Antibiotics

Antibiotics
MAK25JUL17
Outline
• Introduction
• Antimicrobial stewardship
• Antibacterials and their site of action
• Selective toxicity
• β-lactam antibiotics and other cell wall
synthesis inhibitors
• Protein synthesis inhibitors
– Chloramphenicol
– Tetracyclines
– Macrolides
Outline…
– Streptogramin
– Linezolid
– Aminoglycosides
– Antifolate drugs (Sulfonamides,
Trimethoprim)
– Fluoroquinolones
Introduction
• Microbial resistance poses a constant
challenge to the use of antibiotics (Abx).
• Mechanisms underlying microbial resistance
to cell wall synthesis (CWS) inhibitors incl
– production of abx-inactivating enzymes,
– ∆s in the structure of target receptors,
– ↑ efflux via drug transporters, and
– ↓ in the permeability of microbes’ cellular
membranes to antibiotics
Introduction…
• Strategies to combat microbial resistance incl:
– use of adjunctive agents that can protect
against abx inactivation, e.g. Amoxiclav
– use of abx combinations,
– Intro. of new (and often expensive)
chemical derivatives of established abx, and
– efforts to avoid the indiscriminate use or
misuse of abx.
– Avoiding using similar abx in humans
Introduction…
• To avoid abx apocalypse, all HCWs should be
pro-antimicrobial stewardship
• Antibiotic stewardship refers to systemic
measurement and coordinated interventions
designed to promote optimal use of abx agents,
by advocating selection of appropriate abx drug
regimens (incl. dosing, duration of therapy, and
route of admin.)
Introduction…
• 10 goal of abx stewardship is to
– optimize clinical outcomes while
– minimizing unintended consequences of
Abx use (incl toxicity, selection of
pathogenic organisms such as C. difficle,
and the emergence of antimicrobial
resistance)
Introduction…
• In general, mgt of pts with suspected or
proven bacterial infn consist of initiation of
empiric therapy (ie, prior to availability of
definitive microbiology data)’ followed by
adjustment once microbiology data become
available.
Introduction…
• Abx oversight should include
– prospective audit and feedback (PAF),
– preauthorization, or
– both
Introduction…
• In programs using PAF, trained staff review
abx orders and advise regarding optimization
of abx use.
• In programs using preauthorization, approval

is required before certain agents may be
admin.
Introduction…
• Abx stewardship programs should develop
facility-specific clinical practice guidelines for
common infns based on local epidemiology,
susceptibility patterns, drug availability and
preferences
Introduction…
• Pharmacy-led interventions can be used by
pharmacists to optimize antimicrobial Rx, incl. dose
optimization (e.g. vancomycin dosing) and
systematic conversion of IV to oral antimicrobial
therapy
• Correcting an inaccurate abx allergy hx in the

medical record can be very useful for guiding
subsequent decisions regarding a pt’s abx therapy
Introduction…
• The clinical microbiology lab has an integral
role in promoting appropriate abx use, by
– providing ongoing culture results and
susceptibility data,
– preparing an annual antibiogram, and
– providing guidance regarding
implementation and interpretation of RDT
Some clinically important pathogenic bacteria
Genus Species Disease
Gram-negative
Bordetella B. pertusis Whooping cough
Brucella B. abortus Brucellosis (cattle
n humans)
Campylobacter C. jejuni Food poisoning
Escherichia E. coli Septicaemia,
wound infn, UTI
Haemophilus H. influenzae Acute RTI,
meningitis
Some clinically important pathogenic bacteria…
Gram-negative
Helicobacter H. pylori Peptic ulcer,
gastric cancer
Klebsiella K. pneumoniae Pneumonia,
septicaemia
Legionnella L. pneumophila Legionniares
disease
Neisseria N. gonorrhea Gonorrhea
Pseudomonas P. aeruginosa Septicaemia, RTI,
UTI
Gram-negative
Ricketssiae Several spp. Tick- and insect

borne infns
Salmonella S. typhimurium Food poisoning

Shigella S. dysenriae Bacillary dysentry
Yersinia Y. pestis Bubonic plague
Vibrio V. cholera Cholera
Gram-positive
Bacillus B. anthrax Anthrax
Clostridium C. tetani Tetanus
Corynebacteriu C. diptheriae Diptheria
m
Mycobacterium M. tuberculosis Tuberculosis
M. leprae Leprosy
Staphylococcus S. aureus Wound infns, boils,
septicaemia
Gram-positive
Streptoccocus S. pneumoniae Pneumonia,
meningitis
S. pyogens Scarlet fever,
rheumatic fever,
cellulitis
Other
Chlamydia C. trachomatis Eye disease,
infertility
Treponema T. pallidum Syphillis
Anti-bacterials and their site of action
Family Examples Target MoA
organisms
Sulfonamides Sulfadiazine, T. gondi, Bacterial
sulfamethoxazole P. jiroveci
(trimethoprim) folate
synthesis or
action
β-lactams Penicillins: Mainly Bacteial CW
Benzylpenicillins G+ve
phenoxymethylpeni peptidoglyca
Some G-ve n synthesis
cillins
Penicillinase- Used for
resistant penicillins staph.
Flucloxacillin,
infns
temocillin
Anti-bacterials and their site of action…
organisms
β- Broad spectrum A wide range Bacteial CW

penicillins of G+ve and peptidoglyca
lactams Amoxicillin, G-ve spp. n syntheis
ampicillin
Antipseudomonal Selected G-ve

penicillins spp.
Piperacillin, Especially P.
ticarcillin aureginosa
MECILLINAMS Mainly
G-ve spp
Pivmecillinam
organisms
β-lactams CEPHALOSPORINS Broad Bacteial
Cefaclor, spectrum CW
cefadroxil,
cefalexin,
activity peptidoglyc
cefixime, against G-ve an syntheis
cefotaxime, and G+ve
cefpodoxime, spp
cefradine,
ceftaroline,
ceftazidime,
ceftriaxone,
cefixime
organisms
β-lactams CARBAPENEMSMany G-ve Bacterial

Ertapenem, and G+ve CW
Imipenem, spp. peptidoglyc
meropenem, an synthesis
doripenem
MONABACTAMS G-ve rods
Aztreonam
Glycopeptides Vancomycin, G+ve spp.
Teicoplanin,
Daptomycin
organisms
Polymixins Colistimethate, G-ve spp Bacterial

polymixin B outer CM
structure
Tetracycline Demeclocycline Many G-ve Bacterial protein

Doxycycline, synthesis
s and G+ve (multiple
lymecycline, spp mechanisms
minocycline, inhibited incl.
oxytetracycline initiation,
Tetracycline transpeptidation
tigecycline and
translocation;
organisms
Aminogycosides Amikacin, Many G-ve, Bacterial

gentamicin, some G+ve protein
neomycin, synthesis
tobramycin (multiple
mechanisms
inhibited incl.
initiation,
transpeptidation
and
translocation;
organisms
Macrolides Azithromycin, Similar to Bacterial

Clarithromycin, penicillin protein
Erythromycin s synthesis
Spiramycin, (multiple
mechanisms
Telithromycin
inhibited incl
initiation,
Oxazolidinones Linezolid G+ve spp. transpeptidation
and
translocation;
Lincosamides Clindamycin G+ve spp.
organisms
Amphenicols Chloramphenicol G-ve and Bacterial

