classes
Mechanisms of bacterial resistance to each drug classes
Major C/Is & indication of each class of antibacterial drugs
38
38
Outline
Beta-lactam & other cell wall- & membrane- active

antibiotics
Protein Synthesis Inhibitors
Nucleic acid synthesis inhibitors
Antimycobacterial agents
Misc Antimicrobials
39
39
Beta-lactam & Other Cell wall- & Membrane-
active antibiotics
Outline
β-Lactam antibiotics
Penicillins, Cephalosporins, Carbapenems, Monobactams, β-lactamase inhibitors
Glycopeptide antibiotics
Vancomycin, Teicoplanin, Telavancin, Dalbavancin
Other cell wall or Mn active agents

Cycloserine, Bacitracin, Fosfomycin, Daptomycin
40
Drugs targeting Peptidoglycan synthesis
• Peptidoglycan synthesis
40
– Precursor formation in the cytoplasm
– Transport across the lipid Mn
– Assembly at the growing point
• Transglycosylation reaction
• Transpeptidation reaction
Introductory Case study
A 55-year-old man is brought to the local hospital emergency

department by ambulance. His wife reports that he had been in
his normal state of health until 3 days ago when he developed a
fever & a productive cough. During the last 24 hrs he has
complained of a headache & is increasingly confused. His wife
reports that his medical history is significant only for HTN, for
which he takes HCT & lisinopril, & that he is allergic to
amoxicillin. She says that he developed a rash many years ago
when prescribed amoxicillin for bronchitis. 41
41
Introductory Case study…
In the emergency department, the man is febrile (38.7°C

[101.7°F]), hypotensive (90/54 mm Hg), tachypneic (36/min), &
tachycardic (110/min). He has no signs of meningismus but is
oriented only to person. A stat chest x-ray shows a left lower lung
consolidation consistent with pneumonia. The plan is to start
empiric antibiotics & perform a lumbar puncture to rule out
bacterial meningitis. What antibiotic regimen should be started to
treat both pneumonia & meningitis? Does the history of
amoxicillin rash affect the antibiotic choice? Why or why not? 42
42
Inhibitors of Cell
wall synthesis
Beta –Lactam Other

Antibiotics Antibiotics
Penicillin Vancomycin
** Natural penicillin Cephalosporin
** Penicillinase-resistant ** 1st Generation
penicillins
**Aminopenicillins ** 2nd Generation
** Extended-spectrum ** 3rd Generation
penicillins ** 4th Generation
07/13/2024 43
β-Lactam antibiotics…
Mechanism of action
β-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating enzymes
located in the bacterial cell Mn, which are involved in the 3rd stage of cell wall synthesis
It is during this stage that linear strands of peptidoglycan are

cross-linked into a fishnet-like polymer that surrounds the
bacterial cell & confers osmotic stability
They are generally bactericidal against organisms that they inhibit
44
44
MZMs of bacterial resistance

↓ed penetration to the target site
Alteration of the target site
Inactivation of the antibiotic by a bacterial enzyme
45
45
Adverse effects
A number of ADRs have been described: Table: Gell and Coombs classification of immunologic reactions
IgE-mediated allergic reactions

Serum sickness SJS/TEN: Stevens-Johnson syndrome/ Toxic epidermal necrolysis
Dermatologic reactions
Neurologic reactions
Pulmonary reactions
GI reactions
Hepatobiliary reactions
Renal reactions
Hematologic reactions
46
46
Beta –Lactam Antibiotics
Penicillin
 The basic structure of the penicillins consists
 A thiazolidine ring (A) connected to
 A -lactam ring (B) to which is attached a side chain (R)
07/13/2024 47
Structural & Activity relation
1. The Beta lactam ring is essential for antibacterial Action.

2. Properties of individual penicillin are determined by
addition made to the basic nucleus.
 These modification determine:
 Affinity for plasma bound protein (PBP)
 Resistance to penicillinase
 Ability to penetrate the G-ve cell envelop
 Resistance to stomach acid &
 Pharmacokinetics properties of drug
MOA: inhibition of last step of bacterial cell wall synthesis,
inhibition of transpeptidase.
07/13/2024 48
Mechanism of Action
• Two major components are required for β-lactam activity:
– The first is the binding to penicillin-binding proteins(PBP).
– The second is the destruction of the bacterial cell wall.
• All β-lactams (penicillins, carbapenems, and cephalosporins) act

through this common sequence of events.
• Binding: Virtually all bacteria contain PBP but .
• D/t bacteria have different amounts and different types of

penicillin-binding proteins. For example, E. coli has seven types,
and Staph. aureus has four.
• Different PBP have different affinities for β-lactams, and therefore
07/13/2024 49
different bacteria will demonstrate different sensitivities to β-lactams.
Mechanism of Action
• inhibit bacterial growth by interfering with the transpeptidation
reaction of bacterial cell wall synthesis.
• The cell wall is a rigid outer layer that completely surrounds the
cytoplasmic membrane maintains cell shape and integrity, and
prevents cell lysis from high osmotic pressure.
• The cell wall is composed of a complex, cross-linked polymer of
polysaccharides and polypeptides, peptidoglycan
07/13/2024 50
Cont…..
• Transpeptidases are enzymes that cross-link peptidoglycan

molecules in bacterial cell walls. Cross-linking these molecules
gives strength to the cell wall.
• β-Lactams work by inhibiting transpeptidase, preventing it from
forming cross-links.
– This results in a bacterium with a structurally deficient cell wall,
typically leading to bacterial lysis
• Gram-positive bacteria have a thick peptidoglycan layer.
– They are therefore sensitive to β-lactams.
• Gram-negative bacteria have a thinner peptidoglycan layer, but

external to this layer is a lipopolysaccharide layer.
07/13/2024 51
Cont..
• This lipopolysaccharide layer protects the peptidoglycan layer

from β-lactam activity, and therefore gram-negative bacteria are
significantly more resistant to β-lactams
• It is penetrated by porins, proteins that form channels providing
hydrophilic access to the cytoplasmic membrane.
• Penicillin-binding proteins (PBPs) are membrane proteins that
cross-link peptidoglycan.
• Beta lactamases, if present, reside in the periplasmic space or on
the outer surface of the cytoplasmic membrane, where they may
destroy β-lactam antibiotics that penetrate the outer membrane52
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Fig. cell envelope of a gram-negative bacterium 54
Classification of PCNs
PCNs can be classified into the following categories:

Prototypes PCNs & Repository PCNs
Anti-Staphylococcal PCNs:
Extended-spectrum PCNs
Antipseudomonal PCNs
55
55
Antimicrobial
Penicillin Class Drug Spectrum
•
Natural penicillin Penicillin G, Pen V G+ve cocci & bacilli,
They are prototype some G-ve
cocci(neisseria)
Penicillinase Naficillin, Staphylococcus
resistant(narrow Cloxacillin, Aureus
spectrum) Dicloxacillin,
Anti-Staphylococcus Oxacillin
Broad Amoxacilline, Same as Pen G &
spectrum(Amino Ampicillin some G-ve Organism
penicillin) Bacampicillin
Extended Carbencillin Same as broad
spectrum(antipseudo piperacillin spectrum & some
monal) coverage's to
pseudomonas
organism
07/13/2024 56
Mechanism of bacterial resistance
• Resistance to penicillins and other β-lactams is due to one of

four general mechanisms:
(1) inactivation of antibiotic by β-lactamase,
(2) modification of target PBPs,
(3) impaired penetration of drug to target PBPs, and
(4) Antibiotic efflux.
• Beta-lactamase production is the most common mechanism of
resistance.
07/13/2024 57
Cont.
• Hundreds of different β-lactamases have been identified, produced by:
– S. aureus, H. influenzae, and E. coli, are relatively narrow in
substrate specificity, preferring penicillins to cephalosporins.
– β-lactamase produced by P.aeruginosa and
Enterobacter sp, and extended–spectrum β-lactamases (ESBLs),
hydrolyze both cephalosporins and penicillins.
• Carbapenems are highly resistant to hydrolysis by penicillinases and
cephalosporinases,
• but they are hydrolyzed by metallo-βlactamase and
carbapenemases.
07/13/2024 58
Cont….
• Altered target PBPs are the basis of methicillin resistance in

staphylococci and of penicillin resistance in pneumococci
and enterococci.
• These resistant organisms produce PBPs that have low affinity
for binding β-lactam antibiotics, and consequently, they are
not inhibited except at relatively high conc’.
• Resistance due to impaired penetration of antibiotic to target
PBPs occurs only in G-ve species B/c of the impermeable
outer membrane of their cell wall, which is absent in gram-
07/13/2024 59
positive bacteria.
Penicillins: Subgroups & activity…
• Spectra at a Glance
– G-(+): very good, esp. for the narrow-spectrum pen.
– G- (-): good for amino & antipseudomonal penicillins
– Anaerobes: very good but only with antipseudomonal
penicillins
– Resistant organisms:
• Methicillin-resistant Staph aureus (MRSA): resistant
• Vancomycin-resistant Enterococcus (VRE): resistant
• Pseudomonas: good, but only with antipseudomonal
penicillins
– Special sensitivities: Neisseria meningitidis (G- (-) coccus):
susceptible to IV penicillin G
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Prototype & Repository PCNs
Penicillin G : The 1st penicillin
Coverage:
G (+) cocci & rods: Streptococcus Grp A & B, Strep. viridans,
Enterococcus, Actinomyces
G (+) anaerobes: Peptostreptococcus, C. tetani, C. perfringens, C.
botulinum
G (-) cocci: N. meningitidis,
Spirochetes: T. pallidum, Leptospirosis
However, they have little activity against gram-negative rods, and61
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Prototype & Repository PCNs…
Penicillin G…
Indications:
Endocarditis
Skin & soft tissue infection
Neurosyphilis & Venereal infections
Respiratory tract infections
Rheumatic fever prophylaxis
62
62
Prototype & Repository PCNs…
Penicillin V
The first synthetic orally effective penicillin
Indications:
For Tx of mild to moderately infections due to microorganisms whose susceptibility
to pen G is within the range of serum levels common to this particular dosage form
Tonsillitis & streptococcal URTIs
63
63
Anti-Staphylococcal PCNs
Includes: nafcillin, oxacillin, cloxacillin & dicloxacillin

