Chemotherapy lecture note.pptx

CHEMOTHERAPY OF INFECTIOUS DISEASES

GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY
• Chemotherapy is treatment of infectious diseases and cancer
• Antimicrobial agents are drugs used in treating infectious diseases
 Antibacterial drugs, Antifungal drugs, and Antiviral drugs,
Antiparasite drugs (anthelminths, antiprotozoa, antiarthropods)
• Antibiotics are antibacterial substances produced by various species
of microorganisms (bacteria, fungi, and actinomycetes) that suppress
the growth of other microorganisms
 Include synthetic antimicrobial agents (sulfonamides and
quinolones)
• Antimicrobial agents are the most commonly used and misused drugs

• What is infection?
 An invasion of body tissue by microorganisms
• What is infectious agent?
 Microorganism that causes infection
• What is subclinical or asymptomatic infection?
 No clinical evidence of disease
• What is disease?
 A detectable alteration in tissue function
• What is pathogen and pathogenicity?
 Ability to produce disease
• What is true pathogen?
• What is opportunistic pathogen?

What is the ideal antimicrobial drug ?
• Have highly selective toxicity to the pathogenic MOs in
host body
• Low propensity for development of resistance
• Not induce hypersensitivies in the host
• Have rapid and extensive tissue distribution
• Be free of interactions with other drugs
• Be relatively inexpensive

• Selective toxicity: kills harmful microbes without damaging the host
• Resistance: Intrinsic versus acquired
• Host defense: Immune response
• Antimicrobial spectrum: The scope that a drug kills or suppresses
the growth of microorganisms
• Narrow-spectrum: The drugs that only act on one kind or one strain
of bacteria (e.g. isoniazid )
• Broad-spectrum: The drugs that have a wide antimicrobial scope
(e.g. tetracycline, chloramphenicol)
• MIC: Lowest concentration of antibiotic that prevents visible
microbial growth
• MBC: Lowest concentration of antibiotic that reduces the number of
viable cells by at least 1000-fold
• The MBC of a truly bactericidal agent is equal to or just slightly
above its MIC

• Extended-spectrum antibiotics
Effective against G+ve organisms & also against a significant No. of
G-ve bacteria or against specific microorganisms
 e.g Antipseudomonal penicillin's
• Trough Levels:
 Levels of antibiotics reach minimal levels (troughs) at roughly
predictable times after administration
 The troughs may be at, or below the MIC
 This may or may not be a problem because of two factors:
 Post Antibiotic Effect, a prolonged period before bacteria resume
growth
 Synergism between host defenses and sub- MIC levels of
antibiotics

• Post-antibiotic effect (PAE):
PAE is a persistent suppression of microbial growth that occurs
after levels of antibiotic have fallen below the MIC
Antimicrobial drugs exhibiting a long PAE (several hours)
require only one dose per day (e.g. Aminoglycosides &
Fluroquinolones)
• Trough levels may increase the frequency of drug-resistant bacteria
Frequency of developing resistance is greatly increased at levels
just above the MIC
Development of resistance to ciprofloxacin is 10,000 times more
frequent at 2 times the MIC compared to 8 times the MIC

Spectrum of action for selected antimicrobial agents

Bacterial Resistance to Antimicrobial Agents
• The rampant spread of antibiotic resistance mandates a more
responsible approach to antibiotic use
• A series of steps to prevent or diminish antimicrobial resistance (CDC)
Appropriate use of vaccination
Judicious use and proper attention to indwelling catheters
Early involvement of infectious disease experts
Choosing antibiotic therapy based on local patterns of
susceptibilities of organisms
Proper antiseptic technique to prevent infection rather than
contamination
Appropriate use of prophylactic antibiotics in surgical procedures
Infection control procedures to isolate the pathogen
Strict compliance to hand hygiene

• Bacterial resistance to an antimicrobial agent is attributable to three
general mechanisms:
1. The drug does not reach its target e.g.
Gentamicin targets the ribosome
Efflux pump mechanism (tetracycline, chloramphenicol,
fluoroquinolones, macrolides, and β-lactam antibiotics)
2. The drug is not active
Drug inactivation (beta-lactamase, aminoglycoside-modifying
enzyme, failure of the bacterial cell to activate a prodrug, INH)

The “anti-missile” of resistant bacteria:
penicillinase for penicillin
betalactamase for cephalosporins
Penicillin “missile” is its beta-
lactam ring

3. The target is altered
Mutation of the natural target (e.g., fluoroquinolone resistance),
Target modification (e.g., ribosomal protection, macrolides and
tetracyclines)
Acquisition of a resistant form of the native, susceptible target
(e.g., staphylococcal methicillin resistance caused by production
of a low-affinity penicillin-binding protein)

• Drug resistance may be acquired by mutation and selection
 Passage of the trait vertically to daughter cells
• Horizontal transfer, from another bacterial species, by transduction,
transformation or conjugation
Clonal spread of the resistant strain or by subsequent transfers to
other susceptible recipient strains
The plasmid-encoded staphylococcal β-lactamase gene transferred
to unrelated strains (enterococci)
Plasmid-encoded class A β-lactamases of G-ve bacteria transferred
to E. coli, Neisseria gonorrhoeae and Haemophilus spp

Offers several advantages over mutation-selection
Level of resistance often is higher than that produced by mutation
The gene, which still can be transmitted vertically
The resistance gene can be eliminated when it no longer offers a
selective advantage
• Mutation-Selection, e.g.
Streptomycin (ribosomal mutation)
Quinolones (gyrase or topoisomerase IV gene mutation)
Rifampin (RNA polymerase gene mutation)
Linezolid (ribosomal RNA mutation)
This mechanism underlies all drug resistance in M. tuberculosis

• Where does mutation occur?
The target protein, altering its structure so that it no longer binds
the drug
A protein involved in drug transport
A protein important for drug activation or inactivation
In a regulatory gene or promoter affecting expression of the target,
a transport protein or an inactivating enzyme
• Mutations are not caused by drug exposure per se
• However, certain drugs (fluoroquinolones) induce the bacterial SOS
system of DNA repair proteins (lethal protein)
Facilitate resistance by induction of error-prone polymerases

• Horizontal Gene Transfer
 Largely dependent on mobile genetic elements, transposable
elements, integrons, and gene cassettes
 Transposable elements: insertion sequences, transposons and
transposable phages
 Transduction
Transduction is acquisition of bacterial DNA from a phage
 Transformation
Uptake and incorporation into the host genome of free DNA from
environment
 Conjugation
Gene transfer by direct cell-to-cell contact through a sex pilus or
bridge

Selection of an antimicrobial agent
• Factors affecting selection:
 Causative MOs (susceptibility): The lack of susceptibility
guarantees therapeutic failure, determined from:
Clinical picture
Bacteriological examination (culture and sensitivity)
Serology-measures antibody levels
PCR detects the specific DNA for a specific organism

 Pharmacokinetic factors:
 Site of infection CSF, CNS, prostate, vitreous body of the
eye…
 Renal disease (e.g. amino glycosides)
Liver disease (e.g. erythromycin & tetracycline)
Route of administration
Toxicity and side effects to antibiotic
Interactions with other drugs
Cost

Host factors
 Age (Newborn & old patients have less kidney and liver
function compared to adults)
 Allergic reaction to a given antimicrobial agent
 Host defense mechanisms (Alcoholism, DM, HIV,
malnutrition, poor hygiene, advanced age, neutropenia,
& the use of immunosuppressive drugs can affect a
patient’s immunocompetency
 Such patients need higher-than-usual doses or longer
courses of treatment)

Genetic factors
Sulfonamides, Chloramphenicol, Nitrofurantoin →
severe hemolysis in G6PD deficient individuals
Pregnancy Streptomycin → Deafness
Lactation: Sulfonamides → hemolysis in G6PD deficient
newborn
Local factors at site of infection e.g. Abscess

Combined therapy
• Indications:
 To obtain synergism or reduce the dose of a toxic drug
 To reduce emergence of resistance
 Treat mixed infections with microorganisms of different
sensitivities
 Treat infections at different anatomical sites ( bile, CSF )
 Treat infections of unknown etiology especially in patients at
high risk of developing infections e.g. AIDS patients or
patients with agranulocytosis

• Three major mechanisms of antimicrobial synergism have been
established:
1. Blockade of Sequential Steps in a Metabolic Sequence:
Trimethoprim-sulfamethoxazole
2. Inhibition of enzymatic inactivation
 Inhibition of β-lactamase by β-lactamase inhibitor drugs
3. Enhancement of antimicrobial agent uptake
 Penicillins and other cell wall-active agents can increase the
uptake of aminoglycosides by a number of bacteria
 Enterococci are intrinsically resistant to aminoglycosides because
of permeability barriers
 Amphotericin B enhances the uptake of flucytosine by fungi

• Outcome of combined chemotherapy:
 Cidal (β-lactam antibiotics, vancomycin, and aminoglycosides) +
static (tetracyclines, erythromycin, and chloramphenicol) =
antagonism
 Cidal ( Penicillins )+ Cidal (aminoglycosides ) = Synergism
• Disadvantages of combined chemotherapy:
 Toxicity and ↑ cost
 Selection of multiple-drug-resistant microorganisms
 Eradication of normal host flora with subsequent superinfection
 Antibiotic antagonism in combination therapy is insignificant
clinically
 However, significant in meningitis, endocarditis, and gram-negative
infections in neutropenic patients where cidal effect is required

Prophylactic use of antibacterial agents
• Indications:
Protection of healthy individuals against highly contagious disease or
infections e.g. syphilis, gonorrhea, TB, meningococcal meningitis
 Prevent 2º infection in very ill patients
 e.g. AIDS, before major surgeries, delivery, organ transplantation,
recurrent UTI’s…etc
 Structural lesions of the heart predisposing to endocarditis who are
undergoing dental, surgical or other procedures that produce a high
incidence of bacteremia
 Therapy, generally as a single dose, should begin 1 hour before
the procedure for oral drugs and 30 minutes for parental drugs

• Chemoprophylaxis after various surgical procedures … most
extensive and probably best-studied
 Given preoperatively (1 hour before incision) and perhaps
intraoperatively for prolonged procedures
 Drug should be active against most likely contaminating MOs
 Cephalosporins are commonly used
 Prolonged use (beyond 24 hours ) after surgical procedure is
unwarranted & is harmful, emergence of drug resistance (routine
use)

• Prophylaxis is successful if:
A single antibiotic is used
The dose required for prophylaxis is less than the therapeutic dose
The drug is needed or used for a brief period
chronic therapy or prophylaxis is not advised → bacterial
resistance
• Complications of antibiotic therapy:
Hypersensitivity
Direct toxicity and super infection

Misuses of Antibiotics
• Treatment of nonresponsive infections
 The common misuse of antimicrobials
 Most of the diseases caused by viruses are self-limited and do not
respond to any of the currently available anti-infective compounds
 Ineffective treatments are measles, mumps, and at least 90% of
infections of the URT and many GI infections
• Therapy of fever of unknown origin
 Treated frequently & inappropriately with empirical antimicrobial
agents
 Fever of short duration probably is associated with undefined viral
infections
Antimicrobial therapy is unnecessary (spontaneous fever resolution)

 Fever persisting for 2 or more weeks (fever of unknown origin) …1/4
are infections
E.g., 1. TB or disseminated fungal infections may require treatment
E.g., 2. occult abscesses (bacterial endocarditis) … surgical drainage
or prolonged courses of pathogen-specific therapy
 Inappropriate drug administration may mask an underlying infection
 Noninfectious causes of fever, including regional enteritis, lymphoma,
renal cell carcinoma, hepatitis, collagen-vascular disorders, and drug
fever, do not respond to antimicrobial agents at all
 Rather than embarking on a course of empirical antimicrobial therapy
for fever of unknown origin, the clinician should search for its cause

• Improper dosage
Wrong frequency or sub-therapeutic dosage is common…resistance
Antimicrobials are safest and less toxic, but at excessive amounts can
result in significant toxicities
• Inappropriate reliance on chemotherapy alone
 Infections complicated by abscess formation drainage, debridement,
and removal of the foreign body are at least as important as the
choice of antimicrobial agent
 When an appreciable quantity of pus, necrotic tissue, or a foreign
body is present, antimicrobial agent in adequate dose + surgery