G+ve spp. protein
synthesis
(multiple mechanisms
inhibited including
initiation,
transpeptidation and
translocation;
Streptogramins Quinupristin, G+ve
dalfopristin spp.
Family Examples Target organisms MoA
Antimycobacterials Capreomycin, Most used for Various unrelated

Clofazimine, mycobacterial mechanisms
Cycloserine, infns only
Dapsone,
Ethambutol,
Isoniazid,
Pyrazinamide,
Rifabutin,
Rifampicin
Quinolones Ciprofloxacin, Gram-ve and Bacterial DNA
Levofloxacin, Gram+ve synthesis
Moxifloxacin,
spp.
Nalidixic acid,
Norfloxacin,
Ofloxacin
organisms
Miscellaneous Fusidic acid G+ve spp. Bacterial

protein
synthesis
Nitrofurantoin G-ve UTIs Damages

bacterial DNA
Methenamine G-ve UTIs Formaldehyd

e pro-drug
Beta-lactam Antibiotics & Other Cell
Wall Synthesis Inhibitors
• Penicillins and cephalosporins are major abx
that inhibit bacterial CWS.
• Called β-lactams becoz of the unusual 4-
member ring that is common to all their
members.
• β-lactams incl. some of the most effective,
widely used, and well-tolerated agents
available for the Rx of microbial infns.
β-Lactams
β-lactam ring
Beta-lactam Antibiotics & Other Cell
Wall Synthesis Inhibitors…
• Vancomycin, fosfomycin, and bacitracin also
inhibit CWS but are not nearly as important as
the β-lactam drugs.
• Selective toxicity of the drugs is mainly due to

specific actions on the synthesis of a cellular
structure that is unique to the microorganism.
High yield terms
• Bactericidal: An antimicrobial drug that can
eradicate an infn in the absence of host
defense mechanisms; kills bacteria
• Bacteriostatic: An antimicrobial drug that

inhibits antimicrobial growth but requires host
defense mechanisms to eradicate the infn;
does not kill bacteria
High yield terms
• β-lactam antibiotics: Drugs with structures

containing a β-lactam ring: incl the penicillins,
cephalosporins and carbapenems.
• This ring must be intact for antimicrobial

action
High yield terms…
• β-lactamases: Bacterial enzymes (penicillinases,
cephalosporinases) that hydrolyze the β-lactam
ring of certain penicillins and cephalosporins
• β-lactam inhibitors: Potent inhibitors of some

bacterial β-lactamases used in combos to
protect hydrolyzable penicillins from
inactivation (e.g. clavulanic acid)
High yield terms…
• Ex. of β-lactamase inhibitors
– Amoxicillin/clavulanate (Augmentin)
– Ampicillin/sulbactam (Unasyn)
– Piperacillin/tazobactam (Zosyn)
– Clavulanate/ticarcillin (Timentin)
High yield terms…
• Minimal inhibitory concentration (MIC): Lowest
conc. of antimicrobial drug capable of inhibiting
growth of an organism in a defined growth
medium
• Penicillin-binding proteins (PBPs): Bacterial
cytoplasmic membrane proteins that act as the
initial receptors for penicillins and other β-lactam
abx
High yield terms…
• Peptidoglycan: Chains of polysaccharides and
polypeptides that are cross-linked to form the
bacterial cell wall
• Selective toxicity: More toxic to the invader than
to the host; a property of useful antimicrobial
drugs
• Transpeptidases: Bacterial enzymes involved in
the cross-linking of linear peptidoglycan chains,
the final step in CWS
Selective toxicity
• Selective toxicity refers to the ability of the drug to
targets sites that are relative specific to the
microorganism responsible for infn.
• Sometimes these sites are unique to the
microorganism or simply more essential to survival
of the microorganism than to the host.
• Ex. of such specific or relatively specific sites incl:
• Specific fungal or bacterial CW synthesizing
enzymes
• Bacterial ribosomal or
• Molecular machinery of viral replication
Selective toxicity…
• The principle of selective toxicity is to have
negative effect on an organism with min
effect on the host
• Brought about by drugs which exploit

differences btn the invading organism and the
host
1. By inhibiting CWS e.g. Penicillins,
cephalosporins.
Human cells do not have a CW, so these drugs
are specific only for bacteria.
They will kill or stop replication of the bacteria
without damaging the host
2. Altering CW permeability
3. Inhibition of protein synthesis e.g. Tetracyclins,
aminoglycosides, chloramphenicol,
erythromycin
• Selective toxicity relies on the fact that the
bacterial ribosome differs in size to the human
ribosome
4. Inhibition of nucleic acid synthesis. Affect

microbial specific enzymes, e.g. DNA
dependent RNA polymerase
5. Antimetabolites.
• Affect the metabolism of the organism by
having a -ve effect on some vital metabolite.
• Humans are unable to synthesize folate and so
must get it from the food, whereas bacteria
must make their own.
• Hence, inhibition of folate metabolism can
hinder bacterial growth. e.g. Trimethoprim.
So many choices… which one to pick?
• What is the likely organism?
• What’s its major mode of resistance?
• Where’s the infection?
• What’s my local environment?
– the local Hospital antibiogram
• What does the micro lab say?

– in vitro sensitivity testing
PENICILLINS
• Hx: First abx discovered as natural products
from the mold Penicillium.
• 1928; Sir Alexander Fleming, professor of
bacteriology at St. Mary's Hospital in London,
was culturing S. aureus.
• Noticed zones of inhibition where mold spores
were growing.
• He named the mold Penicillium rubrum.
• It was determined that a secretion of the mold
was effective against Gram+ve bacteria
PENICILLINS
• Classification
• Derivatives of 6-aminopenicillanic acid
• Contain a β-lactam ring structure that is
essential for antibacterial activity.
• Subclasses have additional chemical
substituents that confer differences in
– antimicrobial activity,
– susceptibility to acid and
– enzymatic hydrolysis, and biodisposition.
Classification
• Penicillins
– Natural penicillins
• PenG, PenVK, Benzathine Pen, Procaine Pen
– Aminopenicillins
• Ampicillin, Amoxicillin
– Anti-Staph penicillins
• Oxacillin, Dicloxacillin
– Anti-Pseudomonal
• [Carboxy] Ticarcillin
• [Ureido] Piperacillin
PENICILLINS…
• PKs
• Vary in their resistance to gastric acid and
therefore vary in their oral bioavailability.
• Parenteral formulations of ampicillin,
piperacillin, and ticarcillin are available for
injection.
• Are polar compounds and are not
metabolized extensively.
• Usually excreted unchanged in the urine via
glomerular filtration and tubular secretion;
the latter process is inhibited by probenecid.
PENICILLINS…
• Nafcillin excreted mainly in bile and ampicillin
undergoes enterohepatic cycling.
• Plasma t1/2 of most penicillins vary (30m - 1h).
• Procaine and benzathine forms of penicillin G
are admin. IM and have long plasma t1/2
becoz the active drug is released very slowly
into the bloodstream.
• Most penicillins cross the BBB only when the
meninges are inflamed.
Penicillin G
• Available PO, IM, IV (dosed in units)
• Drug of Choice (DoC) [2-4 MU IV q4h]
– T. pallidum, N. meningitidis, Group A Strep, and
Actinomycosis
• Long-acting forms
– Procaine PenG (12 hrs)
– Benzathine Pen (5 days) [2.4 MU IM for syphilis]
• AEs – other than skin rash
– Penicillin “serum sickness”/drug fever
– Jarisch-Herxheimer rxn (1° and 2° syphilis)
– Hemolytic anemia, pancytopenia,
neutropenia
PENICILLINS…
• Penicillin G aqueous (Benzyl penicillin)
• Meningococcal Meningitis/Septicemia
• 20-30 MU/d IV continuous infusion x14 days
or afebrile x7d, OR
• 200,000-300,000 units/kg/day IV divided q2-
4hr x24 doses
• Rat-Bite Fever
• Indicated for Streptobacillus moniliformis and
Spirillum minus (rat-bite fever)
• 12-20 MU/day IV divided q4-6hr x3-4 weeks
PENICILLINS…
• Penicillin G aqueous (Benzyl penicillin)…
• Anthrax
• Minimum: 5MU /day IV
• 12-20 MU/day IV have been used
• Streptococcal Infections
• Empyema, pneumonia, pericarditis,
endocarditis, meningitis: 5-24 MU/day IV
divided q4-6hr
• Syphilis
• Neurosyphilis: 18-24 MU/day IV x10-14 days
PENICILLINS…
• PK:
• T1/2: 20-50 min (ESRD 3-5 hr)
• Peak Plasma Time: IM 30 min, IV 1 hr
• Protein Bound: 65%
• Distribution: crosses placenta, poor BBB diffusion
• Metabolism: hepatic to active metabolites
• Excretion: urine
• MoA: Interferes with synthesis of CW mucopeptide
during active multiplication, resulting in bactericidal
activity against susceptible microorganisms.
PENICILLINS…
• Penicillin G Benzathine
• T1/2 20-30m after hydrolysis to P. G.
• For deep IM admin. Absorption slow
• ↓ dose in Renal dysfn, Admin. Post dialysis
• Do not inject near artery or nerve (permanent