Coverage:
Staph aureus (MSSA), Strept Grp A,B (C,G), Strep
pneumoniae (most strains now resistant)
Holes in Coverage:
Not active against enterococci , G (-) cocci & rods, anaerobic
bacteria
Common indications:
Endocarditis, Endovascular infection, Septic arthritis, SSTI
64
64
Aminopenicillins
They retain the antibacterial spectrum of penicillin & have
improved activity against G-(-) organisms
Like penicillin, however, they are relatively susceptible to
hydrolysis by β-lactamases
Includes: Ampicillin, Amoxicillin
65
65
Aminopenicillins……
↑ed Spectrum:
Better G-(-) coverage than the penicillin G
Coverage:
Same as pen G plus: E. faecalis, E. Faecium, L.
monocytogenes, H. Influenzae, Salmonella, Shigella, E. coli,
P. mirabilis, H. pylori
66
66
Amino penicilline…
Holes in Coverage: not active

E. faecium (VRE), Staph. aureus (MSSA & MRSA),
Legionella / atypicals, Klebsiella, Enterobacter, Serratia, P.
aeruginosa, B. fragilis
Indications (most common uses):
URTIs: Otitis media, Sinusitis
L. monocytogenes
H. pylori
67
67
Antipseudomonal PCNs
• Includes: Ticarcillin, Piperacillin, Azolicillin

Effective against many G-(-) bacilli, but not against klebsiella,
b/c of its constitutive penicillinase
Extends the antimicrobial spectrum of these antibiotics to
include penicillinase-producing organisms
β-lactamase-producing strains of S aureus
β-lactamase-producing G-(-) bacteria
68
68
Pharmacokinetics
• Absorption of orally administered drug differs greatly for

different penicillins, depending in part on their acid stability
and protein binding.
• GI absorption of nafcillin is erratic, so it is not suitable for oral
administration.
• Dicloxacillin, Penicillin V, ampicillin, and amoxicillin are
acid-stable and relatively well absorbed.
07/13/2024 69
Cont…..
• Absorption of most oral penicillins (amoxicillin being an

exception) is impaired by food, and the drugs should be
administered at least 1–2 hours before or after a meal.
• IV Pen G is preferred than IM route b/c of irritation & local
pain after injection of large dose through IM.
• Highly protein-bound penicillins (eg, nafcillin) generally
achieve lower free-drug conc in serum than less protein bound
penicillins (eg, penicillin G or ampicillin)
07/13/2024 70
Cont….
• Penicillins are widely distributed in body fluids & tissues with a few
exceptions
• They are polar molecules, so intracellular conc are well below those
found in extracellular fluids.
• Elimination:
– All of the available penicillins have relatively short half-

lives (generally 1hr or less)
– Penicillin G is rapidly excreted by the kidneys; small
amounts are excreted by other routes
• The normal t1/2 of penicillin G is approx 30 min, in renal
07/13/2024 71
Pk of Penicillins…
Extended- spectrum penicillins are secreted more slowly than penicillin G & have half-
lives of 1 hr
Nafcillin is primarily cleared by biliary excretion
Oxacillin, dicloxacillin, & cloxacillin are eliminated by both the kidney & biliary
excretion
72
72
Clinical Use
Penicillin G
Active against
 G+ve cocci except penicillinase producing Staphylococci.
 Against G+ve bacilli( C.tetani, C. Anthrax).
 G-ve cocci(N.meningitidis, N.Gonorrhea).
 Depending on the organism, the site, and the severity of
infection, effective doses range b/n 4 & 24 million units per
day administered IV in four to six divided doses.
 High-dose penicillin G can also be given as a continuous IV
infusion.
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 Drug of choice for :
use Pneumonia or Meningitis by streptococcus
Pneumonia
Pharyngitis by streptococcus pyogenes
Infectious endocarditis by streptococcus viridians
Drug of choice for syphilis: Benzathine penicillin G,
2.4 million units IM once a week for 1–3 weeks
 Prophylactic application
Syphilis in sexual partner
Bacterial endocarditis
07/13/2024 74
Pharmacokinetics
• pen G is available as salt form(Na+, K+,procaine, Benzathine

Pen G). Pen G : orally ineffective due to gastric acid.
• Distribute to most tissue , inflammation increase distribution
into CSF, joints & eye.
• Excretion is delayed by probenecid.
Penicillin V( phenoxy methyl Penicillin)

o Acid stable : given orally
o Used for streptococcal pharyngitis, prophylaxis of rheumatic
fever.
o Not given for serious infection B/c they are not given
parentally, hence only given orally
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Penicillins Resistant to Staphylococcal Beta
Lactamase (Methicillin, Nafcillin, and Isoxazolyl
Penicillins)
• Isoxazolyl Penicillins include cloxacillin, Oxacillin,
Dicloxacillin
• They have chain that protects Beta lactam ring.
• Are penicillinase resistant, used against penicillinase producing
strains of Staph aureus & Staph Epidermidis.
• the empirical use of these drugs has decreased substantially
because of increasing rates of Methicillin-resistance in
staphylococci.
•07/13/2024
Listeria monocytogenes, enterococci, and methicillin-resistant76
Cont……
• Isoxazolyl penicillin are relatively acid-stable and have reasonable

bioavailability. However, food interferes with absorption, and the
drugs should be administered 1 hour before or after meals.
• 0.25–0.5 g orally every 4–6 hours (15–25 mg/kg/d for children), is
suitable for treatment of mild to moderate localized staphylococcal
infections (soft tissue infection).
• Methicillin : acid labile, the first antistaphylococcal penicillin to
be developed, is no longer used clinically due to high rates of
adverse effects, result allergic reaction.
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Cont….
• Naficillin: erratic & incomplete absorption from GIT, so given
IM or IV
• Oxacillin and nafcillin, 8–12 g/d, given by intermittent IV
infusion of 1–2 g every 4–6 hours (50–100 mg/kg/d for
children),
• considered the drugs of choice for serious systemic
staphylococcal infections
07/13/2024 78
C. Extended-Spectrum Penicillins
(Aminopenicillins, Carboxypenicillins, and
Ureidopenicillins)
• have greater activity than penicillin against G-ve bacteria B/c of

their enhanced ability to penetrate the G-ve outer membrane.
• Like penicillin G, they are inactivated by many β-lactamases.
• The aminopenicillins(ampicillin and amoxicillin), have very
similar spectrums of activity, but amoxicillin is better absorbed orally.

• Amoxicillin, 250–500 mg TID, is equivalent to the same amount of
ampicillin given QID.
07/13/2024 79
Cont…..
• Amoxicillin is given PO to treat UTI, sinusitis, otitis, and LRTI.
• Ampicillin and amoxicillin are the most active of the oral β-lactam
antibiotics against pneumococci with elevated MICs to penicillin and
are the preferred β-lactam antibiotics for treating infections
suspected to be caused by these strains.
• Ampicillin (but not amoxicillin) is effective for shigellosis.
• Ampicillin, at dosages of 4–12 g/d IV, is useful for treating serious
infections caused by susceptible organisms, including anaerobes,
enterococci, L monocytogenes, and β-lactamase-negative strains of
gram-negative cocci and bacilli such as E coli, and Salmonellasp.
07/13/2024 80
Cont….
• Due to production of βlactamases by gram-negative bacilli,
ampicillin can no longer be used for empirical therapy of UTI and
typhoid fever.
• Ampicillin is not active against :
– Klebsiella sp, Enterobacter sp, P aeruginosa,
– Citrobacter sp, indole-positive proteus species, and

other gram-negative aerobes that are commonly
encountered in hospital-acquired infections.
• These organisms intrinsically produce βlactamases that inactivate
ampicillin.
07/13/2024 81
Cont….
• Carbenicillin, the first antipseudomonal carboxypenicillin, is no
longer used, because there are more active, better tolerated
alternatives.
• A carboxypenicillin with activity similar to that of carbenicillin is
ticarcillin.
• The ureidopenicillins(piperacillin,mezlocillin, and Azlocillin), are
also active against selected gram-negative bacilli, such as Klebsiella
pneumoniae.
07/13/2024 82
Beta- lactamase inhibitor : clavulinic acid ,
sulbactum, tazobactum
 Inhibit bacterial Beta- lactamase, ‘ve weak antibacterial.
 Most active against Beta- lactamase produced by S.aureus,
Influenza, some enterobacteriaceae.
• Ampicillin, amoxicillin, ticarcillin, and piperacillin are also
available in combination with one of several β-lactamase
inhibitors: clavulanic acid, sulbactam,or tazobactam.
• The addition of a β-lactamase inhibitor extends the activity of
these penicillins to include β-lactamase-producing strains of S
aureus as well as some β-lactamase-producing gram-negative
bacteria.
07/13/2024 83
Drug-Drug interactions
Major drug Interactions for the drug class

Drugs affecting penicillins
Probenecid: ↓ the renal tubular secretion of penicillins & will

result in ↑ed & prolonged serum conc.
Chloramphenicol, macrolides, sulfonamides, & TTCs interfere
with the bactericidal effects of Penicillins
Aminoglycosides.
84
84
Penicillins: General considerations & SEs
• General considerations
– Activity enhanced if used in combination with β- lactamase
inhibitors (Clavulanic acid, Sulbactam)
– Synergy with aminoglycosides against pseudomonal &
enterococcal spp
• Side effects
– Hypersensitivity: most commonly only a rash, but can include
anaphylaxis
– NVD if given orally
– Stinging in the vein if given IV
07/13/2024 85
Penicillins: Contraindications
• Hypersensitivity (allergy)
– Incidence is as high as 10%.