Classification of Antimicrobial Agents
(Baesd on Mechanism of Action)

• Mechanisms of antimicrobial agents
A. Inhibition of cell wall synthesis
Penicillins, cephalosporins, monobactams and carbapenems
Cycloserine, vancomycin and bacitracin
B. Inhibition of functions of cellular membrane
Polymyxin, nystatin, amphotericin B and daptomycin
C. Inhibition of protein synthesis:
 Bind to 30S or 50S ribosomal subunits, bacteriostatic
Chloramphenicol, tetracyclines, erythromycin, clindamycin,
streptogramins, and linezolid
Bind to the 30S ribosomal subunit, bactericidal
Aminoglycosides

D. Inhibition of nucleic acid synthesis
Inhibit RNA polymerase
Rifampin and rifabutin
Inhibit topoisomerases
Quinolones
E. Inhibition of folic acid synthesis
 Trimethoprim and the sulfonamides
F. Antiviral agents
Nucleic acid analogs, inhibit viral DNA polymerase
Acyclovir or ganciclovir
NRTIs, NNRTIs, PIs, Fusion inhibitors and DNA integrase
inhibitors

Penicillin G
Penicillin V
M ethicillin
O xacillin
Nafcillin
Cloxacillin
Dicloxacillin
Am picillin
Piperacillin
Ticarcillin
Carbenicillin
Am oxycillin
M ezlocillin
Azlocillin
Penicillins
Cefazolin
Cefadroxil
Cephalexin
Cephalothin
Cephradine
Cephapirin
1st generation
Cefaclor
Cefam andole
Cefonicid
Cefam etazole
Cefotetan
Cefoxitin
Cefuroxim e
2nd generation
Cefdinir
Cefixim e
Cefoperazone
Cefotaxim e
Ceftazidim e
M oxalactam
Ceftriaxone
Ceftibuten
Ceftizoxim e
3rd generation
Cefepim e
4th generation
Cephalosporins
Im ipenam s/Cilastatin
Carbepenams
Aztreonam
M onobactams
Beta lactam antibiotcs
Vancom ycin
Bacitracin
O ther antibiotics
INHIBITORS OF CELL W ALL SYNTHESIS
5th generation
Ceftaroline
Ceftobiprole

Inhibiting synthesis of bacterial cell walls

The Penicillins
• They share features of chemistry, mechanism of action,
pharmacologic and clinical effects, and immunologic characteristics
with
 Cephalosporins, monobactams, carbapenems, and β–lactamase
inhibitors, which also are β-lactam compounds
Inactive (Major Determinant)
Responsible for
hypersensitivity
Active material
Raw material for other
penicillin

Classification of Penicillins
• Narrow spectrum penicillins
 Penicillin G (benzylpenicillin, parentr), Penicillin V (oral)
 Natural penicillins
 Have the greatest activity against G+ve, G-ve cocci, and non- β-
lactamase-producing anaerobes
• Broad Spectrum Penicillins (aminopenicillin)
 Amoxicillin, Ampicillin, Bacampicillin
 Effective against streptococci, enterococci, and some G-ve
organisms
 Have variable activity against staphylococci
 Ineffective against P. aeruginosa

• Penicillinase-resistant penicillin
Cloxacillin, Nafcillin, Methicillin, Dicloxacillin, Oxacillin
Anti-staphyloccocal and streptococci penicillins
 Inactive against enterococci, anaerobic bacteria, and G-ve cocci
and rods
• Extended-Spectrum penicillins (Anti-pseudomonal penicillins)
 Carbenicillin, Mezlocillin, Piperacillin, Ticacillin
 Retain the antibacterial spectrum of penicillin G and have
improved activity against G-ve organisms, but they are destroyed
by lactamases
• Beta-lactamase inhibitors
Clavulanic acid, Sulbactam, Tazobactam

I. Narrow spectrum penicillins
A. Penicillin G ( Benzyl penicillin )(i.m ,slow i.v infusion)
 Highest activity against Gram-+ve organisms but susceptible to
beta-lactamase
 Effective against :
 Gram-+ve aerobic cocci - S. aureus- not producing penicillinase,
S. pneumoniae ( group A ), S. pyogenes
G-ve aerobic cocci -N. meningitidis, N. gonorrhea-not a choice
G+ve bacilli : Bacillus anthracis
Spirochetes : T. pallidum – drug of choice
• Half-life of IM penicillin G is 30 minutes
• To prolong duration of penicillin G Penicillin G procaine and Penicillin
G benzathine) were produced

1. Penicillin G procaine
 Duration 12- 24 hr
 It is given IM and not IV ( risk of procaine toxicity)
 Crystalline sodium penicillin G contains approximately 1600 units/mg (1 unit =
0.6 µg; 1 million units of penicillin = 0.6 g)
 Seldom used now ( increased frequency of penicillinase producing N. gonorrhea)
 Injections of penicillin G procaine are virtually painless
2. Penicillin G benzathine ( IM )
 Duration 3- 4 weeks
 Painful at the injection site ( limits its use )
 Disadvantages of penicillin G
HCl labile, inactivated by penicillinase, narrow spectrum
B. Penicillin V
 Similar spectrum as penicillin G, and more acid stable than Pen G

Therapeutic use of Penicillin G and penicillin V
• Pneumococcal Infections
 Pneumococcal Pneumonia (sensitive)
 Third-generation cephalosporin or
 20 - 24 million units (MU) of penicillin G or penicillin G procaine
/day by constant iv infusion or
 500 mg penicillin V every 6 hrs po, not recommended (resistance)
 Pneumococcal Meningitis (sensitive)
Vancomycin + third-generation cephalosporin + Dexamethasone
Or 20-24 MU of penicillin G daily by constant IV infusion/14
days

• Streptococcal Infections
 Streptococcal Pharyngitis (Including Scarlet Fever)- sensitive
 Penicillin V, 500 mg po every 6 hours for 10 days or
 600,000 units of penicillin G procaine IM/day for 10 days or
 Single injection of 1.2 MU of penicillin G benzathine
 Streptococcal toxic shock and necrotizing fascitis
 Penicillin G + clindamycin
 Streptococcal pneumonia (pyogenes), arthritis, meningitis and
endocarditis
 Penicillin G
 Streptococcal viridans endocarditis
 1.2 MU of procaine penicillin G 4x/day for 2 weeks +
streptomycin 500 mg IM/12 h or gentamicin 1 mg/kg/8 h or
 12 -20 MU /day of IV penicillin G for 2 weeks + streptomycin
500 mg IM/12 h or gentamicin 1 mg/kg/8 h or

• Enterococcal endocarditis
20 MU of penicillin G or 12 g ampicillin daily iv in combination
with a low dose of gentamicin for 6 wks
• Infections with anaerobes
Many anaerobic infections are caused by mixtures of microorganisms
Lung abscess,
Mild to moderate… penicillin G or penicillin V 400,000 MU
4x/day
Severe infections… 12-20 MU of penicillin G iv
Brain abscess,
Penicillin G (20 MU/day) plus metronidazole or chloramphenicol
• Staphylococcal Infections…produce penicillinase…treat with
penicillinase resistant pencillins (cloxacillin, nafcillin or oxacillin)

• Meningococcal infections…Penicillin G remains the drug of choice
• Gonococcal infections
Gonococci is resistant to penicillin G, and penicillins are no longer
the therapy of choice
Uncomplicated gonococcal urethritis is treated with a single IM of
250 mg ceftriaxone
• Syphilis
For less than1 year duration
 Penicillin G procaine (2.4 MU/day IM) + probenecid (1g/day po)
for 10 days
 Or 2.4 MU of penicillin G benzathine IM 1-3 weekly
Latent syphilis, neurosyphilis or cardiovascular syphilis progression
can be halted by 20 MU of penicillin G daily for 10 days

• Actinomycosis:Penicillin G is the agent of choice for the treatment of
all forms of actinomycosis
• Clostridial infections: Penicillin G is the agent of choice for gas
gangrene
Adequate debridement of the infected areas is essential
• Fusospirochetal infections
 500 mg penicillin V given every 6 hours for several days
• Listeria monocytogenes
 Ampicillin and penicillin G are the drugs of choice
• Lyme disease: Although a tetracycline is the usual drug of choice for
early disease, amoxicillin is effective
• Pasteurella multocida is the cause of wound infections after cat or
dog bite…penicillin G and ampicillin

• Prophylactic use-
A. Rheumatic fever: Benzathine pen. : 1.2 MU every 4 wks till 18
years of age
B. Gonorrhoea or syphilis : Procaine or Benzathine pen. 2.4 MU
single dose within 12 hrs of contact

Methicillin Oxacillin
Cloxacillin Dicloxacillin
Floxacillin Nafcillin
• Lower activity against G+ve compared to Penicllin G
• Are the choice for infections caused by penicillinase producing S.
aureus and S. epidermidis that are not methicillin-resistant
• For methicillin resistant strains vancomycin is considered the drug of
choice, rifampin can be added when foreign body is involved
• Not effective against G-ve aerobes (E. coli, klebsiella, N. gonorrhea
or pseudomonas spp.)
• Less active than penicillin G on anaerobes
II. Penicillinase-resistant penicillins

III. Broad- spectrum penicillins
• Ampicillin, Ampicillin- sulbactam, Amoxicillin, Amoxicillin-
clavulanic acid
• Talampicillin, Bacampicillin, Pivampicillin and Hetacillin are prodrugs
of ampicillin …better absorption and tissue penetration
• Less active than penicillin G against G+ve cocci
• Active against G-ve organisms
• Ampicillin and amoxicillin (rapid and complete abs’n) have
1. Similar spectrum to Penicillin G but more active against Gram-ve
cocci and enterobacteria
2. Inactive against P. aeruginosa
3. Non-toxic and can be taken orally
4. High doses….change gut flora….problems such as diarrhea

• Therapeutic Uses
 H. Influenza infections ( otitis media, sinusitis, chronic bronchitis,
pneumonia, bacterial meningitis )
 M. catarrhalis
 E. Coli infections ( Urinary & biliary infections )
 Samonella infections ( typhoid fever )
 Shigella infections ( ampicillin )
 Gonococcal infections ( alternative for penicillin in the treatment of
gonorrhea )
 Prophlaxis of infective endocarditis
• Amoxicillin & ampicillin alone are readily destroyed by Staph.
Penicillinase

• Ticarcillin, ticarcillin-clavulanic acid, piperacillin, piperacillin-
tazobactam (Tazocin ), azlocillin, mezlocillin, carbenicillin
• Carbenicillin and ticarcillin
Active against P. aeruginosa and certain Proteus spp (ampi resistant)
Ineffective against most strains of S. aureus, Enterococcus faecalis,
Klebsiella, and L. monocytogenes
Mezlocillin and piperacillin, have superior activity against P.
aeruginosa compared with carbenicillin and ticarcillin
Mezlocillin and piperacillin are useful for treatment of infections with
Klebsiella
• Are sensitive to destruction by β-lactamases
IV. Antipseudomonal Penicillins

• Ticarcillin is two to four times more active against P. aeruginosa
• Ticarcillin is inferior to piperacillin for the treatment of serious
infections caused by Pseudomonas
• Piperacillin-tazobactam has the broadest antibacterial spectrum of the
penicillins
• Piperacillin and related agents are important agents for the treatment of
patients with serious infections caused by G-ve bacteria
 Bacteremias, pneumonias, infections following burns, and urinary
tract infections
 Bacteremias- P. aeruginosa, indole-positive strains of Proteus, and
Enterobacter spp

• Therapeutic uses
Piperacillin and related agents are important for g-ve bacterial
hospital infection
Treating bacteremias, pneumonias, infections following burns, and
UTI (resistant to penicillin G and ampicillin)

Absorption, distribution & metabolism of penicillins
• Oral absorption of most penicillins is poor
 Exception: penicillin V and amoxicillin
• Food interfere with absorption (not ampicillin)
 To increase GI absorption: give ester form:
 Bacampicillin
 Carbenicillin indany
• Distribution
 Widely distributed
 Relatively insoluble in lipid
 Hence, have poor penetration into cells and BBB
 Inflammation (eg. Meningitis) permits entrance into CSF