neurologic damage)
PENICILLINS…
• Penicillin G Benzathine…
• Neonates, infants, small children: Mid lateral aspect
of thigh preferable
• Older children and adults: deep IM inj in UOQ of
buttock
• Becoz of high conc. Of suspended matter, needle
may be blocked if inj. is not made at slow, steady
state
PENICILLINS…
• Group A Streptococcal Respiratory Infections
• 1.2 MU IM x1
• Rheumatic Fever Prophylaxis
• 1.2 MU IM monthly foll. acute attack, OR 600,000 units
IM q2Weeks
• Syphilis
• Primary or secondary (CDC Guidelines 2006)
• 2.4 MU IM x1
• If pregnant: Some recommend 2.4 MU IM qWeek x2
• If HIV+: Some recommend 2.4 MU IM qWeek x 3
• Early Latent: 2.4 MU IM x1
• Neurosyphilis: 2.4 MU IM qWeek x 3
• Yaw, Bejel, & Pinta 1.2 MU IM x1
PENICILLINS…
• Penicillin G procaine
• Streptococcal Infns (Group A)
• For moderately severe-to-severe tonsillitis,
erysipelas, scarlet fever, URTIs, skin and soft
tissue infns 600,000-1,000,000 units IM qDay for
at least 10 days
• Staphylococcal Infns
• 600,000-1,000,000 units IM qDay
• Bacterial Endocarditis
• Only for Rx of extremely sensitive infns; not
indicated for prophylaxis 600,000 -1,000,000
units IM qDay
PENICILLINS…
• Syphilis
• 10, 20, and latent: 600,000 units IM qDay for 8 days
• Late (30 and latent syphilis with positive CSF):

600,000 units IM qDay for 10-15 d (total 6-9 MU)
• Neurosyphilis: 2.4 MU IM qDay x10-14 d;

administer with probenecid 500 mg PO QID
(penicillin G aqueous preferred)
PENICILLINS…
• Anthrax
• Cutaneous: 600,000-1,000,000 units IM qDay
• Inhaled (post-exposure): 1.2 MU IM q12hr for up
to 2 wks, THEN switch to PO Rx (total Rx 60 days)
• Diphtheria
• Adjunct with antitoxin: 300,000-600,000 units IM
qDay
• Carrier state: 300,000 units IM qDay
• Other: rat bite fever, vincents infn, erysipeloid,
whipples disease
PENICILLINS…
• Contraindications: Hypersensitivity; serious
and occasionally fatal rxns have been reported
• Cautions: For deep IM admin only; do not
admin IV, SC, or IT. Do not inject near nerve or
artery
• No longer indicated for gonorrhea; should
not be used for β-lactamase producing
organisms which include most strains of N.
gonorrhea
PENICILLINS…
• Pseudomembranous colitis reported with
antibacterial agents, incl. penicillin G
• Procaine rxns: Immediate toxic rxns to procaine

reported, particularly when a large single dose
is admin (4.8 MU)
• Avoid use in neonates; ↑ risk for sterile

abscess development and procaine toxicity
PENICILLINS…
• MoA and Resistance
• β-lactam abx are bactericidal drugs.
• Act to inhibit CWS by the foll. steps
• (1) binding of the drug to specific enzymes
(penicillin-binding proteins [PBPs]) located in
the bacterial cytoplasmic membrane;
• (2) inhibition of the transpeptidation rxn that
cross-links the linear peptidoglycan chain
constituents of the CW; and
• (3) activation of autolytic enzymes that cause
lesions in the bacterial CW.
How do they work?
1. The β-lactam binds to Penicillin Binding Protein
(PBP)
2. PBP is unable to crosslink peptidoglycan chains
3. The bacteria is unable to synthesize a stable cell