– Signs and symptoms are as follows:
• Maculopapular rash (mostly flat & confluent, not itchy)
• Urticarial rash (hives)
• Anaphylaxis
– Cross-reactivity b/n penicillin allergy & other β-

lactam antibiotics (cephalosporins & carbapenems)
07/13/2024 86
SJS
07/13/2024 87
Penicillins & considerations
• Some Penicillins may inactivate AminoGlycosides if given
together
– Never be mixed in the same IV fluid
– Should be administered an hr or so apart when the pt is to
receive both
• Give PO penicillins 1 hr before or 2 hrs after meals
• Assess for allergies before administering penicillin
• Assess for allergic rxns after administering penicillin
– Rxns can be a mild rash or anaphylactic shock
07/13/2024 88
07/13/2024 89
Cephalosporin
• are bactericidal and similarly to the penicillins, they act by
inhibiting synthesis of the bacterial cell wall.
• The most widely used system of classification of cephalosporin
is by generations and is based on the general features of their
antibacterial activity.
Mechanism of Bacterial resistance
 Production of Beta-lactamase(cephalosporinase)
 Altered cephalosporin binding protein(CBP)
07/13/2024 90
Types of Cephalosporin
**1stGeneration: Cefadroxil,cefazolin, cephalexin, Cephalothin
**2nd Generation:eg. Cefuroxime, Cefoxitin Cefaclor, cefprozil
**3rdGeneration: Cefixime, Cefotaxime,Ceftazidime, Ceftriaxone
** 4th Generation: Cefepime, Cefpirome

 From 1st G to 3rd G
 Increasing in activity against to G-ve & anaerobic

bacteria.
 Increase resistant to destruction to Beta-lactamse.
 Increasing ability to reach CSF

07/13/2024 91
Cephalosporins: Generations & activity
• Spectra at a Glance
– G-(+): v. good, esp. the 1st -generation agents
– G-(-): 3rd -generation agents v. good, 2nd -generation
agents good
– Anaerobes: resistant against 1st -generation agents,
good with 2nd - & 3rd -generation agents
– Resistant organisms:
• MRSA & VRE : resistant
• Pseudomonas: v. good with ceftazidime & - Cefepim only
– Special sensitivities:
• N. meningitidis (G- (-) coccus: susceptible to IV 3rd -
07/13/2024
generation agents 92
Cephalosporins
1st generations:
Includes: Cephalothin, Cefazolin (Parentral), Cephalexin (oral)
Coverage: MSSA, Streptococci Grp A,B,C,G, Strep viridans, S.
pneumoniae, H. influenzae, E. coli, K. pneumoniae, P. mirabilis
PK: No CNS penetration
Common Uses: SSTI, URTIs, surgical prophylaxis,
Uncomplicated UTIs
93
93
Pharmacokinetics & Dosage
A. Oral
• Cephalexin, cephradine, and cefadroxil are absorbed from the gut
to a variable extent.
• Cephalexin and cephradine are given orally in dosages of 0.25–
0.5 g QID (15–30 mg/kg/d) and cefadroxil 0.5–1 g BID.
• Excretion is mainly by glomerular filtration & tubular secretion
into the urine.
• Drugs that block tubular secretion, eg, probenecid, may increase
serum levels substantially.
• In patients with impaired renal function, dosage must be reduced
94
Cont……
B. Parenteral
• Cefazolin is the only first-generation parenteral cephalosporin.
• After an IV infusion of 1 g, the peak level of cefazolin is 90–
120 mcg/mL.
• The usual IV dosage of cefazolin for adults is 0.5–2 g IV every
8 hours.
• Cefazolin can also be administered IM.
• Excretion is via the kidney, and dose adjustments must be
made for impaired renal function. 95
Clinical Uses
• Oral drugs may be used for the treatment of UTI and

staphylococcal or streptococcal infections, including
• cellulites or soft tissue abscess.
• However, oral cephalosporins should not be relied on in
serious systemic infections.
96
cont…….
• Cefazolin penetrates well into most tissues. It is a drug of choice
for:
– surgical prophylaxis.
– In individuals with staphylococcal or streptococcal infections
who have a history of penicillin allergy other than immediate
hypersensitivity
• Cefazolin does not penetrate the CNS ,not be used to treat
meningitis.
97
Subgroups & antimicrobial activity…
· 2nd generation: Cefotetan (Parentral), Cefuroxime (oral &

parantral)
Coverage: Same as 1st generation Plus
β-lactamase positive H. influenzae, M. catarrhalis, N.

meningitidis, E. coli, K. pneumoniae, Proteus
Anaerobic infections - Cefoxitin & Cefotetan only
PK: no drugs enter the CNS, except Cefuroxime
98
98
Pharmacokinetics & Dosage
A. Oral
• Cefaclor, cefuroxime axetil, cefprozil, and loracarbef can be
given orally.
• The usual dosage for adults is 10–15 mg/kg/d in two to four
divided doses;
• Children should be given 20–40 mg/kg/d up to a maximum of 1
g/d.
B. Parenteral
• After a 1 g IV infusion, serum levels are 75–125 mcg/mL for
most 2nd generation cephalosporins.
– IM administration is painful and should be avoided.
• There are marked differences in half-life, protein binding, and
interval between doses.
• All are renally cleared and require dosage adjustment in renal
99
failure.
Clinical Uses
• The oral 2nd -generation are active against β-lactamase-

producing H. influenzae or Moraxella catarrhalis and used to
treat sinusitis, otitis, and LRTI.
• Cefoxitin, cefotetan, or cefmetazole can be used to treat
mixed anaerobic infections such as peritonitis, diverticulitis,
and pelvic inflammatory disease.
• Because of their activity against anaerobes
• Cefuroxime is used to treat CAP because it is active against β-
lactamase-producing H influenzae and K pneumoniae and also
most pneumococci.
• cefuroxime crosses the BBB, it is less effective in treatment of
meningitis than ceftriaxone or cefotaxime and should not be
used. 100
2nd generation: Common uses

CAP, Bronchitis, Sinusitis, Otitis media
SSTI
MSSA
Abdominal surgical prophylaxis
Cefoxitin or Cefotetan can be used as monotherapy
of mild intra-abdominal & pelvic infections
Cefuroxime
Covers pneumococcus & H. influenzae
CAP, Sinusitis & Otitis
Does not cover gut anaerobes
101
101
· 3rd generations: Ceftriaxone Cefotaxime, Ceftazidime

& (Parentral), Cefditorine & Cefixime (oral)
Coverage:
Same as 1st Generation Plus:
Expanded G-(-)coverage, Oral anaerobes, S.
aureus (MSSA), Strep pneumoniae, Strep Grp A,B,C,G,
Strep viridans, G (-) rods, N. gonorrhea
All cover B. fragilis except cefotaxime & ceftazidime
PK: most enter CNS (not cefoperazone)
Important in empiric management of meningitis
102
102
Holes in 3rd Generation Coverage

Poor G-(+) coverage
E. faecium, MRSA
All cover MSSA except ceftazidime
Legionella / atypicals
Listeria
Acinetobacter
Not all cover Pseudomonas
103
103
3rd generation: common uses

CAP
Bacterial meningitis (except Listeria)
Lyme disease
strep Viridans : endocarditis
Intra-Abdominal & Pelvic Infections: ceftriaxone + metronidazole or
clindamycin
HAP: ceftazidime only
Anogenital gonorrhea: ceftriaxone or cefixime
104
104
· 4th generation: Cefepim (IV)

Good G-(+) & G-(-)coverage
Anti-Pseudomonal (including ceftazidime resistant
isolates)
Penetrates CSF
Limited anaerobic coverage
105
105
Adverse effects of Cephalosporins
Hypersensitivity: incidence: 2%
Wide range: anaphylaxis, fever, skin rashes, nephritis,
granulocytopenia, and hemolytic anemia. but rashes & drug fever most
common
Assume complete-allerginicity b/n individual cephalosporins & partial
cross –allergenicity with penicillins (<10%)
Cross-allergenicity appears to be most common among
penicillin, aminopenicillins, and early generation cephalosporins.
106
106
Cont….
• Patients with a history of anaphylaxis to penicillins should not

receive 1st or 2nd -generation cephalosporins, while 3rd - and 4th -
generation cephalosporins should be administered with caution,
preferably in a monitored setting.
B. Toxicity
• Local irritation can produce pain after IM injection and
thrombophlebitis after IV injection.
• Renal toxicity, including interstitial nephritis and tubular
necrosis 107
SIDE EFFECTS
• Hematologic: rare cases of bone marrow suppression

resulting in a low white blood cell (WBC) count (aka
neutropenia or granulocytopenia)
• Nephrotoxicity: occasional interstitial nephritis and tubular
necrosis
• Pseudomembranous colitis: many antibiotics, including
cephalosporins, can wipe out gut flora and permit the
bacterium C. difficile to colonize, which causes this condition.
This is more common in the broad-spectrum (higher-
108
Cont….
• Methylthiotetrazole( Cefamandole, cefmetazole, cefotetan,
and cefoperazone) may cause hypoprothrombinemia and
bleeding disorders.
• Oral administration of vitamin K1, 10 mg twice weekly, can
prevent this uncommon problem.
• Drugs with the methylthiotetrazole ring can also cause severe
disulfiram-like reactions; consequently, alcohol and alcohol
containing medications must be avoided
109
CONTRAINDICATIONS
• Anaphylaxis to penicillins is an absolute contraindication.

• Non-anaphylactic allergy to penicillins is a relative
contraindication; however, the cross-reactivity is reported to
be 2% to 10%, and cephalosporins have been used frequently
in patients with a penicillin allergy.
– ▴ Maculopapular rash (flat confluent red rash)
– ▴ Urticaria (itchy hives)
– ▴ Eosinophilia (which is common to allergic reactions)
110
IMPORTANT NOTES
• First-generation cephalosporins are:
– ▴ Good for skin infections (which are commonly Streptococcus or Staphylococcus)
– ▴ Commonly used as prophylactic antibiotics (preventative) given before surgery to
prevent wound infections
• Second-generation cephalosporins are:
– ▴ Good for Bacteroides infection (anaerobic), which can occur with intraabdominal
infections
– ▴ Used less commonly for severe infections because third-generation cephalosporins
are more efficacious. Second-generation cephalosporins can be used for mild
infections in which gram-negative organisms are predicted or known
• Third-generation cephalosporins are:
– ▴ Commonly used for severe infections in combination with another drug of a different
class (different MOA)
• Fourth-generation cephalosporins are:
– ▴ Reserved for severe nosocomial (hospital-acquired) infections, which have a
tendency to be:
• Resistant to multiple other antibiotics
• More severe infections
111
• Commonly caused by gram-negative organisms
Other β-lactam antibacterials…
Monobactams : Aztreonam
• Their spectrum of activity is limited to aerobic G-ve rods
(including P aeruginosa).
• Unlike other β-lactam antibiotics, they have no activity against
gram-positive bacteria or anaerobes.
• It has structural similarities to ceftazidime, and its G-ve spectrum
is similar to that of the 3rd -generation cephalosporins.
112
Other β-lactam antibacterials…
• It is stable to many β-lactamases with the exceptions extended spectrum β