• Protein binding differs :
Ampicillin and penicillin G 20% bound
Nafcillin, oxacillin, 90% bound
cloxacillin , dicloxacillin
• Metabolism and excretion
 Not metabolized in human
 Excreted mostly unchanged in urine( except. Nafcillin, oxacillin,
cloxacillin, dicloxacillin )
 Probenecid blocks their secretion
 Half-life 30-60 min ( increased in renal failure)

Resistance against Penicillin
•Natural
Target enzymes and PBPs are deeply located (Lipoprotein barrier in
G–ve)
PBPs of organisms have low affinity for penicillin
•Acquired
Production of Penicillinase (Beta-Lactamase) enzyme, (>300
subtypes). Common organisms producing Beta-Lactamase are
Staphylococcus
Bacillus subtilis
Gonococci
E. coli
Enterococci
Haemophilus influenza
•Loss or alteration of Porin channels in G-ve
•Modification of penicillin binding proteins (PBPs)- having low affinity
•Activation of antibiotic efflux mechanism- Some G-ve bacteria

Adverse effects of penicillins
1. Hypersensitivity reactions (immediate, accelerated & late allergic
rxns)
Urticarial rash, Fever, Bronchspasm, Serum sickness, Exfoliative
dermatitis, Stevens- Johnson syndrome and Anaphylaxis
The major antigenic determinant of penicillin hypersensitivity other
than anaphylaxis is its metabolite, penicilloic acid, which reacts
with proteins and serves as a hapten to cause an immune reaction
Minor determinants ( Penicillamine and Penicillenate) are
responsible for anaphylaxis

2. Diarrhoea
3. May cause convulsions after high doses by IV or in renal failure
4. Super infections (Ampicillin)
5. Nephrotoxicity (Methicillin causing interstitial nephritis)
6. Increase in Prothrombin time leading to bleeding
7. Jarisch -Herxheimer Reaction-
Characterized by fever, myalgia, exacerbation of lesions,
Usually occurs within 2 hours of first dose
Treatment- NSAIDs and Corticosteroids
Also in Borelliosis, Leptospirosis, and Brucelosis

Drug Interactions
• With Tetracyclines, Chloramphenicol, Erythromycin-
– Antagonism
• Penicillin with Aminoglycosides-
– Synergism
• Penicillin and Aminoglycosides or Penicillin and hydrocortisone in
same syringe –
– Inactivate each other (Pharmaceutical)???
• Ampicillin with Allopurinol –
– High incidence of non-urticarial maculopapular rashes
• Penicillin with Probenecid
– Prolongs action of penicillin by decreasing tubular secretion

Cephalosporins and Cephamycins
• Similar to penicillins chemically, in mechanism of action and toxicity
• Originally derived from the fungus, Cephalosporium acremonium
• Are more stable than penicillins to many bacterial β-lactamases and
therefore usually have a broader spectrum of activity
• They are not active against enterococci and Listeria monocytogenes

Generatio
n
Drugs Route of
administration
Activity
1st gen. Cefadroxil Oral •Strong G+ve coverage
•Some G-ve coverage
•Some activity againt E. Coli,
Klebsiella, H. influenza, P.
miriabilis
•Major role in surgical
prophylaxis
•Strong action against MSSA and
strep
•Poor at anaerobes
Cefazolin Parenteral
Cephalexin Oral
Cephalothin IV
Cephapirin IV
Cephradine Oral, IM, IV
Classification of cephalosporins

Gener
ation
Drugs Route activity
2nd
gen.
Cefaclor Oral
• Stronger G-ve coverage, retain some G+ve
coverage (b/n 1st &3rd gen)
• Retain activity against aerobic and anaerobic
strep, lose some effectiveness against MSSA
• Effective against N. gonorrhea, cefuroxime
for N. meningitidis
• Activity against Enterobacteriaceae except
Enterobacter
• No activity against Acinetobacer,
Pseudomonas or Stenotrophomonas
• All are strong against E. Coli & K.
pneumoniae
• Cepamycins and Carbacephems have
activity against G-ve anerobics, including B.
fragilis
Cefamandole
Cefminox IV
Cefonicid IV
Ceforanide IM, IV
Cefotiam IV, IM
Cefprozil Oral
Cefbuperaz
one
Cefuroxime Oral, IV,
IM
Cefuzonam
Cephamycin
(Cefoxitin,
Cefotetan,
Cefmetazole)
IV
Carbacephe
m
(Loracarbef)
Oral

3rd gen. Cefixime Oral
• Extremely popular choices for
parenteral route
• Are relatively resistant to β-lactamases
• Lack activity against G+ve (except
ceftriaxone and cefotaxime) and
anaerobes
• Effective againt Enterbacteriaceae,
(Enterobacter, Citrobacter, Providencia,
Morganella), Aeromonas
• Variable against Acinetobacter,
Pseudomonads
•No activity against Stenotrophomonas
maltophilia
Cefapene Oral
Cefdinir Oral
Cefditoren Oral
Cefpodoxime Oral
Cefetamet Oral
Cefteram Oral
Ceftibuten Oral
Cefotaxime Parenteral
Ceftazidime Parenteral
Ceftriaxone Parenteral
Cefmenoxime Parenteral
Cefpiramide Parenteral
Cefodizime Parenteral
Cefoperazone Parenteral
Cefsulodin Parenteral
Ceftizoxime Parenteral
Oxacephem, Cefdaloxime
Cefpimizole, Ceftiolene

Gen. Drugs Route Activity
4th
gen.
Cefepime IV, IM • Excellent penetration (brain)
• Broadest spectrum of activity of any
cephalosporins
G-ve activity is broader than 3rd
gen with good activity against
Pseudomonas
G+ coverage comparable to 1st
generation
More resistant to hydrolysis by β-
lactamase
Little activity for Enterococci or
enteric anerobes
Cefozopran
Cefpirome

Gen. Drugs Activty
5th
gen.
Ceftobiprole • Combines the activity of the 3rd
and 4th generation cephalo
• Best in vitro activity of any β-
lactam agent against MRSA
• Designed to bind to and inactivate
PBP2a, which confers resistance in
MRSA to β-lactam agents
• Active against MRSA,
penicillin-resistant S
pneumoniae, P aeruginosa,
and Enterococci
• Non-inferior to the
combination of vancomycin
and ceftazidime for skin and
soft tissue infections
Ceftaroline
• Activity against MRSA and
G+ve
• Retains broad spectrum
activity against G-ve

Therapeutic Uses
• Skin and soft tissue infections owing to S. aureus and S. pyogenes….
first-generation cephalosporins
• Prophylaxis for procedures in which skin flora are the likely pathogens
… single dose of cefazolin just before surgery
• For colorectal surgery…. second-generation agents cefoxitin or
cefotetan are preferred
• The second-generation cephalosporins generally have been displaced
by third-generation agents

• Gram-negative bacteria and anaerobes are involved (intra-abdominal
infections, pelvic inflammatory disease and diabetic foot infection,
cefoxitin and cefotetan both are effective
• Drugs of choice for serious infections caused by Klebsiella,
Enterobacter, Proteus, Providencia, Serratia, and Haemophilus spp
Third generation cephalosporins with or without aminoglycosides
• Ceftriaxone is the therapy of choice for all forms of gonorrhea and for
severe forms of Lyme disease

• Cefotaxime or ceftriaxone + vancomycin and ampicillin is used to
treat meningitis in non-immunocompromised patients age >3 yrs
• Third gen ceph are drugs of choice for
Meningitis caused by H. influenzae, sensitive S. pneumoniae, N.
meningitidis and G-ve enteric bacteria
• Ceftazidime + aminoglycoside is the drug of choice for Pseudomonas
meningitis
• Community-acquired pneumonia…. cefotaxime and ceftriaxone
• Empirical treatment of antibiotic resistant nosocomial infections…
fourth generation cephalosporin

Adverse Reactions of Cephalosporins
• Hypersensitivity reactions
Reactions appear to be identical to those caused by the penicillins
Anaphylaxis, bronchospasm, and urticaria are observed
After several days of therapy maculopapular rash develops
Patients who are allergic to cephalosporins are cross allergic to
penicillins
• Synergistic nephrotoxicity with cephalothin and gentamicin or
tobramycin

Other Beta Lactam Drugs
Monobactams
• Aztreonam is a monobactam
• Differs from beta lactam, resembles aminoglycosides
• They are relatively resistant to β-lactamases and active against gram-
negative rods
• Active against pseudomonas and serratia
• They have no activity against gram-positive bacteria or anaerobes
• Penicillin-allergic patients tolerate aztreonam without reaction
• The clinical usefulness of aztreonam has not been fully defined
• Patients who are allergic to penicillins or cephalosporins do not react to
aztreonam
• Quite useful for treating gram negative infections, that could be treated
with above drugs, but without allergy was there

Carbapenems
• Include: Imipenem / cilastatin, meropenem and ertapenem
• They are the broadest spectrum beta lactam antibiotics
• Plays a role in emperical therapy because it is active against
penicillinase producing G-ve and G+ve organisms, anaerobes, and p.
Aeruginosa
• Imipenem
 Marketed in combination with cilastatin
 Produced by Streptomyces cattleya
 Binds to PBPs, disrupts bacterial cell wall synthesis
 It is very resistant to hydrolysis by most β-lactamases

 Imipenem-cilastatin is used to treat
UTI, lower respiratory infection
Intra-abdominal and gynecological infections
Skin, soft tissue, bone and joint infections
Cephalosporin-resistant nosocomial bacterial infections
Should not be used as monotherapy for infections owing to P.
aeruginosa
• Meropenem: therapeutically equivalence with imipenem
 Effective without cilastatin
• Ertapenem: have inferior activity against P. aeruginosa and
Acinetobacter spp. than imipenem and meropenem
 Have a larger serum half-life

• Adverse effects
 Nausea and vomiting
 Seizures , when high doses given in patients with CNS lesions and
those with renal insufficiency
 Allergic to penicillins may show hypersensitivity
 Lesser eosinophilia and neutropenia

• β-lactamase inhibitors
Clavulanic acid, Sulbactam and Tazobactam
Most active against plasmid-encoded β-lactamases
Inactive against the type I chromosomal β-lactamases
Amoxicillin plus clavulanate + ciprofloxacin effective for
Low-risk, febrile patients with neutropenia (oral) from cancer
chemotherapy
Acute otitis media in children, sinusitis, animal or human bite
wounds, cellulitis and diabetic foot infections

Other Cell Wall- Active Agents
Vancomycin
• Produced by Streptococcus orientalis
• Active only against G+ve bact., staphylococci (except flavobacterium)
• Narrow-spectrum against MRSA and pseudomembranous colitis
caused by clostridium defficile
• It binds firmly to the D-Ala-D-Ala terminus and inhibits
transglycosylase
• Prophylaxis for sub-acute bacterial endocarditis in penicillin allergic
patients for high risk surgery
• Oral route only for P. colitis and IV for systemic infections
• Resistance: modification of the D-Ala-D-Ala binding site, terminal D-
ala is replaced by D-lactate

• Clinical uses of Vancomycin
Mainly for sepsis or endocarditis caused by MRSA
Not as effective as an antistaphylococcal penicillin for tt of serious
endocarditis caused by MSSA
Vancomycin + gentamicin alternative for enterococcal endocarditis
during penicillin allergy
Vancomycin + cefotaxime, ceftriaxone, or rifampin for tt of
meningitis caused by penicillin-resistant strain of pneumococcus
• Toxicity:
 Fever, chills, phlebitis, rash, ototoxicity and nephrotoxicity
 Slow IV administration- fast causes histamine release (“red man
syndrome”) and hypotension

Newer glycopeptide antibiotics
• Teicoplanin
– very similar to vancomycin in mechanism of action and
antibacterial spectrum
– It can be given by IM and IV
• Dalbavancin
– Derived from teicoplanin
– Effective on methicillin-resistant and vancomycin-intermediate S
aureus
• Telavancin
– Derived from vancomycin
– Active versus gram-positive bacteria
– Including strains with reduced susceptibility to vancomycin