wall
4. The bacteria is lysed

Peptidoglycan Synthesis
“Penicillin binding
protein”
PK/PD
• The β-lactams are “time-dependent” killers
– The effect is directly proportional to the
amount of time the concentration of the
abx at the site of infn is above the MIC of
the organism.
• The β-lactams are bactericidal… (at
therapeutically attainable levels)
PK/PD…
• Time-dependent abx exert optimal bactericidal
effect when drug concs are maintained above
MIC
• Typically concs are maintained at 2 to 4X the MIC
throughout dosing
• Higher concs do not result in greater kill of
organisms
• Tend to have minimal or no post-antibiotic
effect (PAE)
PK/PD…
• Concentration dependent abx achieve
increasing bacterial kill with ↑ levels of drug
• Have associated conc-dependent PAE in which
bacterial action continues for a period of time
after the antibiotic level falls below MIC
• Peak conc and AUC determine efficacy of these
abx
• Concs of at least 10x the MIC are needed for
optimal bactericidal effect e.g. gentamycin
“Time Dependant”
H Derendorf
“Time Dependant”
WA Craig
PENICILLINS…
• Enzymatic hydrolysis of the β-lactam ring
results in loss of antibacterial activity.
• Formation of beta-lactamases (penicillinases)
by most staphylococci and many G-ve
organisms is a major mechanism of bacterial
resistance.
• Inhibitors of these bacterial enzymes (e.g.
clavulanic acid, sulbactam, tazobactam) are
often used in combo with penicillins to Px
their inactivation.
PENICILLINS…
• Structural ∆ in target PBPs is another
mechanism of resistance and is responsible for
methicillin resistance in staphylococci (MRSA)
and for resistance to penicillin G in
pneumococci (eg, PRSP, penicillin resistant
Streptococcus pneumoniae) and enterococci.
• In some G-ve rods (e.g, P. aeruginosa), ∆s in
the porin structures in the outer CWM may
contribute to resistance by impeding access of
penicillins to PBPs.
β-Lactamase Inhibitors
• How do you evade a β-lactamase?
1. Use a non-β-lactam agent
2. Steric Inhibition
Penicillins with large side chains
Cephalosporins
3. β-lactam + β-lactamase inhibitors
Not all β-lactamases are inhibitable (!)
Clavulanic Acid
• Augmentin (Amox/Clav) PO
• Spectrum: MSSA and URTIs (S. pneumo, H. flu,
M. catarrhalis) and most anaerobes
• Clav is responsible for most of the GI AEs seen
with Amox/Clav
• Variable ratios of Amox/Clav in
liquids/tabs/chewtabs
Sulbactam
• Unasyn (Amp/Sulbactam)
• Spectrum: Amp + most anaerobes + many
enteric Gm -ve rods, OSSA
• DoC: for GNR mixed infn – E.coli, Proteus,
anaerobes when Pseudomonas is not
implicated
– Diabetic foot (once Pseudomonas is r/o)
– Wound infns
• Sulbactam alone is very active against
Acinetobacter spp.
Tazobactam
• Zosyn (Pip/Tazo)
• THE most broad-spectrum penicillin
• Tazobactam may improve the activity of
piperacillin vs. gram-negative rods, incl.
anaerobes
• 4.5g IV q8h = 3.375g IV q6h
• 4.5g IV q6h for Pseudomonas
PENICILLINS…
• Clinical uses:
• 1. Narrow-spectrum penicillinase-susceptible
agents—
• Prototype drug is Penicillin G
• Have a limited spectrum of antibacterial
activity and are susceptible to β-lactamases.
• Uses incl. Rx of infns caused by common
streptococci, meningococci, G+ve bacilli, and
spirochetes.
PENICILLINS…
• Many strains of pneumococci are now
resistant to penicillins (PRSP).
• Most strains of S. aureus and a significant # of
strains of N. gonorrhoeae are resistant via
production of β-lactamases.
• Although no longer suitable for Rx of
gonorrhea, parenteral penicillin G remains the
DoC for all stages of syphilis.
PENICILLINS…
• Activity against enterococci is enhanced by
aminoglycoside abx.
• Penicillin V is an oral drug used mainly in
oropharyngeal infns. E.g. Streptococcal
pharyngitis: 500mg PO q12h or 250mg PO
q6h for 10d, Periodontal infns: 250-500mg PO
q6h 5-7d, Recurrent rheumatic fever:
prophylaxis 250mg PO q12h
PENICILLINS…
• 2. Very-narrow-spectrum penicillinase-
resistant drugs
• Includes methicillin (the prototype, but rarely
used owing to its nephrotoxic potential),
nafcillin, and oxacillin.
• Their 10 use is in the Rx of known or
suspected staphylococcal infns.
• MRSA and MRSE are resistant to all penicillins
and are often resistant to multiple abx.
PENICILLINS…
• 3. Wider-spectrum penicillinase-susceptible
drugs
• a. Ampicillin and amoxicillin
• Have a wide spectrum of antibacterial activity

than penicillin G but remains susceptible to
penicillinases.
PENICILLINS…
• Clinical uses incl indications similar to
penicillin G as well as infns resulting from
enterococci, L. monocytogenes, E. coli, P.
mirabilis, H. influenzae, and M. catarrhalis,
although resistant strains occur.
• In combo with inhibitors of penicillinases (eg,
clavulanic acid), their antibacterial activity is
often enhanced.
• In enterococcal and listerial infns, ampicillin is
synergistic with aminoglycosides.
PENICILLINS…
• b. Piperacillin and ticarcillin
• Have activity against several G-ve rods, incl.
Pseudomonas, Enterobacter, and in some
cases Klebsiella spp.
• Most have synergistic actions when used with
aminoglycosides against such organisms.
• Piperacillin and ticarcillin are susceptible to
penicillinases, often used in combo with
penicillinase inhibitors (eg, tazobactam and
clavulanic acid) to enhance their activity.
PENICILLINS…
• Toxicity
• 1. Allergy
• Allergic rxns incl. urticaria, severe pruritus,
fever, joint swelling, hemolytic anemia,
nephritis, and anaphylaxis.
• About 5–10% of persons with a hx of penicillin
rxn have an allergic response when given a
penicillin again.
• Methicillin causes interstitial nephritis, and
nafcillin is a/c neutropenia.
PENICILLINS…
• 2. Gastrointestinal disturbances
• Nausea and diarrhea may occur with oral
penicillins, especially with ampicillin.
• GIT upsets may be caused by direct irritation
or by overgrowth of G+ve organisms or
yeasts.
• Ampicillin has been implicated in
pseudomembranous colitis.
CEPHALOSPORINS
• Classification
• Incl. the closely related cephamycin cpds
• Most cephaloporins are semi-synthetic
derivatives of cephalosporin C, a cpd with
antibacterial activity produced by the fungus
Cephalosporium
• Have a β-lactam ring.
The Cephalosporins (generalized)
*Not effective vs. Enterococcus or Listeria
1st Generation Gram (+)
2nd Generation ↓Gram (+) and ↑Gram (-)
3rd Generation Gram(-), but also some GPC
4th Generation Gram (+) and Gram (-)

CEPHALOSPORINS…
• In clinical practice, grouped into 5 generations
based upon spectrum of activity against
aerobic and fucultative G-ve bacilli and G+ve
bacteria
• Parenteral agents
• 1st generation
• Cefazolin
CEPHALOSPORINS…
• 2nd generation
– 2nd generation subgrp active against H. Influenzae
(cefuroxime)
– Cephamycin subgrp active against Bacteroides spp
(cefoxitin and cefotetan)
• 3rd generation
– Subgrp with broad G-ve activity but poor activity
against P. aureginosa (cefotaxime and
ceftriaxone)
– Subgrp with broad G-ve activity incl. good activity
against P. aureginosa (ceftazidime)
CEPHALOSPORINS…
• 4th generation (Cefepime)
• 5th generation (Ceftaroline)
CEPHALOSPORINS…
• 3rd-Generation
• Marked stability to β-lactamases of G-ve bacilli
• Highly active against
– Enterobactericiae (E. coli, P. mirabilis,

Klebsiela, Enterobacter, Serratia, Citrobacter),
– Neisseria and
– H. influenza
CEPHALOSPORINS…
• 3rd-Generation…
• DoC for G-ve meningitis due to susceptible
enterobactericiae
• Useful alternative to Aminoglycosides in Rx of G-

ve infns resistant to other β-lactams esp. in pts
with renal dysfn
CEPHALOSPORINS…
• Less active against G+ve’s than 1st-G
• Inactive agaist enterococci, Listeria, ORS
• Cefotaxime and Ceftriaxone have poor
activity against P. aureginosa
• Ceftriaxone have the longest serum t1/2
(6.4hrs)
• Admin. OD or BD
CEPHALOSPORINS…
• Ceftriaxone particulary recommended for:
– penicillin resistant gonorrhea,
– lyme disease involving CNS or joints,
– menengitis due to ampicillin resistant H.