lactamases (ESBL)
• Aztreonam is given IV every 8 hours in a dose of 1–2 g,
• It penetrates well into the CSF, by Renal clearance
• The half-life is greatly prolonged in renal failure
• No cross allergenicity with penicillins
Clinical use:
Infections caused by aerobic, G- (-) bacteria in pts with

immediate hypersensitivity to penicillins, like serious infections
such as pneumonia, meningitis, and sepsis caused by
susceptible gram-negative pathogens.
113
113
Carbapenems… Doripenem, ertapenem,
imipenem,and meropenem
• Imipenem
• has a wide spectrum with good activity against many G-ve
rods, including P aeruginosa, G+ve organisms, and anaerobes.
• It is resistant to most β- lactamases but not carbapenemases or
metallo-β-lactamases.
• E.faecium, MRSA, C.difficile, are resistant
– It is inactivated by metabolism in the kidney to products that are

potentially toxic to renal tubules
• Combining imipenem with Cilastatin, a specific inhibitor of
dihydropeptidase (the enzyme responsible for its renal 114
07/13/2024 114
metabolism), prevents both inactivation & toxicity
Cont…..
– Use: Septicaemia, Intra-abdominal infection & Nosocomial
pneumonia
– Adverse effects: GI upset, blood disorders, allergic rxns,
confusion & convulsions
Doripenem and meropenem
– similar to imipenem but have slightly greater activity against
G-ve aerobes and slightly less activity against G+ve.
– They are not significantly degraded by renal
dehydropeptidase and do not require an inhibitor.
– Ertapenem is less active than the other carbapenems against P
aeruginosa and Acinetobacter species.
– It is not degraded by renal dehydropeptidase
07/13/2024 115
Cont…..
• Carbapenems penetrate body tissues and fluids well, including

CSF.
• All are cleared renally, and the dose must be reduced in
patients with renal insufficiency.
• The usual dosage of imipenem is 0.25–0.5 g given IV 6–8
hours , meropenem is 0.5–1 g IV TID, doripenem is 0.5 g
administered as a 1- or 4-hour infusion every 8 hours.
• Ertapenem has the longest half-life and is administered as a
once-daily dose of 1 g IV or IM
07/13/2024 116
Clinical use
• for infections caused by susceptible organisms that are
resistant to other available drugs, eg, P aeruginosa, and for
treatment of mixed aerobic and anaerobic infections.
• are active against many penicillin-non-susceptible strains of
pneumococci.
• highly active in the treatment of enterobacter infections ,
• b/c resistant to destruction by the β-lactamase produced
by these organisms.
• Carbapenems are generally reserved for very severe infections
07/13/2024 117
Adverse effects of carbapenems
• imipenem—are N,V,D, skin rashes, and reactions at the

infusion sites.
• Excessive levels of imipenem in patients with renal failure
may lead to seizures (Neurotoxicity).
• Meropenem, doripenem, and ertapenem are much less likely to
cause seizures than imipenem.
• Patients allergic to penicillins may be allergic to carbapenems,
but the incidence of cross-reactivity is low.
07/13/2024 118
Cont……
• Nausea and vomiting
• Neurotoxicity: Imipenem can cause seizures. Meropenem and
ertapenem do not.
• Fever: This can cause diagnostic dilemmas because carbapenems
are administered to patients with suspected infections, who usually
already have a fever. If the drug starts to create a fever, then it can be
very difficult to know when the infection is gone
IMPORTANT NOTES
• MRSA is an important resistant strain of S. aureus. It is not sensitive
to carbapenems. It is treated with vancomycin.
• VRE is another important resistant strain
• Carbapenems are very broad-spectrum agents. They are considered
"big guns" and are used only in patients who are very sick or
suspected of having resistant organisms.
07/13/2024 119
• They are generally not used as first-line treatment.
Glycopeptide antibiotics
Prototype: Vancomycin
Others: Teicoplanin, telavancin
Vancomycin: MOA:
Bind to D-alanyl-D-alanine in the growing bacterial cell wall→ catalyzed by
transglycosylase.
preventing the elongation of peptidoglycan strands & halting cell wall synthesis
Does not interfere with PBP
Spectrum : MRSA, Entrococci, C.difficile (back up drug)
120
120
Vancomycin…
Resistance:
Vancomycin-resistance staphylococcal (VRSA), entrococcal (VRE) strains
Entrococcal resistance is due to modification of the d-Ala-d-Ala

binding site of the peptidoglycanis replaced by D-lactate
As a result of targeting the peptidoglycan layer, glycopeptides are effective only against
gram-positive organisms. This is because gram-negative bacteria possess a thick outer
layer of lipopolysaccharide that covers the peptidoglycan layer.
121
121
Mechanisms of Resistance
• Modification of the d-Ala-d-Ala binding site of the peptidoglycanis
replaced by D-lactate
– Vancomycin-resistance staphylococcal (VRSA), entrococcal (VRE)
strains
• Excess cell wall production by the bacteria.
• Biofilm production: Staphylococcus epidermidis can produce a film that

can block penetration of the antibiotic.
• As a result of targeting the peptidoglycan layer, glycopeptides are effective
only against gram-positive organisms.
• B/c gram-negative bacteria possess a thick outer layer of
122
lipopolysaccharide that covers the peptidoglycan layer
PHARMACOKINETICS
• The half-life of vancomycin is 6 hours, whereas the half-life of
teicoplanin is much longer (assuming normal kidney function).
• Having a longer half-life, enables it can actually be administered
once a week in patients without any renal function
• Glycopeptides are very poorly absorbed from the GI tract.
• If the infection that is being treated is inside the GI tract (for
example, C. difficile colitis or pseudomembranous colitis), then
administering the drug orally provides the highest exposure of
antibiotic to the infection.
• If the infection is anywhere other than inside the GI tract (e.g.,
blood, soft tissues, brain, heart), then the drug must be administered
via the intravenous route-or, for teicoplanin, also intramuscularly.
123
Cont…..
• They are renally cleared, and in patients who have renal
dysfunction or renal failure, the frequency of administration
must be reduced
• Gram-positive: very good
• Gram-negative: resistant
• Anaerobes: resistant
• Resistant organisms:
– ▴ MRSA: very good
– ▴ VRE: resistant
– ▴ Pseudomonas: resistant
• Special:
– ▴ C. difficile
– ▴ Enterococcus (excluding VRE)
07/13/2024 124
Vancomycin…
Uses:
Effective for antibiotic-associated pseudomembranous colitis
Combined with an AGs for treating streptococcal endocarditis in pts
who are allergic to Pen G, & for serious infection with multiply
resistant staphylococci
ADR: Most Common
Infusion related: “red man’s syndrome” (rash, flushing, tachycardia,
hypotension), phlebitis, Nephrotoxicity (higher doses)
125
125
Vancomycin…
ADR: rare/severe/important
Bone marrow suppression (rare), hypersensitivity (rare)
Major Drug Interactions

Drugs affecting vancomycin
Nephrotoxic or ototoxic agents: Enhanced toxicity

Vancomycin’s effect on other drugs
Anesthesia: May result in enhanced histamine release &

rash
126
126
Other Glycopeptide antibiotics…
• Teicoplanin
– It is very similar to vancomycin in MOA & antibacterial
spectrum
– Unlike vancomycin, it can be given IM as well as IV
– It has a long half-life (45–70 hrs), permitting once-daily
dosing
• Telavancin
– Dual MOA results in improved activity against bacteria with
reduced susceptibility to vancomycin
– Once-daily dosing
• Dalbavancin
– Very long half-life (6–11 days) permits once-weekly dosing,
– More active than vancomycin
Reading Assignment on Other cell wall or Mn active agents127
07/13/2024 127
Other cell wall or Mn active agents
· Daptomycin
It binds to the bacterial cell Mn, causes rapid depolarization, resulting in a loss
of Mn potential leading to inhibition of protein, DNA & RNA synthesis, which
results in bacterial cell death
It is bactericidal in a conc-dependent manner
Renal clearance
Used in the Tx of G (+) infections
Toxicity: Myopathy
128
128
Other cell wall or Mn active agents…
· Fosfomycin
It inhibits the cytoplasmic enzyme pyruvate transferase by covalently
binding to the cysteine residue of the active site & blocking the addition of
PEP to UDP-N-acetylglucosamine
Active against both G-(+) & G-(-) organisms
Approved for use as a single 3-g dose for Tx of uncomplicated lower UTIs in
women
The drug appears to be safe for use in pregnancy
129
129
· Bacitracin
Bacitracin inhibits cell wall formation by interfering with dephosphorylation in
cycling of the lipid carrier that transfers peptidoglycan subunits to the growing
cell wall
There is no cross-resistance b/n bacitracin & other antimicrobial drugs
It is active against G-(+) microorganisms
It is highly nephrotoxic when administered systemically & is only used topically
130
130
· Cycloserine
It inhibits the incorporation of D-alanine into peptidoglycan pentapeptide by
inhibiting alanine racemase, which converts L-alanine to D-alanine, & D-alanyl- D-
alanine ligase
It Inhibits many G-(+) & G-(-) organisms
But it is used almost exclusively to treat TB caused by strains of M. tuberculosis
resistant to 1st-line agents
Causes serious dose-related CNS toxicity with headaches, tremors, acute
psychosis, & convulsions
131
131
Case study answer
• An IV third-generation cephalosporin (ceftriaxone or

cefotaxime) with adequate penetration into inflamed
meninges that is active against the common bacteria that
cause CAP & meningitis (pneumococcus,
meningococcus, Haemophilus ) should be ordered
• Vancomycin should also be administered until culture &
sensitivity results are available in case the pt is infected
with a resistant pneumococcus
07/13/2024 132
Case study answer …
• Although the pt has a history of rash to amoxicillin,

the presentation is not consistent with an
anaphylactic reaction
• The aminopenicillins are frequently associated with
rashes that are not allergic in nature
– In this instance, cross-reactivity with a
cephalosporin is unlikely
07/13/2024 133
• Aminoglycosides
• Tetracycline
• Macrolides
• Chloramphenicol
07/13/2024 134
Introductory Case study 1
A 45-year-old man with no medical history was admitted to the

intensive care unit (ICU) 10 days ago after suffering third-degree
burns over 40% of his body. He had been relatively stable until
the last 24 hours. Now he is febrile (39.5°C [103.1°F]), and his
WBC count has risen from 8,500 to 20,000/mm3 . He has also
had an episode of hypotension (86/50 mm Hg) that responded to a
fluid bolus. Blood cultures were obtained at the time of his fever
and results are pending.
135
135
Introductory Case study 1…
The ICU attending physician is concerned about sepsis and