• Daptomycin
– Novel cyclic lipopeptide
– Similar to that of vancomycin
– Active against vancomycin-resistant strains of enterococci and S.
aureus
• Fosfomycin
– Analog of phosphoenolpyruvate
– It inhibits the cytoplasmic enzyme enolpyruvate transferase
– Active against both gram-positive and gram-negative bacteria
– A single 3 g dose for tt of uncomplicated lower UTI in women

• Cycloserine
 Produced by Streptomyces orchidaceus
 Inhibits many G-ve and G+ve organisms, MTB
 Structural analog of D-alanine and inhibiting alanine racemase and
D-alanyl-D-alanine ligase
• Bacitracin
 Bacitracin inhibits cell wall synthesis by interfering with
dephosphorlyation in cycling of the lipid carrier
 Effective against G+ve microorganisms
 Topical application due to nephrotoxicity
 Often used for traumatic abrasions

Classıfıcatıon of ınhıbıtors of bacterıal proteın synthesıs
• Drugs that affect the 30S ribosomal subunit
 Aminoglycosides -Tetracyclines - Other Antibiotics
 Gentamicin Doxycycline -Spectinomycin
 Neomycin Minocycline
 Streptomycin Tetracycline
• Drugs that affect the 50s ribosomal subunit
Macrolides - Ketolide -Other Antibiotics - Other Inhibitors
Azithromycin Telithromycin Chloramphenicol Linezolid
Clarithromycin Clindamycin
Erythromycin Quinupristin-dalfopristin

Tetracyclines (TTCs)
• All of the tetracyclines have the basic structure shown below:
• Tetracyclines are classified as
 Short-acting (chlortetracycline, tetracycline, oxytetracycline)
 Intermediate-acting (demeclocycline and methacycline),
 Long-acting (doxycycline and minocycline)

• Antimicrobial Activity
 Tetracyclines are broad-spectrum bacteriostatic antibiotics
 Rickettsia (all tetracyclines are highly effective)
 Coxiella burnetii
 Mycoplasma pneumoniae
 Chlamydia spp.
 Legionella spp.
 Ureaplasma
 Some atypical mycobacteria
 Plasmodium spp, amoeba
 G-ve and G+ve bacteria, aerobes, anaerobes
 But no activity to Enterococci, Proteus and P. aeruginosa

• They enter microorganisms by passive diffusion and active
transport
• They 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 amino acids to the growing peptide
• Tetracyclines can inhibit mammalian protein synthesis, but
because they are "pumped" out of most mammalian cells do
not usually reach concentrations needed to significantly
reduce mammalian protein synthesis

• Resistance:
1) Impaired influx or increased efflux (most important)
2) Production of proteins that interfere with TTC binding to the
ribosome
3) Enzymatic inactivation
Tetracycline resistance is a marker for resistance to multiple
drugs
(aminoglycosides, sulfonamides, and chloramphenicol)
Doxycycline & minocycline are active against TTC resistant
bacteria

• Pharmacokinetics
Tetracyclines do not differ much in their antibacterial activity and are
distinguished more by their pharmacokinetic behavior
Oral absorption:
30% for chlortetracycline
60–70% for TTC, oxytetracycline, demeclocycline, and
methacycline
95–100% for doxycycline and minocycline
Impaired by food (except doxycycline and minocycline)
All tetracyclines chelate with metals
 Tetracyclines are 40–80% bound by serum proteins
 Distribute widely to tissues and body fluids except for CSF

• TTCs cross the placenta to reach the fetus and excreted in milk
• Doxycycline and minocycline are the most widely used
 They do not aggravate renal failure so that they can be used in
patients suffering renal impairment
 They exhibit marginally better antibacterial activity
 They display sufficiently long serum half-lives to allow them
to be given only once or twice daily
• TTCs should not be given to young children (< 8yrs), pregnant
and lactating women
• Upsurge of resistant strains cause the decline of TTC use
(enterobacteria and streptococci)

• Clinical use:
First choice for treatment of rickettsial infections
Rocky Mountain spotted fever, recrudescent epidemic typhus,
murine typhus, scrub typhus, rickettsialpox, and Q fever
Chlamydia infections (Psittacosis)
Mycoplasmas infection, nontuberculous mycobacterial
infections
 Spirochete infection, recurrent fever
Bacterial infection: First choice for treatment of cholera,
brucella, plague and tularemia infection (with aminoglycosides)
 Doxycycline is sometimes used for antimalarial prophylaxis &
treatment (combined with quinine to treat P. falciparum)

• Trachoma: Doxycycline or tetracycline
• Used in combination regimens to treat gastric and duodenal
ulcer disease caused by Helicobacter pylori
• Anthrax: Doxycycline
• Acne: Tetracyclines
• Not used in treatment of gonococcal disease because of
resistance

• Adverse reactions:
 Gastric mucosa, cramps, burning, nausea, vomiting...Can add
food if using minocycline or doxycycline
 Superinfection
 Brown discoloration of teeth & deformation of bone
 Liver Toxicity, during pregnancy and in hepatic insufficiency
when high doses are given IV
 Photosensitivity, especially demeclocycline
 Vestibular reactions, dizziness, vertigo, nausea, and vomiting
(minocycline or doxycycline at high doses)
 Tetracyclines other than doxycycline may accumulate to toxic
levels in patients with impaired kidney function

Aminoglycosides
• Molecules comprised of amino sugars which are bacteriocidal
• Produced by various species of Streptomyces and Micromonospora
• Drugs: Gentamicin, tobramycin, amikacin, netilmicin, kanamycin,
streptomycin and neomycin
• Used primarily to treat infections caused by aerobic G-ve bacteria
• Little and limited activity on G+ve and anaerobic bacteria, MTB
• Kanamycin and streptomycin have a more limited spectrum compared
with other aminoglycosides
• Tobramycin & gentamicin exhibit similar activity against most G-ve
bacilli (tobramycin > active on P. aeruginosa and some Proteus spp)
• Are rapidly conc. dependent bactericidal, have post-antibiotic effect

• Gentamicin and tobramycin exhibit cross resistance but not
amikacin and netilmicin
• All members of the group share the same spectrum of toxicity,
most notably nephrotoxicity and ototoxicity
• Not absorbed adequately after oral administration ( polycations -
polar)
• Distribution…inner ear and kidney
• Streptomycin and tobramycin can cause hearing loss in children
born to women who receive the drug during pregnancy
• They have limited value in infections caused by intracellular
bacteria

• GF is the major mode of excretion
• Inadequate concentrations are found in cerebrospinal fluid (CSF)
• Diffuse through aqueous channels in the outer membrane of G-ve
bacteria
• Transport across the cytoplasmic (inner) membrane depends on
electron transport (interior negative)
• Bind to polysomes and cause misreading and premature termination of
mRNA translation
 Aberrant proteins produced…inserted into the cell membrane
...altered permeability … further stimulation of aminoglycoside
transport
• The primary site is the 30S
• They also appear to bind to several sites on the 50S ribosomal subunit

Effects of aminoglycosides on protein synthesis

• Microbial resistance to the aminoglycosides
Bacteria may be resistant due to
Failurity of the antibiotic to penetrate intracellularly
Low affinity of the drug for the bacterial ribosome
Inactivation of the drug by microbial enzymes (Clinically
common)
Enterococcus faecalis and E. faecium are highly resistant to all
aminoglycosides
Aminoglycoside-resistant strains of enterococci can be especially
difficult to treat … cross-resistant to vancomycin and penicillin
Resistance to gentamicin indicates cross-resistance to tobramycin,
kanamycin , but streptomycin

Dosing of aminoglycosides
• Current practice is to give the total daily dose as a single injection
 Less toxicity and is just as effective as multiple-dose regimens
 Provides a longer period treatment when concentrations fall below
the threshold for toxicity
 Bactericidal activity and post-antibiotic effect is related directly to
the peak concentration achieved
 Exceptions once daily dosage
 In pregnancy, neonatal and pediatric infections
 Low-dose combination therapy of bacterial endocarditis and
kidney impairment
 In patients with creatinine clearances of < 20 to 25 ml/min
(accumulation prob) (every 48 hrs is more appropriate)

 For more than 3 to 4 days admin., plasma concentrations should be
monitored to avoid drug accumulation
 Monotherapy is poor (poor tissue penetration) except UTI
• For twice- or thrice-daily dosing regimens… peak and trough conc
should be monitored
• Gentamicin, tobramycin & amikacin are most commonly used at
present
• Neomycin and kanamycin are now largely limited to topical or oral
use

Clinical uses
• Streptomycin (the oldest and best-studied)
– Bacterial endocarditis (+ Pen), streptococcal, enterococcal
o Replaced almost entirely by gentamicin
– Tuberculosis (at least one or two drugs combination)
o 15 mg/kg per day as a single intramuscular injection for 2 to 3
months and then 2 or 3 times a week thereafter
– Tularemia: Streptomycin or Gentamicin is drug of choice
– Plague
– Less active than other members of the class against aerobic gram-
negative rods, it has fallen into disuse
– 1000 mg single daily dose or 500 mg twice daily

• Gentamicin:
 Combination with Pen/Ceph
o Urinary tract infections (E. coli, enterobacter)
o Pneumonia (pseudomonas, E. coli, kleb)
o Meningitis
o Peritonitis
o Sepsis
 Tularemia, drug of choice
 Aminoglycoside of first choice, low cost, effective against all G-ve
 Gentamicin, tobramycin, amikacin and netilmicin can be used
interchangeably
 Should be restricted to the therapy of life-threatening infections

 IM or IV gentamicin sulfate, 2mg/kg loading dose, 3 to 5 mg/kg per
day… 1/3 every 8 hrs or
 The once-daily dose is 5 to 7 mg/kg given over 30 to 60 minutes for
patients with normal renal function
o The upper limit of this dose range may be required to achieve
therapeutic levels for trauma or burn patients, those with septic
shock, and others in whom drug clearance is more rapid or volume
of distribution is larger than normal
 Periodic determinations of the plasma concentration of
aminoglycosides are recommended strongly
 Trough concentrations continually above 2 mg/ml have been
associated with toxicity

•Tobramycin
– Same as gentamicin in indications, dosage, conc & toxicity
– Poor activity against enterococci
– Superior activity against P. aeruginosa
– Should be used concurrently with an antipseudomonal β-
lactam antibiotic
– Shows poor activity in combination with penicillin against
many strains of enterococci
– Most strains of Enterococcus faecium are highly resistant
– Ineffective against mycobacteria

• Amikacin
 The broadest of the group
 Initial treatment of serious nosocomial G-ve bacilli
infections when resistance to gentamycin and tobramycin
has become a significant problem
 Similar to kanamycin in dosage and pharmacokinetic
properties
 Active against M. tuberculosis
 Used in the treatment of disseminated atypical
mycobacterial infection in AIDS patients

• Netilmicin
– The latest of the aminoglycosides
– Broad against aerobic G-ve bacilli
– Serious infections with enterobacteriaceae and other aerobic G-ve
bacilli
– Like amikacin, it is not metabolized by the majority of the
aminoglycoside inactivating enzymes
• Kanamycin
– Few indications
– Has been employed to treat tuberculosis in combination with other
effective drugs
• Neomycin
– Topical skin and mucosa infections

• Adverse Reactions
i. Ototoxicity
1. Vestibular – usually associated with total dose
2. High frequency hearing loss – associated with total dose or
persistent elevated serum concentrations
3. Risk – increases with age, length of therapy and other ototoxic
agents (loop diuretics, vancomycin, possibly clarithromycin)
ii. Nephrotoxicity
1. Characterized by decreased urine specific gravity oliguria,
proteinuria or elevated serum creatinine
2. Associated with elevated serum concentration and other renal toxic
agents
3. Renal function changes are usually reversible upon discontinuation
of the aminoglycoside
iii. Hypersensitivity
1. Rashes, as well as fever occasionally seen.