influenzae and
– menengitis in children
CEPHALOSPORINS…
• One of complications of ceftriaxone is the
formation in the biliary tract of ‘sludge’
composed of ceftriaxone crystals, causing
syndrome of biliary pseudolithiasis
• Fatal rxns due to calcium-ceftriaxone ppts in
the lungs and kidneys of neonates have been
reported.
CEPHALOSPORINS…
• Ceftriaxone should not be reconstituted or

mixed with Ca containing product (e.g.
Ringers or hartmans solution or parenteral
nutrition)
CEPHALOSPORINS…
• Ceftriaxone should be avoided in infants aged
≤ 28d if they are receiving or expected to
receive IV Ca-containing products
• Cefriaxone and Ca-containing products may
be used concomitantly in pts aged > 28d,
provided that the infusion lines are thoroughly
flushed btn infusions
CEPHALOSPORINS…
• Ceftazidime is an effective therapy for serious
infns due to P. aureginosa when the organism
is resistant to the anti-pseudomonal penicillins
or the pt is allergic to penicillins
• Has poor activity vs G+ve’s and should be
reserved for infns proven or highly suspected
to be due to P. aureginosa
CEPHALOSPORINS…
• Cefepime is 4th-G currently available
• Similar activity to cefotaxime and ceftriaxone
against pneumococci and oxacillin sensitive S.
aureus
• Active as ceftazidime for P. aureginosa and is active
against some ceftazidime-resistant isolates.
• As with other anti-pseudomonal penicillins, should
be given in combo with aminoglycosides in Rx of
serious P. aureginosa infn
CEPHALOSPORINS…
• Ceftaroline is 5th –G cephalosporin whose
active metabolite has spectrum of in vitro
activity similar to ceftriaxone but with
improved G+ve activity
• Has higher affinity for PBP2a in oxacillin-

resistant staph, (ORSA) and has activity
against MRSA as well as VISA
CEPHALOSPORINS…
Oral cephalosporins are available
• Cephalexin • Cefixime
• Cefadroxil • Cefpodoxime
• Cefaclor proxetil
• Cefuroxime axetil • Ceftibuten,
• Cefprozil • Cefdinir
• Cefditoren
CEPHALOSPORINS…
• Pharmacokinetics
• Available for oral use, but most are admin.
parenterally.
• Cephalosporins with side chains may undergo
hepatic metabolism, but the major elimination
mechanism is renal excretion via active
tubular secretion.
CEPHALOSPORINS…
• Pharmacokinetics…
• Cefoperazone and ceftriaxone are excreted
mainly in the bile.
• Most 1st- and 2nd-G cephalosporins do not
enter the CSF even when the meninges are
inflamed.
CEPHALOSPORINS…
• MoA and Resistance
• Cephalosporins bind to PBPs on bacterial cell
membranes to inhibit bacterial cell CWS by
mechanisms similar to those of the penicillins.
• Cephalosporins are bactericidal against

susceptible organisms.
CEPHALOSPORINS…
• Structural differences from penicillins render

cephalosporins less susceptible to
penicillinases produced by staphylococci, but
many bacteria are resistant through the
production of other β-lactamases that can
inactivate cephalosporins.
CEPHALOSPORINS…
• Resistance can also result from ↓ in

membrane permeability to cephalosporins
and from ∆s in PBPs.
• MRSA are also resistant to cephalosporins.

CEPHALOSPORINS…
• Clinical Uses
• 1. First-generation drugs
• E.g. Cefazolin (parenteral) and cephalexin
(oral).
• Active against G+ve cocci, including staph. and
common streptococci.
• Strains of E. coli and K. pneumoniae are also
sensitive.
CEPHALOSPORINS…
• Clinical Uses
• 1. First-generation drugs…
• Clinical uses incl Rx of infns caused by these
organisms and surgical prophylaxis in selected
conditions.
• Min. activity against G-ve cocci, enterococci,

MRSA, and most G-ve rods.
CEPHALOSPORINS…
• 2. Second-generation drugs
• Have slightly less activity against G+ve
organisms than the 1st-G drugs but have an
extended G-ve coverage.
• Marked differences in activity occur among

the drugs in this subgroup.
CEPHALOSPORINS…
• 2. Second-generation drugs…
• E.g. of clinical uses incl.
– infns caused by the anaerobe B. fragilis

(cefotetan, cefoxitin) and
– sinus, ear, and respiratory infns caused by

H. influenzae or M. catarrhalis
(cefamandole, cefuroxime, cefaclor)
CEPHALOSPORINS…
• 3. Third-generation drugs
• E.g. of 3rd generation drugs (eg, ceftazidime,
cefoperazone, cefotaxime)
• Have ↑ acNvity against G-ve organisms
resistant to other β-lactam drugs
• Have the ability to penetrate the BBB (except

cefoperazone and cefixime).
CEPHALOSPORINS…
• 3. Third-generation drugs…
• Most are active against Providencia, S.
marcescens, and β-lactamase-producing
strains of H. influenzae and Neisseria;
• Less active against Enterobacter strains that

produce extended-spectrum β-lactamases.
CEPHALOSPORINS…
• Ceftriaxone and cefotaxime are currently the
most active cephalosporins against PRSP
strains, but resistance is reported.
• Individual drugs also have activity against

Pseudomonas (cefoperazone, ceftazidime)
and B. fragilis (ceftizoxime).
• Usually reserved for Rx of serious infns.
CEPHALOSPORINS…
• Ceftriaxone (parenteral) and cefixime (oral),
currently DoC in gonorrhea, are exceptions.
• Likewise, in acute otitis media, a single inj. of

ceftriaxone is usually as effective as a 10-day
course of Rx with amoxicillin.
CEPHALOSPORINS…
• 4. Fourth-generation drug
• Cefepime is more resistant to β-lactamases
produced by G-ve organisms, incl.
Enterobacter, Haemophilus, Neisseria, and
some PRSP.
• Cefepime combines the G+ve activity of 1st-G
agents with the wider G-ve spectrum of 3rd-G
Cporins.
• Ceftaroline is a newly introduced agent with
activity against MRSA.
CEPHALOSPORINS…
• Most have short t1/2, except some which may be
dosed less frequently(eg, cefazolin q8h and
ceftraixone q24h)
• All except ceftriaxone requires dose

modification in severe renal failure
• 1st and 2nd G drugs (except cefuroxime)
penetrate CSF barrier poorly and should not be
used in Rx of infns of CNS
CEPHALOSPORINS…
• 3rd-G cephalosporins achieve more reliable

CSF levels in pts with meningeal irritation.
• Cefotaxime, Ceftriaxone and ceftazidime are

approved for Rx of bacterial meningitis
CEPHALOSPORINS…
• Toxicity
• 1. Allergy
• Allergic rxns from skin rashes to anaphylactic
shock.
• Rxns occur less frequently compared to
penicillins.
• Complete cross-hypersensitivity btn different
cephalosporins should be assumed.
CEPHALOSPORINS…
• Toxicity
• 1. Allergy…
• Cross-reactivity btn penicillins and Csporins is
incomplete (5–10%), so penicillin-allergic pts are
sometimes Rx successfully with a Csporin.
• However, patients with a history of anaphylaxis

to penicillins should not be Rx with a
cephalosporin.
CEPHALOSPORINS…
• 2. Other AEs
• May cause pain at IM injection sites and
phlebitis after IV admin.
• May ↑ the nephrotoxicity of aminoglycosides

when the two are admin together.
CEPHALOSPORINS…
• 2. Other AEs…
• Drugs containing a methylthiotetrazole grp
(eg, cefamandole, cefoperazone, cefotetan)
may cause:
– hypoprothrombinemia and
– disulfiram-like rxns with ethanol.