decides to treat with empiric combination therapy directed
against Pseudomonas . The combination therapy includes
tobramycin. The patient weighs 70 kg (154 lb) and has an
estimated Crcl of 90 mL/min. How should tobramycin be dosed
using once-daily and conventional dosing strategies? How should
each regimen be monitored for efficacy & toxicity?
136
136
Introductory Case study 2
A 19-year-old woman with no significant PMH presents to her

college medical clinic complaining of a 2-wk history of foul-
smelling vaginal discharge. She denies any fever or abdominal
pain but does report vaginal bleeding after sexual intercourse.
When questioned about her sexual activity, she reports having
vaginal intercourse, at times unprotected, with two men in the last
6 months. A pelvic examination is performed & is positive for
mucopurulent discharge from the endocervical canal.
137
137
Introductory Case study 2…
No cervical motion tenderness is present. A first-catch urine

specimen is obtained to be tested for chlamydia & gonococcus. A
pregnancy test is also ordered as the pt reports she “missed her last
period.” Pending these results, the decision is made to treat her
empirically for gonococcal & chlamydial cervicitis.
What are 2 potential Tx options for her possible chlamydial
infection?
How does her potential pregnancy affect the Tx decision?
138
138
Intoduction
• Protein synthesis requires ribosomes, transfer RNA (tRNA), and
messenger RNA (mRNA).
• It occurs in two stages: transcription and translation.
• Transcription is the transfer of genetic instructions in DNA to mRNA

in the nucleus.
• It includes three steps: initiation, elongation, and termination.
• Ribosomes have different binding sites, named:
– Aminoacyl (A): Incoming tRNA binds to this site.
– Peptidyl (P): where the existing amino acid chain is
elongated when the incoming amino acid is transferred to it
through the action of peptidyl transferase
139
– Exit or egress (E):
140
140
Aminoglycosides
Includes: Prototype: gentamicin

Others: tobramycin, amikacin, neomycin, streptomycin, kanamycin,
paromomycin
They are water-soluble, stable in solution, and
are weak bases so more active at alkaline than at acid pH
They are used most widely in combination with :
β-lactam antibiotic in serious infections with G-(-Ve) bacteria,
with vancomycin or a β-lactam antibiotic for G-(+Ve) endocarditis,
and for treatment of tuberculosis.
141
141
MOA
– They primarily act by binding to the aminoacyl site of 16S
ribosomal RNA within the 30S ribosomal subunit, leading
to misreading of the genetic code & inhibition of protein
synthesis
– They are bactericidal & exhibit conc.-dependent bacterial
killing
142
MOA…….Cont
• Protein synthesis is inhibited by aminoglycosides in at least

three ways
– interference with the initiation complex of peptide
formation;
– misreading of mRNA, which causes incorporation of
incorrect amino acids into the peptide and results in a
nonfunctional protein; and
– breakup of polysomes into non-functional monosomes.
143
Fig. Putative mechanisms of action of the AG in bacteria ,
source Bertrang Katzung pharmacology 144
Cont…..
• The initial event is passive diffusion via porin channels across
the outer membrane
• Drug is then actively transported across the cell membrane into
the cytoplasm by an oxygen-dependent process.
• The transmembrane electrochemical gradient supplies the
energy for this process, and transport is coupled to a proton
pump.
• Low extracellular pH and anaerobic conditions inhibit
transport by reducing the gradient.
• Transport may be enhanced by cell wall-active drugs such as
penicillin or vancomycin;
• synergism of these antibiotics with aminoglycosides
145
1. Production of a transferase enzyme or enzymes inactivates
the aminoglycoside by adenylylation, acetylation, or
phosphorylation
= Methylation of 16S ribosomal RNA
2. Impaired entry of AG into the cell.
– Genotypic due to mutation or deletion of a porin protein
or proteins involved in transport and maintenance of the
electrochemical gradient; or phenotypic
3. Mutuation: The receptor protein on the 30S ribosomal subunit
146
Pharmacokinetics of AG
AGs are highly polar

absorbed very poorly from the intact GIT, and almost the entire oral dose is excreted in
feces after oral administration.
Largely excreted unchanged via the kidney
Good renal function is an important factor in their safe use

They are usually administered parenterally unless intended for topical use (e.g. in eye drops
Generally well distributed in the tissues after parenteral administration, but penetrate the
CSF poorly unless the meninges are inflamed
147
147
Aminoglycosides…
Pharmacodynamic properties
2 important PD properties of AGs are the PAE & conc.-dependent
killing
Relative to traditional/conventional dosing methods, the consolidated(extended interval)
dosing approach is more likely to achieve optimal peak conc. that result in conc.-dependent
killing
higher concentrations kill a larger proportion of bacteria and at a more rapid rate.
148
148
Cont……
• Traditional/conventional dosing (TDA) refers to
– multiple daily doses of aminoglycosides (e.g. tobramycin or
gentamicin dosed 80mg every 8 hours or 1.5-2.5 mg/kg every
8 hours).
• Extended-interval aminoglycoside therapy (also known as once-
daily aminoglycosides, single daily aminoglycoside dosing,
consolidated or high-dose aminoglycoside therapy)
149
Cont……
• TDA Recommended only for patients where
– the aminoglycoside is being used for gram-positive synergy,
– patients with contraindication to EXTENDED

INTERVAL DOSING OF AMINOGLYCOSIDES, or
– in those patients who cannot safely achieve appropriate
peak/trough concentrations with EIDA.
Gram positive-synergy Dosing.

• Synergy dosing is a low dose of AG in conjunction with an
antimicrobial agent that exhibits activity against the cell wall of
Gram- positive bacteria (i.e. beta-lactams, glycopeptides) for the
150
Aminoglycosides…
Uses include:
G-(-) bacillary infection, particularly septicaemia, renal, pelvic & abdominal sepsis
Bacterial endocarditis
Other infections: TB, tularaemia(from animal -human, brucellosis
Effective for topical Tx of infections of the conjunctiva or external ear
151
151
Aminoglycosides…
Adverse effects
Nephrotoxicity, Ototoxicity, NMJ blockade
The risk of ADRs is higher when:
The dose is high or of long duration > 5days
Renal clearance is inefficient
Other potentially nephrotoxic/ototoxic/NMJ blocker drugs are co-administered, or
The pt is dehydrated
152
152
Aminoglycosides…
Ototoxicity
Both vestibular & auditory damage may occur
auditory damage - Resulting in tinnitus & high-frequency hearing loss initially, or
As vestibular damage, evident by vertigo, ataxia, & loss of balance
Serious ototoxicity can occur with topical application, including ear-drops
153
153
Aminoglycosides…
Nephrotoxicity
Dose-related changes (usually reversible)
Occur in renal tubular cells, where AG accumulate
Low BP, loop diuretics & advanced age are recognized as added
risk factors
Neomycin, kanamycin, and amikacin are the most ototoxic
agents.
Streptomycin and gentamicin are the most vestibulotoxic.
Neomycin, tobramycin, and gentamicin are the most nephrotoxic
NM blockade
They may impair NM transmission & aggravate (or reveal)
myasthenia gravis
Other rxns: rashes & haematological abnormalities
Case study answer
 The pt has normal renal function & thus qualifies

for once-daily dosing
Tobramycin could be administered as a single
154
once-daily injection at a dose of 350–490 mg
(5–7 mg/kg)
A serum level b/n 1.5 & 6 mcg/mL measured 8
hrs after infusion correlates with an appropriate
trough level
154
Tetracyclines
155
Cont……
Mode of action:
Interfere with protein synthesis by binding to bacterial ribosomes &
their selective action is due to higher uptake by bacterial than by
human cells
Mammalian cells lack the active transport system that bacteria use
to take up tetracycline; this provides part of the basis of selectivity
of tetracyclines on microbes and not the host
They are broad spectrum bacteriostatic.
156
156
MOA & Antimicrobial Activity
• Tetracyclines enter microorganisms in part by:

– passive diffusion
– an energy-dependent process of active transport.
• Susceptible organisms concentrate the drug intracellularly.
– Once inside the cell, it bind reversibly to the 30S subunit of
the bacterial ribosome, blocking the binding of aminoacyl-
tRNA to the acceptor site on the mRNA-ribosome complex
– This prevents addition of a.a to the growing peptide
157
Cont….
• Mechanisms of Resistance
– impaired influx or increased efflux-specific pumps
The newer drug tigecycline is not a substrate for these pumps

and microbes that are resistant to other tetracyclines by this
method are still sensitive to tigecycline.
– Ribosomal protection due to production of proteins that
interfere with tetracycline binding to the ribosome
– Enzymatic inactivation: less common MZM
158
Tetracyclines …
Pharmacokinetics:
Oral administration, antacids & Ca (milk) interfere with absorption
Tigecycline is poorly absorbed orally and must be through IV
A portion of an orally administered dose of tetracycline remains in
the gut lumen, alters intestinal flora, and is excreted in the feces
Localization in bone & teeth
Crosses the placental barrier
Poor penetration into the CSF
Renal & hepatic excretion- doses should be reduced in patients with
advanced renal dysfunction
Doxy & Minocycline are primarily excreted in feces, only a lower fraction is excreted
renally (& can therefore be used more safely in pts with renal dysfunction)
159
159
Cont…..
• Demeclocycline has a further action, inhibit the binding of
antidiuretic hormone (ADH) to its receptor.
– This is clinically important and is the basis for using this
drug for treatment of a condition in which ADH levels are
too high.
• Susceptible bacteria include:
– S.pneumoniae, B.anthracis (Anthrax), C.tetani, Brucella
(brucellosis), H. pylori, Actinomyces,
– Atypical bacteria - they are neither G- +ve nor G-ve.
E,g. Rickettsia , Chlamydial diseases & Mycoplasma