Spectinomycin
• Active against a number of G-ve bacterial species
• It is inferior to other drugs to which such microorganisms are
susceptible
• Its only therapeutic use is in the treatment of gonorrhea caused by
strains resistant to first-line drugs, or if there are contraindications to
the use of these drug
• Binds to and acts on the 30S ribosomal subunit
• Its action is similar to that of the aminoglycosides, but spectinomycin
is not bactericidal and does not cause misreading of messenger RNA
• Bacterial resistance may be mediated by mutations in the 16S
ribosomal RNA or by modification of the drug by adenylyltransferase

Chloramphenicol
• It is a potent inhibitor of microbial protein synthesis
• It binds reversibly to the 50S subunit of the bacterial ribosome
(1) chloramphenicol; (2) macrolides,
clindamycin, and type B
streptogramins; and (3) tetracyclines
• Antimicrobial activity:
Broad spectrum
Has effect on G+ve and G–ve
bacteria, ricketts organism,
spirochete, mycoplasma.
H. influenzae, N. meningitidis,
and some strains of
bacteroides are highly
Susceptible…may be
bactericidal
Resist: enzymatic inactivation

Absorption:
After oral administration, crystalline form is rapidly and
completely absorbed
Chloramphenicol palmitate, prodrug … oral
Chloramphenicol succinate, prodrug… parenteral
 After absorption wide distribution including CNS and CSF
 Excretion: 10% unchanged & 90% metabolized through
urine

• Clinical uses
It is an obsolete drug as a systemic drug
 Treatment of rickettsial infections (typhus or Rocky
Mountain spotted fever), contraindicated in children
 Alternative to β-lactam antibiotic for treatment of
meningococcal meningitis in
 Hypersensitivity reactions to penicillin
 Penicillin resistant strains of pneumococci
Topically for treatment of eye infections b/c
Wide antibacterial spectrum
Penetrate of ocular tissues and the aqueous humor

 Gastrointestinal disturbances
 Bone marrow disturbances
 Toxicity for newborn infants (> 50 mg/kg/d)
Gray baby syndrome (vomiting, flaccidity, hypothermia,
gray color, shock and collapse)
• Drug interaction (Chloramphi…enzyme inhibitor)
Phenytoin, tolbutamide, chlorpropamide and warfarin
conc. increased
Antagonize with penicillins or aminoglycosides

Macrolides
• Drugs are: Erythromycin, clarithromycin and azithromycin
• Erythromycin obtained from Streptomyces erythreus, others
are semi-synthetic derivatives

• Erythromycin
 Antimicrobial Activity: active against
o G-ve organisms
Pneumococci, streptococci, staphylococci, and
corynebacteria
Neisseria species, Bordetella pertussis, Bartonella
henselae, and B quintana
Some rickettsia species, T. pallidum, and campylobacter
species
o Mycoplasma, legionella, Chlamydia trachomatis, C
psittaci, C pneumoniae, helicobacter, listeria, and certain
mycobacteria
 It is bacteristatic or bactericidal

 Inhibit protein synthesis by binding reversibly to 50S
ribosomal subunits at or very near the site that binds
chloramphenicol
• Resistance: three mechanisms
 (1) Reduced permeability of the cell membrane or active
efflux
(2) Production of esterases that hydrolyze macrolides
(3) Modification of the ribosomal binding site (mutation
or methylase modification, inducible or constitutive)
Cross-resistance (mech. 3) with other macrolides,
clindamycin & streptogramins … share the same
ribosomal binding site

 Absorption
Destroyed by gastric acid (administered as enteric coated)
Food interferes with absorption
Stearates and esters are fairly acid-resistant and somewhat
better absorbed
Large amounts of an administered dose are excreted in the
bile and lost in feces
Widely distributed except CNS and CSF

• Clinical uses
Erythromycin is the drug of choice in
Diphtheria, corynebacterial sepsis, erythrasma
Respiratory, neonatal, ocular, or genital chlamydial
infections
Treatment of community-acquired pneumonia
 Penicillin substitute in staphylococci, streptococci, or
pneumococci infections
Prophylaxis against endocarditis during dental procedures
(valvular heart disease), clindamycin is better
Higher dosage in the treatment of legionella species

 GI effects
 Liver toxicity
• Drug Interactions
 Increase serum conc. of
 Numerous drugs, including theophylline, oral anticoagulants,
cyclosporine, methylprednisolone and digoxin
• Erythromycin base is incompletely but adequately absorbed from the
upper small intestine (empty stomach)
• Clarithromycin is absorbed rapidly from the GIT (with food)
• Azithromycin administered orally is absorbed rapidly (without food)
• Erythromycin and its congeners have same MOA, and antimicrobial
activty

• Exception:
 Clarith. more active on MTC, M. liprae, T. condii
 Clarithromycin dose adjustment is not necessary unless
CrCl<30ml/min, no need for eryth.
 Clarithromycin: lower frequency of GI intolerance and
less frequent dosing
 Azithromycin is different from the other two in PK
properties
• Azithromycin has the same activity and clinical uses as
clarithromycin

Ketolides (telithromycin)
• Approved for treatment of respiratory tract infections
• Ketolides and macrolides have the same ribosomal target site and have
similar antibacterial properties
• Used to treat MDR S. pneumoniae
• Active against many macrolide-resistant G+ve strains (structural
modification of macrolides)
 ketolides neutralize the common macrolide resistance mechanisms
 3-keto function converts a methylase-inducing macrolide into a
noninducing ketolide…also prevents drug efflux
 The carbamate substitution at C11-C12 enhances binding to the
ribosomal target site, even when the site is methylated

Therapeutic Uses
• Used for treatment of respiratory tract infections
Acute exacerbation of chronic bronchitis (5-day regimen)
Acute bacterial sinusitis (5-day regimen)
Community-acquired pneumonia (7- to 10-day regimen)
 Not indicated for treatment of severe pneumonia or bacteremia, but
pneumococcal bacteremia were clinically cured after taking it
MDR strains of S. pneumoniae (resistant to penicillins,
cephalosporins, macrolides, tetracyclines, or trimethoprim-
sulfamethoxazole)

Lincosamides
• Example
– Clindamycin, Chlorine substituted derivative of lincomycin
– Lincomycin, Streptomyces lincolnensis (toxic and no longer used)
• Resembles erythromycin in activity
• MOA
– Bind to 50S
– Block elongation
– Inhibits protein synthesis
• Clindamycin is more potent than lincomycin especially against
obligate anaerobes

• Clindamycin
Antibacterial Activity
Streptococci, staphylococci & pneumococci, C. difficile (rest.)
Enterococci & G-ve aerobic organisms are resistant (sens. to eryth.)
Bacteroides and other anaerobes (G+ve & G-ve) are susceptible
Clindamycin, erythromycin and CAF act at sites in close proximity
(interact)
Cross-resistance with macrolides due to
o Mutation of the ribosomal receptor site
o Modification of the receptor by a constitutively expressed
methylase
o Enzymatic inactivation of clindamycin
Not a substrate for macrolide efflux pumps (active against macrolide
resistant strains by mechanism)

 MSSA usually are susceptible to clindamycin
 Clindamycin is more active than erythromycin or clarithromycin
against anaerobic bacteria
 Essentially all aerobic gram-negative bacilli are resistant
•PK: 90% protein-bound, excretion is mainly via the liver, bile and urine
• Therapeutic use
 Clindamycin plus primaquine and clindamycin …second-line
regimens for Pneumocystis jiroveci pneumonia
 Clindamycin plus pyrimethamine … second-line regimens for T.
gondii encephalitis

 For serious infections due to aerobic G+ve cocci and the more
sensitive anaerobes
High incidence of diarrhea and the occurrence of
pseudomembranous colitis limit its use
 Clindamycin is not predictably useful for the treatment of bacterial
brain abscesses
 Metronidazole in combination with penicillin or a third-generation
cephalosporin is preferred
Clindamycin is particularly valuable for the treatment of infections
with anaerobes (B. fragilis)
Clindamycin has replaced penicillin as the drug of choice for
treatment of lung abscess and anaerobic lung and pleural space
infections

•Adverse Effects
Diarrhea, nausea, and skin rashes
Impaired liver function
Antibiotic-associated colitis followed administration of
clindamycin and other drugs is caused by toxigenic C
difficile
This potentially fatal complication must be treated with
metronidazole, or vancomycin

Streptogramins
• Two Groups
– A: nonpeptide
– B: cyclic peptides
• Examples
– A: Dalfopristin
– B: Quinupristin
• MOA
– Group A
• Distort ribosomes
• Prevent tRNA binding
– Group B
• Block translocation
• Quinupristin- Dalfopristin combination
(30:70 ratio)
• Bactericidal
• It has a prolonged postantibiotic effect
• Renal elimination accounts for less than
20%

• Therapeutic Uses of Quinupristin-dalfopristin combination
 For treatment of vancomycin-resistant strains of E. faecium and
complicated skin infections caused by MSSA or S. pyogenes
For treatment of nosocomial pneumonia and infections caused by
MRSA
Should be reserved for treatment of serious infections caused by
MDR G+ve organisms such as vancomycin-resistant E. faecium

Oxazolidinones
• New antibiotics
• Example
– Linezolid
• MOA
– Prevents 30S-50S assembly
 binding to the P site of the 50S and prevent formation of the
larger ribosomal-fMet-tRNA complex that initiates protein
synthesis
– Interferes with mRNA
• There is no cross-resistance with other drug classes
• Resistance in enterococci and staphylococci is due to point mutations
of the 23S rRNA

• Therapeutic Uses of Linezolid
Vancomycin-resistant E. faecium
Nosocomial pneumonia (MRSA and MSSA)
Community-acquired pneumonia caused by penicillin-susceptible
strains of S. pneumoniae
Complicated skin infections (streptococci and MSSA and MRSA)
Reserved agent for tt of infections caused by MDR strains
• ADRs
 Generally well tolerated w/ minor SE in short term Rx
 Myelosuppression: anemia, leukopenia, pancytopenia,
thrombocytopenia
 Peripheral and optic neuropathy

Sulfonamides and Trimethoprim
pyrimethamine

Sulfonamides
• They are the first effective chemotherapeutic agents for prevention
and cure of bacterial infections
• Susceptible microorganisms require extracellular PABA in order to
form dihydrofolic acid
• Structural analogs of PABA that competitively inhibit dihydropteroate
synthase
• They are only bacteristatic
• Sulfonamides inhibit
 G+ve and G-ve bacteria
 Nocardia, Chlamydia trachomatis and some protozoa
 E coli, klebsiella, salmonella, shigella and enterobacter
 Rickettsiae are not inhibited (stimulated in their growth)

Sulfonamides: resistance
• Overproduction of PABA due to mutation
• Low affinity dihydropetroate synthase for sulfonamides
• Decreased bacterial permeability or active efflux of the drug
• An alternative metabolic pathway for synthesis of an essential
metabolite

Pk Properties of Some Sulfonamides and Trimethoprim
Drug Half-Life Oral Absorption
Sulfonamides
Sulfacytine Short Prompt (peak levels in 1–4 hours)
Sulfisoxazole Short (6 hours) Prompt
Sulfamethizole Short (9 hours) Prompt
Sulfadiazine Intermediate (10–17 hours) Slow (peak levels in 4–8 hours)
Sulfamethoxazole Intermediate (10–12 hours) Slow
Sulfapyridine Intermediate (17 hours) Slow
Sulfadoxine Long (7–9 days) Intermediate
Pyrimidines
Trimethoprim Intermediate (11 hours) Prompt

Clinical uses
• Infrequently used as single agents
• Formerly drugs of choice for infections such as
 Pneumocystis jiroveci pneumonia, toxoplasmosis, nocardiosis
• Supplanted by fixed combination of trimethoprim-sulfamethoxazole
• Formerly susceptible species, including meningococci, pneumococci,
streptococci, staphylococci and gonococci are now resistant
• Oral absorbable agents
– Sulfisoxazole, sulfamethoxazole
• To treat urinary tract infection
– Sulfadiazine + pyrimethamine (synergistic) : toxoplasmosis
– Sulfadoxine: long acting, in a combination for treatment of malaria

• Oral nonabsorbable agents (Sulfasalazine)
Ulcerative colitis, enteritis, other inflammatory bowel
disease
• Topical agents
Sodium Sulfacetamide solution or ointment: ophthalemic
(Bacterial conjunctivitis and as adjunctive therapy for
trachoma)
Mafenide & silver sulfadiazine: Used topically to treat
infections of burn wounds