OTHER β-LACTAM DRUGS
• Aztreonam
• A monobactam that is resistant to β-
lactamases produced by certain G-ve rods,
incl Klebsiella, Pseudomonas, and Serratia.
• Has no activity against G+ve bacteria or
anaerobes.
• An inhibitor of CWS, preferentially binding to
a specific PBP3, and is synergistic with
aminoglycosides.
OTHER β-LACTAM DRUGS…
• Aztreonam…
• Admin. IV and is eliminated via renal tubular
secretion.
• Its t1/2 is prolonged in renal failure.
• AEs incl GIT upset with possible superinfn,
vertigo and headache, and rarely
hepatotoxicity.
• Although skin rash may occur, there is no
cross-allergenicity with penicillins
• Imipenem, Doripenem, Meropenem, and
Ertapenem
• These are carbapenems (chemically different
from penicillins but retaining the β-lactam ring
structure) with low susceptibility to β-
lactamases.
• Imipenem, Doripenem, Meropenem, and
Ertapenem (the cabapenems)…
• Wide activity against G+ve cocci (incl. some
PRSP), G-ve rods, and anaerobes.
• With the exception of ertapenem, the

carbapenems are active against P. aureginosa
and Acinetobacter spp.
• Carbapenems…
• For pseudomonal infns, often used in combo
with an aminoglycoside.
• Are admin. parenterally and are useful for infns
caused by organisms resistant to other abx.
• However, MRSA strains are resistant.
• Currently co-drugs of choice for infns caused by
Enterobacter, Citrobacter, and Serratia spp.
• Carbapenems…
• Imipenem is rapidly inactivated by renal
dehydropeptidase I and is admin. in FDC with
cilastatin, an inhibitor of this enzyme.
• Cilastatin ↑ the plasma t1/2 of imipenem and
inhibits the formation of a potentially
nephrotoxic metabolite.
• Other carbapenems are not significantly
degraded by the kidney.
• Carbapenems…
• AEs of imipenem-cilastatin incl GIT distress,
skin rash, and, at very high plasma levels, CNS
toxicity (confusion, encephalopathy, seizures).
• There is partial cross-allergenicity with the

penicillins.
• Carbapenems…
• Meropenem is similar to imipenem except
that it is not metabolized by renal
dehydropeptidases and is less likely to cause
seizures.
• Ertapenem has a long t1/2 but is less active
against enterococci and Pseudomonas, and its
IM injection causes pain and irritation.
• β-Lactamase Inhibitors
• Clavulanic acid, sulbactam, and tazobactam
are used in FDC with certain hydrolyzable
penicillins.
• Most active against plasmid-encoded β-
lactamases such as those produced by
gonococci, streptococci, E. coli, and H.
influenzae.
• β-Lactamase Inhibitors…
• Are not good inhibitors of inducible
chromosomal β-lactamases formed by
– Enterobacter,
– Pseudomonas, and
– Serratia.
OTHER CELL WALL OR
MEMBRANE-ACTIVE AGENTS
• Vancomycin
• A bactericidal glycoprotein that binds to the
D-Ala-D-Ala terminal of the nascent
peptidoglycan pentapeptide side chain and
inhibits transglycosylation.
• This Px elongation of the peptidoglycan chain
and interferes with crosslinking.
OTHER CELL WALL OR
MEMBRANE-ACTIVE AGENTS
• Vancomycin…
• Resistance in strains of enterococci (vancomycin-
resistant enterococci [VRE]) and staphylococci
(vancomycin-resistant S aureus [VRSA]) involves
a ↓ affinity of vancomycin for the binding site
becoz of the replacement of the terminal D-Ala
by D-lactate.
OTHER CELL WALL OR
MEMBRANE-ACTIVE AGENTS…
• Vancomycin…
• has a narrow spectrum of activity
• Used for
– serious infns caused by drug-resistant G+ve
organisms, including MRSA, and
– in combo with a 3rd-G Csporin such as

ceftriaxone for Rx of infns due to PRSP.
OTHER CELL WALL OR
• Vancomycin…
• A backup drug for Rx of infns caused by C.
difficile.
• Teicoplanin and telavancin, other

glycopeptide derivatives, have similar
characteristics.
OTHER CELL WALL OR
• Vancomycin…
• VRE are ↑ and pose a potenàlly serious
clinical problem becoz such organisms usually
exhibit multiple-drug resistance.
• Vancomycin-intermediate strains of S. aureus
(VISA) resulting in Rx failures have also been
reported.
OTHER CELL WALL OR
• Vancomycin…
• Vancomycin is not absorbed from the GIT and
may be given PO for bacterial enterocolitis.
• Parenterally, vancomycin penetrates most

tissues and is eliminated unchanged in the
urine.
OTHER CELL WALL OR
• Vancomycin…
• Dosage modification is mandatory in pts with
renal impairment.
• Toxic effects of vancomycin include chills,
fever, phlebitis, ototoxicity, and
nephrotoxicity.
• Rapid IV infusion may cause diffuse flushing
(“red man syndrome”) from histamine release.
OTHER CELL WALL OR
• Fosfomycin
• An antimetabolite inhibitor of cytosolic
enolpyruvate transferase.
• This action Px the formation of N-
acetylmuramic acid, an essential precursor
molecule for peptidoglycan chain formation.
• Resistance to fosfomycin occurs via ↓ IC
accumulation of the drug.
OTHER CELL WALL OR
• Fosfomycin…
• excreted by the kidney, with urinary levels
exceeding the MICs for many urinary tract
pathogens.
• In a single dose, the drug is less effective than

a 7-day course of Rx with fluoroquinolones.
OTHER CELL WALL OR
• Fosfomycin…
• With multiple dosing, resistance emerges
rapidly and diarrhea is common.
• May be synergistic with β-lactam and

quinolone antibiotics in specific infns.
OTHER CELL WALL OR
• Bacitracin
• A peptide antibiotic that interferes with a late
stage in CWS in G+ve organisms.
• Due to its marked nephrotoxicity, the drug is