160
Tetracyclines …
Spectra at a Glance
Gram-positive: good
Gram-negative: good
Anaerobes: poor to good
Resistant organisms:
▴ MRSA: resistant
▴ VRE: resistant
▴ Pseudomonas: resistant
161
161
Tetracyclines …
Indications…
Broad spectrum bacteriostatic & generally 2nd line DOC
Generally not used for Staph/Strep infections
Doxycycline:
Atypical –CAP
Malaria Px
B. anthracis
Alternative indication for syphilis
Inflammatory acne
162
162
Tetracyclines …
Side Effects:
Superinfection
GI toxicity
Hepatic toxicity (reversible)- rare
Staining of teeth, retardation of bone growth
Renal toxicity (rare) – elevation of BUN
Photosensitivity
Diabetes insipidus –water wasting in the urine because of impaired water reabsorption
in the collecting duct
with Demeclocycline blocks ADH
163
163
CONTRAINDICATIONS
• Pregnancy and lactation
• Children under 8 years old, because of tooth discoloration
• Tetracycline spontaneously degrades over time (before it

is ingested).
• Ingesting outdated tetracycline is dangerous because the
degradation products are nephrotoxic and can cause a condition
called Fanconi's syndrome,
– which is characterized by damage to the proximal tubules,
resulting in impaired reabsorption of glucose, amino acids,
and other compounds from the ultrafiltrate within the tubule.
164
Chloramphenicol (CAF)
MOA & Antimicrobial Activity

• It’s is a potent inhibitor of microbial protein synthesis.
It binds reversibly to the 50S subunit of the bacterial
ribosome and inhibits peptide bond formation
• Chloramphenicol is a bacteriostatic broad-spectrum
antibiotic that is active against both aerobic and
anaerobic gram-positive and gram-negative organisms
165
Chloramphenicol (CAF)
Activity & clinical uses

Broad-spectrum antibiotic with a range of activity that includes
G-(+) & G-(-) bacteria, rickettsiae
Infections due to S. typhi, H. influenzae & B. fragilis have previously been the
principal indications for CAF use
It should never be given for minor infections & should only be given systemically
when there is no suitable alternative
Used topically to treat both eye & ear infections
166
166
Chloramphenicol…
Pharmacokinetics:
Oral absorption, wide distribution in body including CSF, hepatic metabolism to
glucuronide & renal excretion
There is an IV formulation
167
167
Chloramphenicol…
Side Effects:
Bone marrow suppression & idiosyncratic aplastic anemia
(lethal)
Gray baby syndrome: type of circulatory collapse
V, limp body tone, gray skin color, cyanosis - blue lips & skin, hypotension, CV
collapse
Superinfection
168
168
Macrolides
• are antibacterial agents that contain a large macrolide ring.
Prototype: erythromycin
Others: azithromycin, clarithromycin
• bind the 23S rRNA molecule of the 50S RSU and inhibit
peptidyl transferase, blocking the transfer of the new amino
acid onto the growing chain.
• they are bacteriostatic, but in high concentrations they can be
bactericidal.
• Macrolides are phagocytosed by macrophages
– WBCs preferentially travel to sites of infection, thereby
theoretically delivering the drug to the site at which it is
needed.
07/13/2024 169
• Modification of the RSU binding site either by chromosomal
mutation or through methylation via methylase
• Reduced intracellular concentrations : through either
– reduced permeability of cell membrane to macrolides or,
– increased efflux of macrolides via active pumps.
• Production of esterases (less): that hydrolyze macrolides;
this is more common with gram-negative enteric bacteria
(bacteria that colonize the GI tract).
• Cross-resistance is complete among all macrolides
07/13/2024 170
Macrolides
Decreased by stomach acid - enteric coating

Available in po, topical & parentraly(IV,IM)
Antimicrobial Spectrum:
General: Staph., S. pyogenes & S. pneumoniae; B.
anthracis (Anthrax), Legionnaire’s disease (Legionella) &
Hemophilus ducreyi (Chancroid disease)
Chlamydia, Mycoplasma
171
171
Macrolides…
Pharmacokinetics:
Erythromycin:
Orally absorbed as stearate or estolate salt
CSF penetration poor
Biliary & fecal excretion
Needs to be given 2 hrs before or after a meal
Clarithromycin:
BID dosing; acid stable with better GI absorption than erythromycin
Azithromycin:
QD dosing; needs to be given 2 hrs before or after a meal
172
172
Macrolides…
Indications:
Erythromycin:
Preoperative bowel preparation (PO of erythromycin base)
The base form of erythromycin is “relatively poorly absorbed” from
the GIT & is given orally along with neomycin or kanamycin as a
pre-op bowel preparation
DOC for Legionnaire's disease, but is now a 2nd line drug for other susceptible bacteria
Use is limited due to increasing resistance
173
173
Macrolides…
Clarithromycin:
Commonly used for RTIs
Tx of infections by H. pylori, H. influenzae, MAC
Azithromycin:
RTIs
SSTIs
STIs (Chlamydia, Chancroid)
Traveler's diarrhea
MAC
174
174
Indication
• In addition to antibacterial activity, erythromycin specifically
is used to enhance GI motility.
– Through direct stimulation of the GI tract, this mechanism
is responsible both for the enhanced motility that is of
benefit in patients who have dysmotility and also,
unfortunately, for the GI intolerance (side effects) in
patients who have normal motility.
• ▴ Examples of conditions associated with dysmotility
include diabetes (gastroparesis), scleroderma, and ileus.
• Clarithromycin and azithromycin are commonly used in
sexually transmitted infections when chlamydia or gonorrhea
is suspected and are also commonly used for treatment of
pneumonias
175
Macrolides…
Side Effects:
Mild GI upset
Hypersensitivity
Cholestatic jaundice (caused by the estolate salt of erythromycin)
Inhibition of CYP450 (drug interactions) but not with azithromycin
QTc prolongation & Torsade de pointes by high conc of erythromycin or
clarithromycin
176
176
Lincosamides: Clindamycin
Spectrum of activity:
Anaerobes
G-(+): peptostreptococci, C. perfringes, actinomyces
G-(-): Prevotella species, most B. fragilis, fusobacteria
G-(+) cocci: Staphlococci, Streptococci
Toxin production inhibition
Group A streptococci, MRSA
177
177
Clindamycin…
Pharmacokinetics
Well absorbed orally & is metabolized by the liver
Penetrates well into most tissues, with brain & CSF being important exceptions
Penetrates well into abscesses & is actively taken up & concentrated by
phagocytic cells
90% protein bound
178
178
Clindamycin…
Indications:
Oral infections & aspiration pneumonia
SSTIs infections caused by streptococci & staphylococci
In combination with an AGs or cephalosporin, to treat:
Penetrating wounds of the abdomen & the gut
Infections originating in the female genital tract, eg, septic abortion, pelvic
abscesses, or PID
Lung abscesses
Combined with pyrimethamine for toxoplasmic encephalitis in sulfa allergy
179
179
Clindamycin…
Side Effects:
Common: D, N, & skin rashes
Rare: Impaired liver function (with or without jaundice) & neutropenia
NB: Administration of clindamycin is a risk factor for colitis due to C
difficile
C. difficile
– Diseases:
• Antibiotic associated pseudomembranous colitis-
esp in hospitalized pts
– Habitat/Transmission:
• Normal flora in 3% of people
– Pathogenesis:
• Suppression of normal flora allows overgrowth,
usually by clindamycin, ampicillin, cephalosporins
– Exotox A (severe diarrhea
– Exotox B (damage to colonic mucosa)
180
180
Antibacterial Drugs…
A.Nucleic acid synthesis

inhibitors
181
Introductory Case study
A 59-year-old woman presents to an urgent care clinic with a 4-

day history of frequent & painful urination. She has had fevers,
chills, & flank pain for the past 2 days. Her physician advised her
to come immediately to the clinic for evaluation. In the clinic she
is febrile (38.5°C [101.3°F]) but otherwise stable & states she is
not experiencing any N or V. Her urine dipstick test is positive
for leukocyte esterase. Urinalysis & urine culture are ordered.
Her Past medical Hx is significant for UTIs in the past year. 182
182
Introductory Case study…
Each episode was uncomplicated, treated with trimethoprim-

sulfamethoxazole, & promptly resolved. She also has osteoporosis
for which she takes a daily Ca supplement. The decision is made to
treat her with oral antibiotics for a complicated UTI with close
follow-up.
Given her history, what would be a reasonable empiric antibiotic
choice?
Depending on the antibiotic choice are there potential drug
interactions? 183
183
Quinolones
Quinolones include:
Nalidixic acid &
Fluoroquinolones: Ciprofloxacin, Norfloxacin, levofloxacin,
Gatifloxacin, Moxifloxacin, Gemifloxacin
184
184
Introduction
 Nalidixic acid: the first quinolone
 Used for many years in treatment of UTIs
 Fluorinated 4-quinolones
 Have broad antimicrobial activity
 Effective after oral administration for the treatment of a wide
variety of infectious diseases
 Relatively few side effects
 Microbial resistance does not develop rapidly
07/13/2024 185
FLUORO QUINOLONES
• They are active against a variety of G-+ve and G-ve bacteria.
Mechanism of Action
• Quinolones block bacterial DNA synthesis by inhibiting
bacterial topoisomerase II (DNA gyrase) and topoisomerase IV.
• Inhibition of DNA gyrase prevents the relaxation of positively
supercoiled DNA that is required for normal transcription and
replication.
• Inhibition of topoisomerase IV interferes with separation of
replicated chromosomal DNA into the respective daughter cells
07/13/2024 186
during cell division
Antibacterial Activity
• Earlier quinolones such as nalidixic acid did not achieve
systemic antibacterial levels and were useful only in the
treatment of lower UTI.
• Fluorinated derivatives (ciprofloxacin, levofloxacin, and
others have greatly improved antibacterial activity compared
with nalidixic acid and achieve bactericidal levels in blood and
tissues.
07/13/2024 187
Classification of quinolones
 Often classified into generations (1st through 4th) with spectrum of
specificity and unique pharmacological properties
 First: nalidixic acid and cinoxacin;