Adverse reactions
• Cross allergenic sulfonamide drugs:
– Thiazide, furosemide, diazoxide, sulfonylurea hypoglycemic agents, and
others
– Fever, skin rashes, exfoliative dermatitis,photosensivity, urticaria,
nausea, vomiting, diarrhea
– Stevens-Johnson syndrom
• Urinary tract disturbances
– Crystalluria, hemturia, obstruction
• Hematopoietic disturbance
– Hemolytic or aplastic anemia
– Granulocytopenia, thrombocytopenia, leukmoid reaction
– Hemolysis in G-6PDH deficient patients
– Kernicterus in newborn of mothers have taken near the end of pergnancy

Trimethoprim & Trimethoprim-Sulfamethoxazole Mixtures
• Trimethoprim inhibits bacterial dihydrofolic acid reductase
about 50,000x more efficiently than the same enzyme of
mammalian cells
• Pyrimethamine inhibits the activity of dihydrofolic acid
reductase of protozoa more than that of mammalian cells
• Trimethoprim or pyrimethamine, given together with
sulfonamides, produces synergistic activity
• The combination often is bactericidal

• Trimethoprim: resistance
 Reduced cell permeability
 Overproduction of DHF reductase
 Mutation: plasmid-encoded trimethoprim-resistant dihydrofolate
reductases
 Altered affinity of reductase
• Trimethoprim: pharmacokinetics
 Usually given orally alone or in combination with
sulfamethoxazole
 Mainly excreted into urine
 More antibacterial activity in prostatic and vaginal fluids

Clinical use
• Oral trimethoprim
– Acute urinary infection
• Oral trimethoprim-sulfamethoxazole
– P. jiroveci pneumonia, shigellosis, systemic salmonella
infection, complicated urinary tract infection
– Active against many respiratory pathogens
• Intravenous trimethoprim-sulfamethoxazole
– G-ve sepsis, pneumocystis pneumonia
– Shigllosis, typhoid fever

• Oral pryrimethamine with sulfonamide
– With sulfadiazine in Leishmaniasis, toxoplasmosis
– With sulfadoxine in malaria
 Two double-strength tablets (trimethoprim 160 mg plus
sulfamethoxazole 800 mg) bid for UTI and prostatitis,
susceptible strains of shigella and salmonella
• Adverse effects
 Megaloblastic anemia
 Hemolysis in G6PD deficient patients
 Leukopenia, granulocytopenia
 Can be prevented by folinic acid
 The AIDS patients have high frequency of unwanted
reactions

Nucleic acid inhibitors
• Quinolones and Fluoroquinolones
 Nalidixic acid, oxolinic acid and cinoxacin are first
members
 Fail to achieve systemic antibacterial levels
 Used only to treat lower urinary tract infections
 Same MOA as FQs
 Rarely used now, having been made obsolete by the
more efficacious fluorinated quinolones

 Fluorination of Quinolones –Fluoroquinolones
 Improved antibacterial activity
 G-ve mainly (Plus G+ve New FQs), aerobic bacteria
 Moxifloxacin and trovafloxacin active against
anaerobic infection
• Ciprofloxacin is the prototype drug
• Norfloxacin is the least active of the fluoroquinolones (MIC
2-8x > MIC of Ciprofloxacin)

Members
Quinolones (Narow
spectrum)
• Nalidixic acid
• Acrosoxacin
• Cinoxacin
• Flumequine
• Oxolinic acid
• Pipemidic acid
• Piromidic acid
Fluoroquinolones improved spectrum
New Generations Clinafloxacin
• Lomefloxacin Gatifloxacin
• Levofloxacin Gemifloxacin
• Prulifoxacin Moxifloxacin
• Sparfloxacin Pazufloxacin
• Gatifloxacin Sparfloxacin
• Gemifloxacin Tosufloxacin
• Moxifloxacin Trovafloxacin
• Trovafloxacin
• Alatrofloxacin
• Finafloxacin
Fluoroquinolones
First Generation
 Ciprofloxacin
 Norfloxacin
 Pefloxacin
 Ofloxacin
Second
Third
Fourth

• MOA- (Queen stops gyrating dancers)
In gram negative –
Inhibition of DNA gyrase enzyme (prevents relaxation of positively
supercoiled DNA required for normal transcription and replication)
 In gram positive –
 Inhibition of Topoisomerase IV (interferes with separation of
replicated chromosomal DNA)
 Both DNA gyrase and Topoisomerase can be inhibited in an
organism
 Why not human cells affected ?
Mammalian cells have Topoiosmerase II (serve as inhibiting
positive supercoiling)

Antibacterial Spectrum of quinolones
• Fluoroquinolones are potent bactericidal agents against
 E. coli, Salmonella, Shigella, Enterobacter, Campylobacter,
staphylococci, P. aeruginosa and Neisseria
 Limited efficacy against Enterococci and Streptococci
 Intracellular bacteria such as Chlamydia, Mycoplasma, Legionella,
Brucella, and Mycobacterium (including MTB)
 Anaerobic bacteria (garenoxacin, Moxifloxacin, trovafloxacin and
gemifloxacin)
• Fluoroquinolones are inactive against MRSA but active on MSSA
• Ciprofloxacin is the most active agent of this group against G-ves, P.
aeruginosa in particular
• Levofloxacin, the L-isomer of ofloxacin and twice as potent, G+ve
MOs

• Resistance-
Due to mutation in chromosomes
Altered DNA gyrase and Topoisomerase IV
Reduced permeability for drug
Increased efflux of drug
Cross-resistance exists (if high level) among members of
this class

Pharmacokinetics
• Orally well absorbed and widely distributed
• Long half-life (once daily dose) drugs
 levofloxacin, moxifloxacin, sparfloxacin, and trovafloxacin
• Oral absorption is impaired by divalent ions (antacids, other metal
containing substances)
• Serum conc. of drug after oral and IV admin. is the same
• Conc. higher than serum in prostate, kidney, neutrophils, and
macrophages
• Dose adjustment is required in renal failure except trovafloxacin,
moxifloxacin and Pefloxacin

Clinical uses
• UTIs (even for MDR bacteria including peudomonas)
 Nalidixic Acid
 Fluoroquinolones are significantly more potent (broad spectrum)
 Norfloxacin 400 mg, ciprofloxacin 500 mg & ofloxacin 400 mg
orally bid are all effective
 More efficacious than co-trimoxazole
• Diarrhea
Caused by shigella, salmonella, toxigenic E coli, or campylobacter
• Tuberculosis and atypical mycobacterial infections
Ciprofloxacin or levofloxacin (occasionally)
• Prostatitis:
Norfloxacin, ciprofloxacin and ofloxacin
Used for patients not responding to co-trimoxazole

• Sexually Transmitted Diseases:
 The quinolones are contraindicated in pregnancy
 Chancroid (H. ducreyi): treated with 3 days of cipro
 Gonorrhea tt - Single dose Ciprofloxacin 500mg
• Chlamydia trachomatis- Ciprofloxacin one week or single
dose Azithromycin
• Respiratory Tract Infections
Levofloxacin, Moxifloxacin, Gemifloxacin, Gatifloxacin,
Sparfloxacin have good activity against S. pneumonia,
respiratory FQs (good activity against anaerobes)

• Bone, Joint and Soft Tissue Infections
 Caused by S. aureus and gram-negative rods
 Ciprofloxacin should not be given to children or pregnant
women
• Ciprofloxacin received wide usage for the prophylaxis of
anthrax (treatment of tularemia)
• Neutropenic cancer patients with fever
 Quinolone + aminoglycoside = β-lactam +
aminoglycoside

Adverse Effects
• They are extremely well tolerated
• The most common effects are nausea, vomiting, and diarrhea
• Trovafloxacin cause hepatic failure
• Grepafloxacin was withdrawn due to QTc interval prolongation,
induce arrythmia
• Sparfloxacin, gatifloxacin, levofloxacin and moxifloxacin also cuase
QTc prolongation…used with caution in
Uncorrected hypokalemia
Quinidine or procainamide
Sotalol, ibutilide, amiodarone
Erythromycin, tricyclic antidepressants
• They are not used in patients under 18 years of age, damage growing
cartilage and cause arthropathy…reversible..Pseudomonas
• Tendenitis in adults…avoid in pregnancy

• Ciprofloxacin-
 Long Post Antibiotic Effect (PAE)
 Less active at acidic pH
 Interacts with food and calcium
 High tissue penetrability ( Except BBB)
 High conc. in urine and bile
 CNS SE and tendonitis and tendon rupture and damage growing
cartilage and cause an arthropathy are FQs SES
 Uses
 CNSI, OI, ENTI, RTI, GITI, UTI, STDs
 Nosocomial infections and septicaemia
 Tuberculosis- MDR TB and XDR TB

Typhoid
oTreatment 2 weeks
oPrevention of carrier state 2 months
oOther drugs- Other FQs
Cephalosporins ,Ceftriaxone (Fastest)
Chloramphenicol, Cotrimoxazole and Ampicillin
• No FQs effective against spirochaetes
• Ofloxacin and Pefloxacin are effective against M. leprae
• Moxifloxacin is the only FQ not used in UTI as its concentration is
poor in urine
• Chronic Prostatitis treatment - Ciprofloxacin for 1 to 2 months

Elimination of Fluoroquinolones
 Renal
•Norfloxacin
•Ofloxacin
•Ciprofloxacin
•Lomefloxacin
•Levofloxacin
•Gatifloxacin
 Hepatic
•Pefloxacin
•Moxifloxacin
•Trovafloxacin
•Sparfloxacin
•Gemifloxacin
Fluoroquinolones safe in renal failure
Pefloxacin
Moxifloxacin
Trovafloxacin

• Other broad spectrum antimicrobials
Nitroimidazoles: Anaerobic infections only
As a group cover bacteria, fungi, viruses, protozoa, and helminths
Include metronidazole, tinidazole, ornidazole, secnidazole and
nimorazole
Metronidazole possesses potent antibacterial activity against
Strict anaerobes
Some micro-aerophilic bacteria (Gardnerella vaginalis and H.
pylori)
Bacterial resistance is uncommon against metronidazole
Now it is the drug of choice for the tt of anaerobic infections
Used for prophylaxis in some surgical procedures (anaerobes are
likely infective bacteria)
Reduced form of metronidazole is thought to induce strand
breakage in DNA
These compounds are best avoided in pregnancy

Treatment of tuberculosis
• Three basic concepts in tuberculosis treatment
Multiple drugs to which the organism is susceptible
Drugs must be taken regularly
Drug therapy must continue for sufficient time
• First-line drugs
 Superior in efficacy and possess an acceptable degree
of toxicity

• First line anti-TB drugs:
 Isoniazid (INH), 300 mg/d
 Rifampicin (RIF), 600 mg/d
 Pyrazinamide (PZA), 25 mg/kg/d
 Ethambutol (EMB), 15–25 mg/kg/d
 Streptomycin (STM), 15 mg/kg/d

•Second-line drugs
 More toxic and less effective
 Indicated only for M. tuberculosis resistant to the first-
line drugs.
 Prolonged Therapy beyond the standard period
 Include
 Amikacin, 15 mg/kg/d
 Cycloserine, 500–1000 mg/d, divided
 Ethionamide, 500–750 mg/d

 Aminosalicylic acid, 8–12 g/d
 Rifabutin, 300 mg/d
 Rifapentine, 600 mg once or bid/wk
 Ciprofloxacin, 1500 mg/d, divided
 Levofloxacin, 500 mg/d
 Capreomycin, 15 mg/kg/d
 Thioacetazone, 500–1000 mg/d, divided
 Clofazimine, 200 mg/d

• DOTS strategy
 Implemented worldwide
Aims at curing 85% of new smear positive cases in 2005,
halt and begun to reverse incidence by 2015
 Purpose:
 Provide standardized regimens
 Provide proper case management to ensure
completion of treatment and cure