limited to topical use.
OTHER CELL WALL OR
• Cycloserine
• An antimetabolite that blocks the incorporation
of D-Ala into the pentapeptide side chain of the
peptidoglycan.
• Becoz of its potential neurotoxicity (tremors,
seizures, psychosis), is only used to Rx TB caused
by organisms resistant to first-line anti-TB drugs.
Ex, MDR-TB
OTHER CELL WALL OR
• Daptomycin
• A novel cyclic lipopeptide with spectrum
similar to vancomycin but active against VRE
and VRSA.
• Eliminated via the kidney.
• Creatine phosphokinase should be monitored
since daptomycin may cause myopathy.
Protein synthesis inhibitors,
sulfonamides, quinolones and
miscellaneous antibiotics
Chloramphenicol,
Tetracyclines,
Macrolides, Clindamycin,
Streptogramins, & Linezolid
Outline
• Protein synthesis inhibitors
– Chloramphenicol
– Tetracyclines
– Macrolides
– Streptogramin
– Linezolid
– Aminoglycosides
– Antifolate drugs (Sulfonamides, Trimethoprim)
– Fluoroquinolones
Protein Synthesis Inhibitors
• These abx inhibit bacterial protein synthesis
• The mechanisms of protein synthesis (PS) in
microorganisms are not identical to those of
mammalian cells.
• Bacteria have 70S ribosomes, whereas
mammalian cells have 80S ribosomes.
• Differences exist in ribosomal subunits RS and
in the chemical composition and functional
specificities of component nucleic acids and
proteins
INHIBITORS OF MICROBIAL
PROTEIN SYNTHESIS
• Vary considerably in chemical structures and
spectrum of antimicrobial activity.
• Chloramphenicol, tetracyclines, and the
aminoglycosides were the 1st PSI.
• Becoz they had a broad spectrum of
antibacterial activity and were thought to
have low toxicities, they were overused.
• Once highly susceptible bacterial species have
become resistant, now these drugs are used
for more selected targets.
PROTEIN SYNTHESIS…
• Erythromycin, an older macrolide abx, has a
narrower spectrum of action but continues to
be active against several important pathogens.
• Azithromycin and clarithromycin, semisynthetic
macrolides, have some distinctive properties
compared with erythromycin, as does
clindamycin.
• Newer PSIs, which incl streptogramins,
linezolid, telithromycin, and tigecycline (a
tetracycline (TTCL) analog), have activity
against certain bacteria that have developed
resistance to older abx.
• MoA
• Most PSIs are bacteriostatic acting at the
ribosomal level with the exception of TTCLs,
the binding sites for these abx are on the 50S
RS.
• MoA…
• Chloramphenicol inhibits transpeptidation
(catalyzed by peptidyl transferase) by blocking
the binding of the aminoacyl moiety of the
charged transfer RNA (tRNA) molecule to the
acceptor site on the ribosome-messenger
(mRNA) complex.
• MoA…
• Thus, the peptide at the donor site cannot be
transferred to its aa acceptor.
• Macrolides, telithromycin, and clindamycin,
which share a common binding site on the 50S
ribosome, also block transpeptidation.
• TTCLs bind to the 30S RS Px binding of aa-
charged tRNA to the acceptor site of the r-
mRNA complex
• Streptogramins are bactericidal for most
susceptible organisms.
• Bind to the 50S RS, constricting the exit
channel on the ribosome through which
nascent polypeptides are extruded.
• In addition, tRNA synthetase activity is
inhibited, leading to a ↓ in free tRNA within
the cell.
• Linezolid is mainly bacteriostatic.
• Binds to a unique site on the 50S R, inhibiting
initiation by blocking formation of the tRNA-
ribosome-mRNA ternary complex. OR
• Binds to bacterial 23S rRNA of the 50S subunit
to Px protein translation
• Elicits nonselective MAO inhibition
• Selective toxicity of these PSIs against
microorganisms may be explained by target
differences.
• Chloramphenicol does not bind to the 80S rRNA
of mammalian cells, although it can inhibit the
functions of mitochondrial ribosomes, which
contain 70S rRNA
• TTCLs have little effect on mammalian PS becoz
an active efflux mechanism Px their IC
accumulation.
CHLORAMPHENICOL
• Classification and PKs
• Has a simple and distinctive structure, and no
other abx have been discovered in this chemical
class.
• Effective PO as well as parenterally
• Widely distributed readily crossing the placental
and BBB.
• Undergoes enterohepatic cycling, and a small
fraction of the dose is excreted in the urine
unchanged.
• Most of the drug is inactivated by a hepatic
glucuronosyltransferase
CHLORAMPHENICOL…
• Antimicrobial Activity
• Has a wide spectrum of antimicrobial activity
• Usually bacteriostatic.
• Some strains of H. influenzae, N. meningitidis,
and Bacteroides are highly susceptible, and for
these organisms chloramphenicol may be
bactericidal.
• Not active against Chlamydia spp.
• Resistance to chloramphenicol, which is plasmid-
mediated, occurs thr’ the formation of
acetyltransferases that inactivate the drug.
CHLORAMPHENICOL…
• Clinical Uses
• Becoz of its toxicity, chloramphenicol has very few
uses as a systemic drug.
• Backup drug for severe infns caused by Salmonella
spp. and for the Rx of pneumococcal and
meningococcal meningitis β-lactam–sensitive
persons.
• Sometimes used for rickettsial diseases and for
infns caused by anaerobes such as B. fragilis.
• Commonly used as a topical antimicrobial agent.
E.g. eye/ear drops
CHLORAMPHENICOL…
• Toxicity
• Due to direct irritation and from superinfns,
especially candidiasis.
• 2. Bone marrow—Inhibition of red cell maturation
leads to a ↓ in circula`ng erythrocytes.
• This action is dose-dependent and reversible.
• Aplastic anemia is a rare idiosyncratic rxn
• (approx, 1 case in 25,000–40,000 pts Rx).
• Usually irreversible and may be fatal.
CHLORAMPHENICOL…
• 3. Gray baby syndrome
• Occurs in infants and is characterized by ↓
RBCs, cyanosis, and cardiovascular collapse.
• Neonates, especially premature, are deficient
in hepatic glucuronosyltransferase and are
sensitive to doses of chloramphenicol, which
would be tolerated in older infants.
CHLORAMPHENICOL…
• 4. Drug interactions
• Inhibits hepatic drug metabolizing enzymes,
thus ↑ the eliminaòn t1/2 of drugs incl
– phenytoin,
– tolbutamide and
– warfarin
TETRACYCLINES
• Classification
• Broad-spectrum bacteriostatic Abx that have
only minor differences in their activities
against specific organisms.
• PKs: Oral absorption is variable, especially for
the older drugs, and may be impaired by
foods and multivalent cations (calcium, iron,
aluminum).
• TTCLs have a wide tissue distribution and
cross the placental barrier.
TETRACYCLINES…
• All TTCLs undergo enterohepatic cycling.
• Doxycycline excreted mainly in feces; the
other drugs are eliminated primarily in the
urine.
• The t1/2 of doxycycline and minocycline are
longer than those of other tetracyclines.
• Tigecycline, only for IV use, is eliminated in
the bile and has a t1/2 of 30–36 h.
TETRACYCLINES…
• Antibacterial Activity
• Broad-spectrum abx with activity against G+ve
and G-ve bacteria, species of Rickettsia,
Chlamydia, Mycoplasma, and some protozoa.
• Resistance to most TTCLs is widespread.

TETRACYCLINES…
• Resistance mechanisms incl.
– development of mechanisms (efflux
pumps) for active extrusion of TTCLs and
– the formation of ribosomal protection
proteins that interfere with TTCL binding.
• These mechanisms do not confer resistance to
tigecycline in most organisms, with the
exception of the multidrug efflux pumps of
Proteus and Pseudomonas spp.
TETRACYCLINES…
• Clinical Uses
• 1. Primary uses
• Rx of infns caused by M. pneumoniae (in
adults), chlamydiae, rickettsiae, vibrios, and
some spirochetes.
• Doxycycline is currently an alternative to
macrolides in the initial Rx of community-
acquired pneumonia (CAP)
TETRACYCLINES…
• 2. Secondary uses
– Alternative drugs in the Rx of syphilis.
– Rx of RTIs caused by susceptible organisms,
– for prophylaxis against infn in chronic
bronchitis,
– in the Rx of leptospirosis, and
– in the Rx of acne.
TETRACYCLINES…
• 3. Selective uses
• Rx of GIT ulcers caused by H. pylori
(tetracycline), in Lyme disease (doxycycline),
and in the meningococcal carrier state
(minocycline).
• Doxycycline also used for Px of malaria and
in the Rx of amebiasis.
• Demeclocycline inhibits the renal actions of
antidiuretic hormone (ADH) and is used in the
mgt of pts with ADH secreting tumors
TETRACYCLINES…
• 4. Tigecycline
• Broad spectrum including organisms resistant
to standard TTCLs.
• Antimicrobial activity of tigecycline incl. G+ve
cocci resistant to MRSA and VRE, β-
lactamase–producing G-ve bacteria,
anaerobes, chlamydiae, and mycobacteria.
• Formulated only for IV use.
TETRACYCLINES…
• Toxicity
• Effects on the GIT system range from mild
nausea and diarrhea to life-threatening
enterocolitis.
• Disturbances in the normal flora may lead to
candidiasis (oral and vaginal) and, more rarely,
to bacterial superinfns with S. aureus or Cl.
difficile.
TETRACYCLINES…
• 2. Bony structures and teeth
• Fetal exposure to TTCLs may lead to tooth
enamel dysplasia and irregularities in bone
growth.
• Although usually CI in pregnancy, there may
be situations in which the benefit of TTCLs
outweigh the risk.
• Rx of younger children may cause enamel
dysplasia and crown deformation when
permanent teeth appear
TETRACYCLINES…
• 3. Hepatic toxicity
• High doses of TTCLs, espec. in preg. pts and
those with preexisting hepatic disease, may
impair liver function and lead to hepatic
necrosis.
• 4. Renal toxicity
• One form of renal tubular acidosis, Fanconi’s
syndrome, has been attributed to the use of
outdated tetracyclines.
• Though not directly nephrotoxic, TTCLs may
exacerbate preexisting renal dysfunction
TETRACYCLINES…
• 5. Photosensitivity
• TTCLs, especially demeclocycline, may cause
enhanced skin sensitivity to UV light.
• 6. Vestibular toxicity
• Dose-dependent reversible dizziness and