 Second: norfloxacin, ciprofloxacin, ofloxacin,
enoxacin, and lomefloxacin;
 Third: levofloxacin, sparfloxacin, gatifloxacin;
moxifloxacin
 Fourth: trovafloxacin
07/13/2024 188
First-generation
 Oldest quinolones
 Exhibit limited Gm(-) activity
 Nalidixic acid and cinoxacin restricted to therapy of bladder
infections caused by urinary pathogens, such as E. coli and
Klebsiella and Proteus spp.
• did not achieve systemic antibacterial levels and were useful
only in the treatment of lower UTI.
 Use is restricted by resistance.
07/13/2024 189
Cont,,,,,
 Second-generation
 Demonstrate activity against G(-) organisms including
Enterobacteriaceae. Haemophilus spp.and STD agents are
also susceptible.
 The piperazine moiety is responsible for the antipseudomonal
activity of some of these drugs
 Resistance is becoming more prevalent.
07/13/2024 190
Cont…..
• Norfloxacin is the least active of the fluoroquinolones against
both G-Ve and G+ve organisms, with MICs 4x to eightfold
higher than those of ciprofloxacin.
• MSSA are generally susceptible to 2nd group fluoroquinolones,
but MRSA are often resistant.
• Streptococci and enterococci tend to be less susceptible than
staphylococci, and efficacy in infections caused by these
organisms is limited.
191
Cont…..
• Ciprofloxacin is the most active agent of 2nd group against
G-(-ve) organism, P. aeruginosa in particular.
• Levofloxacin, the l-isomer of ofloxacin, has superior activity
against gram-positive organisms, including Streptococcus
pneumoniae.
192
Cont…..
3rd group: Gatifloxacin, Gemifloxacin, moxifloxacin

Demonstrate improved G-(+) coverage
Particularly S. pneumoniae & some staphylococci

All are effective for many CA- RTIs
Fluoroquinolones also are active against

Atypical pneumonia (eg, mycoplasmas & chlamydiae)
Intracellular pathogens such as L. pneumophila & some mycobacteria (M. tuberculosis
& MAC)
The 4th generation quinolones also possess activity against anaerobes.
193
193
Mechanism of Resistance
 Via mutations in the bacterial chromosomal genes encoding DNA

gyrase or topoisomerase IV or by active transport of the drug out
of the bacteria.
 No quinolone-modifying or -inactivating activities have been
identified in bacteria
 Resistance has increased in Pseudomonas, staphylococci,
Salmonella, N. gonorrhoeae, and S. pneumoniae
07/13/2024 194
Pharmacokinetics
• available in Oral or IV administration,
• After oral administration well absorbed (BA of 80–95%) and
distributed widely in body fluids and tissue.
• Penetrates in most tissues including prostate, however poor
penetration into the CSF, Serum half-lives range from 3 to 10
hours.
• The relatively long half-lives of levofloxacin, gemifloxacin,
gatifloxacin, and moxifloxacin permit once-daily dosing.
• Oral absorption is impaired by divalent and trivalent cations, including
those in antacids. should be taken 2 hours before or 4 hours after195
07/13/2024
PK…….
Most fluoroquinolones are eliminated by renal mechanisms, either

tubular secretion or glomerular filtration .
Dosage adjustment is required for patients with creatinine clearances
less than 50 mL/min
1st & 2nd group quinolones: mainly renal elimination
3rd group quinolones:
Moxifloxacin: hepatic elimination, no dose adjustment in renal pt
Gemifloxacin: is metabolized to a limited extent by the liver, it is
excreted into the feces & urine
Gatifloxacin : mainly renal elimination
Non-renally cleared fluoroquinolones are relatively contraindicated in
patients with hepatic failure.
196
196
Table: PK properties of some fluoroquinolones
Drug t1/2 Oral Peak Oral Route of

(h) Bioavaila Serum Dose Excretion
bility (%) Conc(mcg/ (mg)
mL)
Ciprofloxacin 3–5 70 2.4 500 Renal
Gatifloxacin 8 98 3.4 400 Renal
Gemifloxacin 8 70 1.6 320 Renal & non renal
Levofloxacin 5–7 95 5.7 500 Renal
Lomefloxacin 8 95 2.8 400 Renal
Moxifloxacin 9–10 < 85 3.1 400 Non-renal
Norfloxacin 3.5–5 80 1.5 400 Renal
Ofloxacin 5–7 95 2.9 400 Renal
197
197
Indications
• UTI caused by many organisms, including P aeruginosa except
moxifloxacin due to low urinary levels
• Prostatitis
• STDs (with the exception of syphilis)
• GI & abdominal infections
– for bacterial diarrhea (Traveler's diarrhea), Enteric fever
caused by Peritonitis Shigella, Salmonella. typhi, toxigenic
E coli,
• Respiratory tract infections
• Bone, joint, & soft tissue infections (except norfloxacin, which
does not achieve adequate systemic concentrations)
• Other Infections: anthrax (Ciprofloxacin is DOC), resistant
TB( Cipro, Levo or Moxifloxacin ), tularemia 198
198
Cont,,,,,,,,
• Cipro, Levo or Moxifloxacin suitable of eradication of
meningococci from carriers and for prophylaxis of infection in
neutropenic cancer patients.
• With their enhanced gram-positive activity and activity against
atypical pneumonia agents (chlamydiae, Mycoplasma, and
Legionella),
• levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin—so-
called respiratory fluoroquinolones—are effective and used
increasingly for treatment of upper and lower respiratory tract
infections.
07/13/2024 199
Adverse Effects
GI (N & V)
CNS (mainly at high concentrations)
Skin reactions
QTc prolongation (levofloxacin & moxifloxacin)
Cartilage toxicity & joint swelling in children
Increased risk of tendonitis & tendon rupture
peripheral neuropathy
Pseudomembranous Colitis by overgrowth of C. difficile
Photosensitivity has been reported with lomefloxacin and pefloxacin
200
200
Drug Interactions & C/Is
Di- & tri-valent cations: Greatly ↓ fluoroquinolone absorption

QTc-prolonging drugs: potentiated QTc prolongation, leading to
polymorphic ventricular tachycardia
Like class 1A (eg, quinidine or procainamide)
class 3 antiarrhythmic agents & erythromycin, TCA
Not recommended in pregnancy & Lactation
Not recommended as drug of 1st choice in pediatric pts (<18 yrs)
due to cartilage toxicity
201
201
202
202
Sulfonamides, trimethoprim
CASE STUDY
• A 59-year-old woman presents to an urgent care clinic with a 4-day history
of frequent and painful urination. She has had fevers, chills, and flank pain
for the past 2 days. Her physician advised her to come immediately to the
clinic for evaluation. In the clinic she is febrile (38.5°C [101.3°F]) but
otherwise stable and states she is not experiencing any nausea or vomiting.
Her urine dipstick test is positive for leukocyte esterase. Urinalysis and
urine culture are ordered. Her past medical history is significant for three
urinary tract infections in the past year. Each episode was uncomplicated,
treated with trimethoprim-sulfamethoxazole, and promptly resolved. She
also has osteoporosis for which she takes a daily calcium supplement. The
decision is made to treat her with oral antibiotics for a complicated urinary
tract infection with close follow-up. Given her history, what would be a
reasonable empiric antibiotic choice? Depending on the antibiotic choice
are there potential drug interactions?
203
SULFONAMIDES
 Has the basic sulfanilamide nucleus (which is structurally similar

to p-aminobenzoic acid)
 Derivatization: attaching substituents to the amido

group (–SO2–NH–R) or the amino group (–NH2)
 Sulphonamides tend to be much more soluble at alkaline than at
acidic pH.
07/13/2024 204
07/13/2024 205
Mechanism of action and resistance
 Susceptible microorganisms require extracellular PABA to form

dihydrofolic acid (Humans cannot synthesize folic acid and must
acquire it in the diet)
 Competitively inhibit dihydropteroate synthase (DHPS) and block
folic acid synthesis
 bacteriostatic
 Inhibit both G(+) and G(-) bacteria, nocardia, Chlamydia
trachomatis, Some enteric bacteria (E coli, klebsiella, salmonella,
shigella, and enterobacter), and some protozoa.
07/13/2024 206
•Activity is poor against
anaerobes.
•Pseudomonas aeruginosa is
intrinsically resistant to
sulfonamide antibiotics.
07/13/2024 207
•Activity is poor against anaerobes.
•Pseudomonas aeruginosa is
intrinsically resistant to
208
sulfonamide antibiotics.
Sulfonamides: Spectra at a Glance
Special sensitivities:
G-(+): good
Pneumocystis jiroveci causes P. jiroveci
G-(-): good pneumonia (PJP) (the older name is
Anaerobes: resistant Pneumocystis carinii pneumonia or PCP)

Toxoplasma
Resistant organisms:
Nocardia
MRSA: resistant
Stenotrophomonas
VRE: resistant
Pseudomonas: resistant
209
209
Resistance
• Some bacteria lack the enzymes required for folate synthesis
from PABA ,therefore, they are not susceptible to sulfonamides.
• Sulfonamide resistance may occur as a result of :
(1) overproduction of PABA,

(2) production of a folic acid synthesizing enzyme that has low
affinity for sulfonamides, or
(3) impair permeability to the sulfonamide.
(4) Active efflux of the sulfonamides

(5) Their inhibitory effect can be reversed by the presence of pus,
tissue fluids, and drugs that contain releasable PABA. 210
Sulfonamides: Pharmacokinetics
Sulfonamides can be divided into 3 major groups:

Topical: Na sulfacetamide (ophthalmic), sulfadiazine (skin ointment)
Oral non-absorbable: Sulfasalazine
Oral, absorbable: short-, intermediate-, or long-acting
Well absorbed from the GIT & distributed widely to tissues

& body fluids (including the CNS), placenta, & fetus
211
211
Sulfonamides: Pharmacokinetics…
Pharmacokinetics (Cont…)
Protein binding varies from 20% to over 90%
A portion of absorbed drug is acetylated or glucuronidated in the liver
Sulfonamides & inactive metabolites are then excreted into the urine, mainly by
glomerular filtration
In significant renal failure, the dosage of sulfonamide must be

reduced
212
212
Pharmacokinetic properties of some sulfonamides and
pyrimidines.
213
Clinical Uses
• Sulfonamides are infrequently used as single agents.