•Treatment regimens for new patients consist of
 An initial phase
 A fixed-dose combination of INH, RIF, PZA and EMB
for two months
 A continuation phase of sterilizing drugs
 INH and RIF, given for four to six months
•Re-treatment patients
 Five drugs in the initial and three drugs in the
continuation phase
• Targets and mechanisms of action of current TB drugs

• Existing TB drugs are only able to target actively growing
bacteria
 Efficient bactericidal activity but weak sterilizing activity
 RIF and PZA are partially sterilizing drugs and shorten
the therapy from 12-18 months to 6 months
Persisting bacteria that are not killed by RIF and PZA
 Achieve a clinical cure, but not a bacteriological cure

• Problems on current chemotherapy for TB
Toxicity, Mycobacterial persistence, Interaction with anti-
HIV drugs
 lengthy therapy also creates poor patient compliance
 Emergence of deadly MDR-TB and XDR-TB

• Isoniazid (INH)
 Bactericidal for actively growing tubercle bacilli
 Less effective against atypical mycobacterial species
 Active against both extracellular and intracellular organisms
 MOA: inhibits synthesis of mycolic acids
Essential components of mycobacterial cell walls
INH is a prodrug, activated by KatG (mycobacterial
catalase-peroxidase)
Activated INH inhibit an acyl carrier protein (AcpM) and
KasA (protein synthetase)…↓mycolic acid synthesis

 Resistance
 Overexpression of inhA…encodes acyl carrier protein reductase
 Mutation or deletion of katG
 Overexpression of ahpC, protect the cell from oxidative stress
 Mutations in kasA
o Low-level INH resistance and cross-resistance to ethionamide
o KatG mutants express high-level INH resistance, no cross-
resistance with ethionamide

 Pharmacokinetics
o Readily absorbed from the GIT
o Widely distributed
o Metabolized by liver N-acetyltransferase (acetylation),
no dose adjustment
 Clinical Uses
Treatment of active TB…300 mg/d for adult, Up to 10
mg/kg/d for serious infections and malabsorption
Treatment of active TB… 900 mg/bid/wk + RIF, 600 mg

Pyridoxine, 25–50 mg/d is recommended to treat
neuropathy
Treatment of latent tuberculosis
Prophylaxis for HIV-infected and AIDS patients
Adverse Reactions
 Fever and skin rashes are occasionally seen
Isoniazid-induced hepatitis
Peripheral neuropathy
Memory loss, psychosis, and seizures

• Rifampin
Bactericidal for mycobacteria
Readily penetrates most tissues and into phagocytic cells
MOA: ↓RNA polymerase and thereby inhibits RNA
synthesis
Human RNA polymerase does not bind rifampin
Resistance: Mutations in rpoB, the gene for the beta
subunit of RNA polymerase
PK: well absorbed, widely distributed and excreted
through bile

Clinical Uses
Treatment of TB, atypical mycobacteria and leprosy
Alternative to INH for prophylaxis (If INH-resistant)
Eliminate meningococcal carriage (600 mg twice daily for
2 days)
Treatment of staphylococcal infections (osteomyelitis and
prosthetic valve endocarditis)
Treatment of meningitis (penicillin-resistant pneumococci
(Plus ceftriaxone or vancomycin)
Prophylaxis for Haemophilus influenzae type b disease
Eradicate staphylococcal carriage, with 2nd agent

Adverse Reactions
oHarmless orange color urine, sweat, tears, and contact
lenses
oCause cholestatic jaundice and occasionally hepatitis
oLight chain proteinuria
oIncreases the elimination of methadone, anticoagulants,
some anticonvulsants, protease inhibitors, and
contraceptives
oReduce serum concentration of ketoconazole,
cyclosporine, or chloramphenicol

• Ethambutol
 MOA: Inhibit arabinosyl transferases (embCAB operon),
polymerize reaction of arabinoglycan
 Resistance: mutation of emb gene
 PK: well absorbed, excreted through urine
 Clinical use:
 Treatment of TB, 15–25 mg/kg once daily
 At higher dose, used for treatment of tuberculous
meningitis
Adverse reactions: loss of visual acuity and red-green
color blindness

• Pyrazinamide
Active intracellularly at acidic pH
Converted to pyrazinoic acid, the active form of the drug,
by mycobacterial pyrazinamidase (encoded by pncA)
The drug target and mechanism of action are unknown
Resistance: mutations in pncA, Impaired uptake of PZA
Clinical Use:
Treatment of TB in combination with others (sterilizing
agent)
ADRs: hepatotoxicity, nausea, vomiting, drug fever, and
hyperuricemia.

• Ethionamide
 Blocks the synthesis of mycolic acids
 Cerebrospinal fluid concentrations are equal to those in
serum
 Hepatotoxic, intense gastric irritation and neurologic
symptoms
 Total daily dose of 500–750 mg required
 Low-level cross-resistance between isoniazid and
ethionamide

• Capreomycin
 Peptide protein synthesis inhibitor antibiotic
 An important injectable agent for treatment of drug-
resistant tuberculosis
 Streptomycin or amikacin resistant MTB are susceptible
 It is nephrotoxic and ototoxic drug
 Toxicity is reduced if 1 g is given two or three times
weekly

• Aminosalicylic Acid
 Folate synthesis antagonist
 Structurally similar to p-aminobenzoic aid (PABA) and
to the sulfonamides
 The dosage is 8–12 g/d orally for adults and 300 mg/kg/d
for children
 Readily absorbed, widely distributed
 Excreted through urine
 Formerly a first-line agent for treatment of TB
 ADRs:
 Anorexia, nausea, diarrhea, and epigastric pain and
burning
 Hypersensitivity reactions

• Drugs active against atypical Mycobacteria
 Nontuberculous infection
 They are not communicable from person to person
 Often less severe than tuberculosis
 Less susceptible than M tuberculosis to antituberculous
drugs
 M kansasii is susceptible to rifampin and ethambutol
(relatively and completely resistant to INH and PZA,
resp.)

Species Clinical Features Treatment Options
M kansasii Resembles tuberculosis Ciprofloxacin, clarithromycin, EMB,
INH,RIF, co-trimoxazole
M marinum Granulomatous cutaneous
disease
Amikacin, clarithromycin, EMB,
doxycycline, minocycline, RIF,
Co-trimoxazole
M
scrofulaceum
Cervical adenitis in children Amikacin, erythromycin, RIF,
streptomycin
MAC Pulmonary disease in
patients
with chronic lung disease;
disseminated infection in
AIDS
Amikacin, azithromycin,
clarithromycin, ciprofloxacin, EMB,
ethionamide, rifabutin
M chelonae Abscess, sinus tract, ulcer;
bone, joint, tendon infection
Amikacin, doxycycline, imipenem,
macrolides, tobramycin
M fortuitum Abscess, sinus tract, ulcer;
bone, joint, tendon infection
Amikacin, cefoxitin, ciprofloxacin,
doxycycline, ofloxacin, co-tri
M ulcerans Skin ulcers INH, streptomycin, RIF, minocycline

Drugs Used in Leprosy
• Dapsone is widely used drug
Like the sulfonamides, it inhibits folate synthesis
The combination of dapsone, rifampin, and clofazimine is
recommended for rsistant M Leprae
Well absorbed from the gut and widely distributed
Retained in skin, muscle, liver, and kidney
ADRs: hemolysis (G6PD deficient patient)
GI intolerance, fever, pruritus, and various rashes
Erythema nodosum leprosum
• Clofazimine: alternative to dapsone, MOA unkown

Treatment of Fungal Infections

Antifungal Agents
• Human fungal infections increased recently due to
 Advances in surgery, cancer treatment, and critical care
 Use of broad-spectrum antimicrobials and the HIV
epidemic
 The antifungal drugs
o Systemic drugs (oral or parenteral) for systemic
infections
o Oral drugs for mucocutaneous infections
o Topical drugs for mucocutaneous infections

• Systemic antifungal drugs for systemic infections
 Amphotericin B
o Amphotericin A (not in clinical use) and B are antifungal
antibiotics
o Poorly absorbed from the GIT
o Oral admin. effective only on fungi within the lumen of
the tract ( not for systemic disease)
o For systemic effect admin. by IV route is needed
o Widely distributed except CSF…. intrathecal therapy for
certain types of fungal meningitis

o Mechanism of amphotericin B
 Several amphotericin B
molecules bind to ergosterol
in the plasma membranes of
sensitive fungal cells
 There, they form pores that
require hydrophobic
interactions between the
lipophilic segment of the
polyene antibiotic and the
sterol.
 The pores disrupt membrane
function, allowing
electrolytes and small
molecules to leak from the
cell, resulting in cell death

o Resistance: impaired ergosterol binding
o ADRs: Infusion-related toxicity
Fever, chills, muscle spasms, vomiting, headache,
and hypotension
Ameliorated by slowing the infusion rate or
decreasing the daily dose or
Premedication with antipyretics, antihistamines,
meperidine, or corticosteroids can be helpful
o Slower toxicity: Renal damage… to prevent, NS infusion

o Antifungal activity
Broadest spectrum antifungal agent
Active against
Yeast: Candida albicans and Cryptococcus neoformans
Antimycosis: Histoplasma capsulatum, Blastomyces
dermatitidis, and Coccidioides immitis
 Pathogenic molds: Aspergillus fumigatus and mucor
o Clinical use
Drug of choice for all life-threatening mycotic infections
Used as initial induction for serious infections…replaced
by azoles

• Flucytosine
Narrower spectrum of action than that of amphotericin B
It is a prodrug, it need phosphorylation to be active
Human cells can’t convert it to 5FU, converted by fungal
cytosine deaminase
Advantages of combination with amphotericin B for
cryptococcal meningitis:
Reduced toxicity
Rapid culture conversion
Reduced duration of therapy & resistance

MOA:
o It enters fungal cells via a cytosine-specific permease an
enzyme not found in mammalian cells
o Then converted by a series of steps to 5-
fluorodeoxyuridine 5'-monophosphate (F-dUMP) and
fluorouridine triphosphate (FUTP), inhibit DNA and RNA
synthesis, respectively
o Synergy with amphotericin B
 Enhanced penetration of the flucytosine through
amphotericin-damaged fungal cell membranes
194 7/4/2023

 Therapeutic uses
7/4/2023 195
For the treatment of serious infections:
– Cryptococcal infections
– Systemic candidiasis
Adverse events:
Bone marrow toxicity
GIT , Alopecia,
Skin rashes, itching
 Rarely hepatitis

Azoles
• Are synthetic compounds
• Classified as either imidazoles or triazoles
• Imidazoles: ketoconazole, miconazole (topical) and clotrimazole
(topical)
• Triazoles: itraconazole, fluconazole and voriconazole
• MOA:
 Reduction of ergosterol synthesis by inhibition of fungal
cytochrome P450 enzymes
 Greater affinity for fungal P450 enzymes than humans
 Imidazoles are less specific
 Resistance to azoles occurs via multiple mechanisms

• Clinical Use
The spectrum of actions is quite broad
Used for treatment of
o Cryptococcus neoformans
o Endemic mycoses (blastomycosis, coccidioidomycosis,
histoplasmosis)
o Dermatophytes
o Aspergillus infections
o Intrinsically amphotericin-resistant organisms
(Pseudallescheria boydii)

• Ketoconazole
 The first oral azole introduced into clinical use
 Inhibit mammalian cytochrome P450 enzymes
 Fallen out of use clinically
• Itraconazole
Available as oral and IV formulations
Absorption is increased by food and by low gastric pH
Interacts with P450 enzymes (lesser extent to
Ketoconazole)
Potent antifungal activity but limitted by reduced bioavail.

 Newer formulations contain cyclodextran to increase
solubility and bioavailability
 Azole of choice for treatment of disease due to
oDimorphic fungi histoplasma, blastomyces, and
sporothrix
 Used extensively in the treatment of dermatophytoses and
onychomycosis
• Fluconazole
 Good CSF penetration
 Oral bioavailability is high (better than Ketocon. &
Itracon.)

Has the least effect of all the azoles on hepatic microsomal
enzymes.. Less drug interaction
Has the widest therapeutic index of the azoles
Available as oral and IV formulations (100–800 mg/d)
Drug of choice for cryptococcal meningitis
Used for the treatment of mucocutaneous candidiasis
No activity against aspergillus or other filamentous fungi

• Voriconazole
 The newest triazole
 Available as oral and IV formulations
 Well absorbed orally
 Hepatic metabolism, inhibition of human P450 is low
 ADRs: rash, elevated hepatic enzymes, visual disturbance
 Similar to itraconazole in its spectrum of action
 More effective in the treatment of invasive aspergillosis
and less toxic than amphotercin B

• Caspofungin
 The newest antifungal agent
 Available only in an intravenous form
 MOA: Inhibition of cell wall synthesis by inhibing (1-3)
glucan
 ADRs: Well tolerated, minor GIT SEs and flushing
oWith cyclosporine elevate enzyemes (avoid combination)
 Used only for salvage therapy in patients with invasive
aspergillosis

Systemic antifungal drugs for mucocutaneous infections
• Griseofulvin (fungistatic)
 Used in the systemic treatment of dermatophytosis
 Absorption is improved when it is given with fatty foods
 Cellular mechanism of action is unclear, bind keratin
 It must be administered for 2–6 weeks for skin and hair
infections
 Nail infections may require therapy for months
 Replaced by newer once (itraconazole and terbinafine)

• Terbinafine
Available as oral formulation
Used in the treatment of dermatophytoses, especially
onychomycosis
Like griseofulvin, it is a keratophilic medication, but
unlike griseofulvin, it is fungicidal
It interferes with ergosterol biosynthesis
Inhibits the fungal enzyme squalene epoxidase
o Accumulation of the sterol squalene, which is toxic to
the organism

Topical antifungal therapy
• Nystatin
 Only used topically (toxic parentrally)
 Available in creams, ointments, suppositories
 Not absorbed from skin, mucous membranes, GIT
 Common indications are:
o Oropharyngeal thrush, vaginal candidiasis, and intertriginous
candidal infections
• Topical Azoles
 Clotrimazole and miconazole- vulvovaginal candidiasis,
oral trush, dermatophytic infections (tinea corporis, tinea
pedis, and tinea cruris)
 Terbinafine and naftifine

Treatment of helminthic infections
• Roundworms (nematodes)
• Flatworms: flukes (trematodes) and tapeworms (cestodes)
• Anthelmintics are drugs that act either locally to expel worms
from the GIT or systemically (adult or developmental forms)
clear the parasite
• 1. nematodes
Ascaris lumbricoides
 Mebendazole, pyrantel pamoate and albendazole are preferred
agents. Piperazine also is effective but neurotoxic
Toxocariasis
 Albendazole is the drug of choice

• Hookworm: Necator americanus, Ancylostoma duodenale
Cause fecal blood loss which leads to iron-deficiency
anemia
Albendazole and mebendazole are first choice against both
worms
Albendazole is superior to mebendazole at removing adult
hookworms from the GIT, iron supplementation
The drug of choice for treating cutaneous larva migrans or
"creeping eruption is albendazole
For A. braziliense. oral ivermectin or topical thiabendazole
also can be used

• Trichuris trichiura
Mebendazole and albendazole are the safest and most effective
agents
Pyrantel pamoate is ineffective against Trichuris
• Strongyloides stercoralis (threadworm or dwarf threadworm)
 Ivermectin is the best drug for treating intestinal strongyloidiasis
 Thiabendazole and albendazole can also be used
• Enterobius vermicularis (pinworm)
 Drugs: Pyrantel pamoate, mebendazole, and albendazole
 Single oral doses of each should be repeated after 2 wks
• Trichinella spiralis
 Albendazole and mebendazole appear to be effective

• Wuchereria bancrofti and Brugia (Lymphatic Filariasis)
 Drugs: albendazole and diethylcarbamazine
• Loa loa (Loiasis)
 Diethylcarbamazine currently is the best single drug for
the treatment of loiasis
 Glucocorticoids often are required to control acute
reactions
• Onchocerca volvulus (Onchocerciasis or River Blindness)
 Ivermectin is the best single drug

• Dracunculus medinensis (guinea, dragon or Medina
worm)
No suitable anthelmintic that acts directly
Metronidazole, 250 mg tid for 10 days can provide relief
Traditional treatment for this disabling condition is to draw
the live adult female worm out day by day
• 2. Cestodes (tapeworms)
o Taenia saginata (beef tapeworm)
 Praziquantel is the drug of choice, although niclosamide
also is used

• Taenia solium (pork tapeworm)
Praziquantel is preferred for treatment of intestinal
infections with T. solium
Albendazole and praziquantel are the drugs of choice for
treating cysticercosis
• Diphyllobothrium latum (fish tapeworm)
Therapy with praziquantel readily eliminates the worm and
ensures hematological remission
• Hymenolepis nana
 Praziquantel is effective against H. nana infections (at
higher doses)
• Echinococcus Species
 Removal of the cysts by surgery is the preferred treatment

• 3. Trematodes (Flukes)
o Schistosoma haematobium, Schistosoma mansoni,
Schistosoma japonicum
 Praziquantel is the drug of choice for treating all species
of schistosomes that infect humans
• Paragonimus westermani and Other Paragonimus Species
 Drugs: praziquantel and Bithionol
• Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis
felineus
 One-day therapy with praziquantel is highly effective
against these parasites

Antihelminthic Drugs
• Most anthelmintics are active against specific parasites;
thus, parasites must be identified before treatment is started
1. Albendazole
• Broad-spectrum oral anthelmintic
• Used for Enterobius vermicularis (pinworm), ascariasis,
trichuriasis, strongyloidiasis and infections with both
hookworm species

• Drug of choice in hydatid disease, cysticercosis, cutaneous
larva migrans, visceral larva migrans, intestinal
capillariasis, gnathostomiasis, trichinosis and clonorchiasis
• Useful adjunct to surgical removal or aspiration of cysts
• Albendazole is administered on an empty stomach when
used against intraluminal parasites but with a fatty meal
when used against tissue parasites
• MOA: Albendazole blocks glucose uptake by larval and
adult stages … the parasite is immobilized and dies
• Teratogenic and embryotoxic …contraindicated in pregn.

• Clinical Uses
1.Ascariasis, trichuriasis, hookworm and pinworm infections:
 A single dose of 400 mg orally for > 2 years old
 In pinworm infection, repeat in 2 weeks
2. Strongyloidiasis: 400 mg bid/d for three days (with meals)
3. Hydatid disease: 800 mg/kg/d in divided doses for 3 months
4. Neurocysticercosis: 15 mg/kg /d for 8 days
5. 200-400 mg bid for cutaneous larval migrans (for 3-5 days)
and in intestinal capillariasis (10-day course)
• ADRs: epigastric distress, diarrhea, headache, nausea,
dizziness, jaundice, alopecia, rash or pruritus

2. Diethylcarbamazine Citrate
• Drug of choice for filariasis, loiasis, and tropical
eosinophilia
• MOA: immobilizes microfilariae and alters their surface
structure …destruction by host defense mechanisms
• Clinical Uses:
1. Wuchereria bancrofti, Loa loa:
 It is the drug of choice
 Microfilariae of all species are rapidly killed; adult
parasites are killed more slowly, often requiring several
courses of treatment

2. Onchocerca volvulus:
 It temporarily kills microfilariae but are poorly effective
against adult worms
 Suramin (a toxic drug) must be added to the regimen to
kill the adult worms
• ADRs
 Headache, malaise, anorexia, and weakness are frequent
 Reactions induced by dying parasites…Vision loss, fever,
malaise, papular rash, headache, GIT effects, cough, chest
pains, and muscle or joint pains

3. Ivermectin
•Drug of choice in individual and mass treatment of
onchocerciasis and for strongyloidiasis
•MOA: paralyze nematodes and arthropods
•Clinical uses: Onchocerciasis, Bancroftian Filariasis,
Strongyloidiasis, scabies and cutaneous larva migrans
• ADRs:
 Mazotti (fever, headache, dizziness, somnolence, weakness,
rash, increased pruritus, diarrhea, joint and muscle pains,
hypotension, tachycardia, lymphadenitis, lymphangitis, and
peripheral edema)
 Steroids may be necessary for several days

4. Levamisole
• Highly effective in eradicating ascaris and moderately effective
against both species of hookworm
5. Mebendazole (broad spectrum), poorly absorbed
• Inhibits microtubule synthesis in nematodes
• Clinical uses:
1. Pinworm infection
2. Ascaris lumbricoides, Trichuris trichiura and Hookworm
3. Hydatid disease: Mebendazole is the alternative
4. Taeniasis, Strongyloidiasis
• ADRs: Mild nausea, vomiting, diarrhea, and abdominal pain

6. Metrifonate (Organophosphate)
• Safe, alternative drug for Schistosoma haematobium infections
• MOA: cholinesterase inhibition
 Paralyzes the adult worms
• ADRs: nausea and vomiting, diarrhea, abdominal pain,
bronchospasm, headache, sweating, fatigue, weakness, dizziness,
and vertigo
7. Niclosamide
• Drug of choice for the treatment of most tapeworm infections
• Adult worms (but not ova) are rapidly killed due to inhibition of
oxidative phosphorylation or stimulation of ATPase activity

• Clinical Uses
Niclosamide should be given in the morning on an empty
stomach
The tablets must be chewed and swallowed
1. T. saginata, T. solium and Diphyllobothrium latum
2. Hymenolepis nana: The course of treatment must be 7 days
3. Intestinal fluke infections: used as an alternative drug
• ADR: nausea, vomiting, diarrhea and abdominal discomfort

8. Oxamniquine
•Clinical Uses:
 Safe and effective in all stages of S. mansoni
 Better tolerated if given with food, although food delays
absorption
 In combination with metrifonate used in mixed infections
with S. mansoni and S. haematobium
•ADRs: nausea and vomiting, diarrhea, colic, pruritus, and
urticaria also occur, contraindicated in pregnancy

9. Piperazines
• Are alternative drugs in the treatment of ascariasis
• Readily absorbed from the GIT
• MOA: paralyze by blocking Ach at the myoneural junction
• The paralyzed roundworms are unable to maintain their
position in the host and are expelled live by normal
peristalsis
• Clinical Uses: Ascariasis
• ADRs: Piperazine cause nausea, vomiting, diarrhea,
abdominal pain, dizziness, and headache

10. Praziquantel
• Used in schistosome, trematode & cestode (cysticercosis)
• Safe & effective at single oral dose, used in mass treatment
• MOA: increases calcium influx…contraction…paralysis of
worm musculature…death follows
• Clinical Uses:
1. Schistosomiasis: the drug of choice for all forms
2. Taeniasis and Diphyllobothriasis: single dose
3. Neurocysticercosis: 50 mg/kg/d tid for 14 days
4. H. nana: the drug of choice, single dose of 25 mg/kg

• ADRs:
 Most frequent: headache, dizziness, drowsiness, and lassitude;
 Ohers include nausea, vomiting, abdominal pain, loose stools,
pruritus, urticaria, arthralgia, myalgia, and low-grade fever
 Better tolerated in children than in adults

11.Pyrantel Pamoate (Broad-spectrum)
• Highly effective for the treatment of pinworm and Ascaris
• Active mainly against luminal organisms (Not absorbed in
GIT)
• Clinical Uses:
 The standard dose is 11 mg, given with or without food
 Given as a single dose and repeated in 2 and 4 weeks
12.Suramin
• Alternative drug for the eradication of Onchocerca volvulus
• A drug of choice for hemolymphatic stage of African
trypanosomiasis

13. Thiabendazole
• Drug of choice for strongyloidiasis & alternative drug for
cutaneous larva migrans
• Vermicidal action is due to interference with microtubule
aggregation
• The drug has ovicidal effects for some parasites
• Clinical Uses: The standard dose is 25 mg/kg (maximum,
1.5 g)
 The drug should be given after meals
 Effective in Strongyloides stercoralis

 In patients with hyperinfection syndrome, the standard
dose is continued twice daily for 5-7 days
 Highly effective in the treatment of cutaneous larva
migrans.
 Cutaneous Larva Migrans (Creeping Eruption)
 The standard dose is given twice daily for 2 days
• ADRs: most common: dizziness, anorexia, nausea, and
vomiting

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