• Many strains of formerly susceptible species, including
meningococci, pneumococci, streptococci, staphylococci, and
gonococci, are now resistant.
• The fixed-drug combination of trimethoprim -sulfamethoxazole
is the drug of choice for infections such as Pneumocystis
jiroveci(formerly P carinii) pneumonia, toxoplasmosis,
nocardiosis, and occasionally other bacterial infections.
214
A. Oral Absorbable Agents
• Sulfisoxazole and sulfamethoxazole are short- to medium-

acting agents used almost exclusively to treat UTI.
• The usual adult dosage is 1 g of sulfisoxazole QID or 1 g of
sulfamethoxazole two or three times daily.
• Sulfadiazine in combination with pyrimethamine is first-line
therapy for Tt of acute toxoplasmosis.
• The combination of sulfadiazine with pyrimethamine, a potent
inhibitor of dihydrofolate reductase, is synergistic because
these drugs block sequential steps in the folate synthesis
215
Cont….
• sulfadiazine is 1 g QID, with pyrimethamine given as a 75 mg
loading dose followed by a 25 mg once-daily dose.
• Folinic acid, 10 mg orally each day, should also be administered
to minimize bone marrow suppression.
• Sulfadoxine is a long-acting sulfonamide that is coformulated
with pyrimethamine (Fansidar). Not used nowadays
216
Sulfonamides: Clinical uses…
· Oral absorbable agents…

Sulfamethoxazole + Trimethoprim (SMX/ TMP):
S. aureus (esp CA-MRSA)
G-(-) bacilli: Enteric bacteria such as E. coli (e.g. cystitis
- UTIs ) & Stenotrophomonas maltophilia (DOC)
Listeriosis (in penicillin allergic pts)
Nocardiosis
Pneumocystis jirovecii (PJP)
Parasites: Isospora belli, Cyclospora cayatenensis
217
217
Sulfonamides: Clinical uses…
Oral non-absorbable agents:

Sulfasalazine (salicylazosulfapyridine):
Ulcerative colitis, enteritis, & other IBD
Topical agents:
Na sulfacetamide:
Ophthalmic solution or ointment is effective in the Tx of
bacterial conjunctivitis & as adjunctive Tx for trachoma
Ag sulfadiazine:
For prevention of infection of burn wounds
218
218
Cont…..
• mafenide acetate, is used topically but can be absorbed from
burn sites.
• The drug and its primary metabolite inhibit carbonic
anhydrase and can cause metabolic acidosis, a side effect that
limits its usefulness.
• Silver sulfadiazine is a less toxic topical sulfonamide and is
preferred to mafenide for prevention of infection of burn
wounds.
219
Sulfonamides: Adverse effects & C/Is
Adverse effects:
Hypersensitivity reactions
Rash, photosensitivity & drug fever
Erythema multiforme Fig. Stevens-
Rare (< 1% ) : Stevens-Johnson Syndrome (20 % fatality)

Johnson Syndrome
220
220
Sulfonamides: Adverse effects & C/Is…
Urinary tract disturbances:

Crystalluria, hematuria, or even obstruction
Allergic interstitial nephritis (AIN)
Sulfadiazine when given in large doses, particularly if fluid intake is poor, can cause
crystalluria.
Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine
and fluids to increase urine flow.
Hematological toxicities:
Hemolytic anemia (G-6-PDH deficiency)
Neutropenia, granulocytopenia, thrombocytopenia
221
221
Cont…..
• Hepatitis (often accompanied by fever & rash)
• Kernicterus (a toxic encephalopathy) in infants
– Sulfonamides are C/I in newborns & during the

last 2 months of pregnancy
222
Sulfonamides: Adverse effects & C/Is…
Contraindications:
C/I in new borns & during last 2 months of pregnancy
Sulfa drug allergic history
223
223
TRIMETHOPRIM & TRIMETHOPRIM-
SULFAMETHOXAZOLE MIXTURES
• Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits

bacterial dihydrofolic acid reductase, which converts dihydrofolic
acid to tetrahydrofolic acid.
• Pyrimethamine, another benzylpyrimidine, selectively inhibits
dihydrofolic acid reductase of protozoa.
• trimethoprim or pyrimethamine in combination with a sulfonamide
blocks sequential steps in folate synthesis, (synergism).
• The combination often is bactericidal, compared with the
bacteriostatic activity of a sulfonamide alone. 224
Resistance
• Resistance to trimethoprim can result from:
– reduced cell permeability,

– overproduction of dihydrofolate reductase, or
– production of an altered reductase with reduced
drug binding.
– Resistance can emerge by mutation
225
Pharmacokinetics
• Trimethoprim is usually given orally, alone or in combination with
sulfamethoxazole.
• Trimethoprim-sulfamethoxazole can also be given IV.
• Trimethoprim is well absorbed from the gut and distributed widely
in body fluids and tissues, including CSF.
• Trimethoprim is more lipid-soluble than sulfamethoxazole, it has
a larger volume of distribution than the latter drug.
• The dose should be reduced by half for patients with creatinine
clearances of 15–30 mL/min.
• Trimethoprim (a weak base) concentrates in prostatic fluid and
in vaginal fluid, which are more acidic than plasma.
• Therefore, it has more antibacterial activity in prostatic and vaginal
fluids than many other antimicrobial drugs
07/13/2024 226
Clinical Uses
A. Oral Trimethoprim
• Trimethoprim can be given alone (100 mg BID) in acute UTI.
B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)

• P jiroveci pneumonia, shigellosis, systemic salmonella infections,
• UTI, prostatitis, and some non-tuberculous mycobacterial infections.
• active against most S.aureus strains, both methicillin-susceptible and

methicillin-resistant, and
• against respiratory tract pathogens such as pneumococcus,
Haemophilussp, Moraxella catarrhalis, and K pneumoniae(but not
07/13/2024 227
Mycoplasma pneumoniae).
Cont……
• One double-strength tablet( trimethoprim 160 mg plus
sulfamethoxazole 800 mg),1:5 ratio given BID is effective Tt for
UTI and prostatitis.
• Single-strength tablet given three times weekly may serve as
prophylaxis in recurrent UTI of some women.
• One double-strength tablet every 12 hours is effective treatment
for infections caused by susceptible strains of shigella and
salmonella.
• The dosage for children treated for shigellosis, UTI or otitis
media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole
07/13/2024 228
C. IV Trimethoprim-Sulfamethoxazole
• 80 mg trimethoprim plus 400 mg sulfamethoxazole per 5 mL

diluted in 125 mL of 5% dextrose in water can be administered
by IVinfusion over 60–90 minutes.
• It is the agent of choice for moderately severe to severe
pneumocystis pneumonia.
• It may be used for gram negative bacterial sepsis, including that
caused by some multidrug-resistant species such as
• Enterobacter and Serratia; shigellosis;
• typhoid fever; UTIc aused by a susceptible organism

07/13/2024 229
cont…..
D. Oral Pyrimethamine with Sulfonamide
• Pyrimethamine and sulfadiazine are used in the treatment of
toxoplasmosis.
• In falciparum malaria, the combination of pyrimethamine
with sulfadoxine (Fansidar) has been used.
• Adverse Effects: sulfonamide allergy, including the
hematologic, GI, CNS, dermatologic, and renal systems.
07/13/2024 230
cont….
• Fansidar is no longer used in prophylaxis because of severe
reactions.
Contraindications: Fansidar is contraindicated in patients who
have had adverse reactions to sulfonamides, in pregnancy at
term, in nursing women, or in children less than 2 months of age.
• Fansidar should be used with caution in those with severe
allergic disorders, and bronchial asthma.
• Nowadays it develop resistant
07/13/2024 231
Adverse effects:
Trimethoprim
produces the predictable adverse effects of Anti-folate effects: megaloblastic anemia,
leukopenia, granulocytopenia
Cotrmoxazole
may cause all of the untoward reactions associated with sulfonamides. N,V, drug fever,,
renal damage, and CNS disturbances.
Patients with AIDS and pneumocystis pneumonia have
a particularly high frequency of untoward reactions to it, especially fever, rashes,
leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and
hyponatremia.
232
232

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CHEMOTHERAP

1: Introduction to antimicrobial drugs

By the end of this chapter you should be able to:

Selective toxicity: it means that a chemical produces injury

The chemical reacts fairly specifically with a cytological or a biochemical feature

Antimicrobial therapy takes advantage of the biochemical

In most instances, the selective toxicity is relative rather

Different antibiotics have different modes of action, owing

· Inhibitors of cell membrane function

· Inhibitors of protein synthesis

Examples: Aminoglycosides, macrolides, lincosamides, streptogramins,

· Inhibitors of nucleic acid synthesis

· Inhibitors of other metabolic processes

Bacteriostatic Vs Bactericidal activity

Act primarily by arresting bacterial multiplication

NB: Bacteriostatic & bactericidal agents are equivalent for the

Minimal inhibitory concentration (MIC):

Conc- dependent killing (Cont…)

Antibacterial drugs are designed to kill bacteria, but no drug

The more broad-spectrum the antibiotic & the more

Common organisms in superinfection include:

1. Antimicrobial should only employed when actually required.

 Recommended in specifically defined situations based on

 Increased risk of toxicity from two or more agents

 Treatment of nonresponsive infections

• Antimicrobial therapy is assessed by monitoring

By the end of this chapter you should be able to demonstrate an

Beta-lactam & other cell wall- & membrane- active

Other cell wall or Mn active agents

A 55-year-old man is brought to the local hospital emergency

In the emergency department, the man is febrile (38.7°C

Beta –Lactam Other

It is during this stage that linear strands of peptidoglycan are

MZMs of bacterial resistance

IgE-mediated allergic reactions

1. The Beta lactam ring is essential for antibacterial Action.

– The first is the binding to penicillin-binding proteins(PBP).

– The second is the destruction of the bacterial cell wall.

• All β-lactams (penicillins, carbapenems, and cephalosporins) act

• D/t bacteria have different amounts and different types of

• Transpeptidases are enzymes that cross-link peptidoglycan

– They are therefore sensitive to β-lactams.

• Gram-negative bacteria have a thinner peptidoglycan layer, but

• This lipopolysaccharide layer protects the peptidoglycan layer

PCNs can be classified into the following categories:

• Resistance to penicillins and other β-lactams is due to one of

• Altered target PBPs are the basis of methicillin resistance in

Includes: nafcillin, oxacillin, cloxacillin & dicloxacillin

They retain the antibacterial spectrum of penicillin & have

improved activity against G-(-) organisms

Like penicillin, however, they are relatively susceptible to

Includes: Ampicillin, Amoxicillin

Holes in Coverage: not active

• Includes: Ticarcillin, Piperacillin, Azolicillin

• Absorption of orally administered drug differs greatly for

• Absorption of most oral penicillins (amoxicillin being an

– All of the available penicillins have relatively short half-

• pen G is available as salt form(Na+, K+,procaine, Benzathine

Penicillin V( phenoxy methyl Penicillin)

• Isoxazolyl penicillin are relatively acid-stable and have reasonable

• have greater activity than penicillin against G-ve bacteria B/c of

similar spectrums of activity, but amoxicillin is better absorbed orally.

– Klebsiella sp, Enterobacter sp, P aeruginosa,

– Citrobacter sp, indole-positive proteus species, and