vertigo have been reported with doxycycline
and minocycline.
MACROLIDES
• The macrolide abx (erythromycin,
azithromycin, and clarithromycin) are large
cyclic lactone ring structures with attached
sugars.
• Have good oral bioavailability, but azithromycin

absorption is impeded by food.
MACROLIDES
• Classification and PKs…
• Macrolides distribute to most body tissues,
but azithromycin is unique in that the levels
achieved in tissues and in phagocytes are
considerably higher than those in the plasma.
MACROLIDES…
• Elimination of erythromycin (via biliary
excretion) and clarithromycin (via hepatic
metabolism and urinary excretion of intact
drug) is fairly rapid (t1/2 of 2 and 6 h,
respectively).
• Azithromycin is eliminated slowly (t1/2 2–4
days), mainly in the urine as unchanged drug.
MACROLIDES
• Antibacterial Activity
• Erythromycin has activity against many spp of
Campylobacter, Chlamydia, Mycoplasma,
Legionella, G+ve cocci, and some G-ve’s.
• Spectra of activity of azithromycin and
clarithromycin are similar but incl. greater
activity against spp of Chlamydia, MAC, and
Toxoplasma
MACROLIDES
• Azithromycin is effective in gonorrhea, as an
alternative to ceftriaxone and in syphilis, as an
alternative to penicillin G.
• Resistance to the macrolides in G+ve’s
involves efflux pump mechanisms and the
production of a methylase that adds a methyl
group to the ribosomal binding site.
MACROLIDES
• Cross-resistance btn individual macrolides is
complete.
• In case of methylase-producing microbial
strains, there is partial cross-resistance with
other drugs that bind to the same ribosomal
site as macrolides, including clindamycin and
streptogramins.
• Resistance in Enterobacteriaceae is the result
of formation of drug-metabolizing esterases.
MACROLIDES
• Clinical Uses
• Erythromycin is effective in the Rx of infns
caused by M pneumoniae, Corynebacterium,
C. jejuni, C. trachomatis, Chlamydophila
pneumoniae, L. pneumophila, U. urealyticum,
and B. pertussis.
• Also active against G+ve cocci (but not PRSP
strains and β-lactamase–producing
staphylococci) but not MRSA strains.
MACROLIDES
• Azithromycin has a similar spectrum of
activity but is more active against H.
influenzae, M. catarrhalis, and Neisseria.
• Becoz of its long t1/2, a single dose of
azithromycin is effective in the Rx of
urogenital infns caused by C. trachomatis, and
a 4-day course of Rx has been effective in CAP.
MACROLIDES
• Azithromycin…
• Acute exercabations of COPD
– 500mg PO once, then 250mg OD 4d OR
alternatively 500mg PO qDay for 3d
• Acute otitis media and pharyngitis/tonsillitis
(as above)
• Genital ulcer disease (chancroid) 1g PO once
MACROLIDES
• Azithromycin…
• Acute bacterial sinusitis
– 500mg PO 3d or 2g PO once
• CAP: 500mg PO once, then 250mg OD 4d, for
severe infn u can give 500mg IV single dose for
at least 2d then oral Rx with 500mg OD to
complete 7-10d
MACROLIDES
• Clarithromycin
• Almost the same spectrum of antimicrobial
activity and clinical uses as erythromycin.
• Also used for prophylaxis against and Rx of

MAC and as a component of drug regimens
for ulcers caused by H. pylori.
MACROLIDES
• Fidaxomicin
• Narrow-spectrum macrolide abx that inhibits
bacterial PS and is selectively active against
G+ve aerobes and anaerobes.
• PO, systemic absorption is minimal.
• Proved to be as effective as vancomycin for
the Rx of C. difficile colitis, possibly with a
lower relapse rate.
MACROLIDES
• Toxicity
• AEs, especially with erythromycin, incl. GIT
irritation (common) via stimulation of motolin
receptors, skin rashes, and eosinophilia.
• A hypersensitivity-based acute cholestatic
hepatitis may occur with erythromycin
estolate.
• Hepatitis is rare in children, but there is an
↑risk with erythromycin estolate in the
pregnant pt.
MACROLIDES
• Toxicity…
• Erythromycin inhibits several forms of hepatic
cytochrome P450 and can ↑ the plasma levels of
many drugs, incl. anticoagulants, carbamazepine,
cisapride, digoxin, and theophylline.
• Similar drug interactions have also occurred with
clarithromycin.
MACROLIDES
• Toxicity…
• The lactone ring structure of azithromycin is
slightly different from that of other
macrolides, and drug interactions are
uncommon because azithromycin does not
inhibit hepatic cytochrome P450
Telithromycin
• A ketolide structurally related to macrolides.
• Has the same MoA as erythromycin and a
similar spectrum of antimicrobial activity.
• However, some macrolide-resistant strains
are susceptible to telithromycin becoz
– it binds more tightly to ribosomes and
– is a poor substrate for bacterial efflux
pumps that mediate resistance.
Telithromycin…
• Can be used in CAP incl. infns caused by MDR
organisms.
• Given PO once daily and is eliminated in the
bile and the urine.
• AEs of telithromycin incl hepatic dysfunction
and prolongation of the QTc interval.
• An inhibitor of the CYP3A4 drug-metabolizing
system.
Clindamycin
• Bacterial PSI via a mechanism similar to that
of the macrolides, although not chemically
related.
• Mechanisms of resistance incl. methylation of
the binding site on the 50S RS and enzymatic
inactivation.
• G-ve aerobes are intrinsically resistant becoz
of poor penetration of clindamycin thr’ the
outer membrane
Clindamycin…
• Cross-resistance btn clindamycin and
macrolides is common.
• Good tissue penetration occurs after oral
absorption.
• Undergoes hepatic metabolism, and both
intact drug and metabolites are eliminated by
biliary and renal excretion.
Clindamycin…
• Clinical Use and Toxicity
• Rx of severe infns caused by certain anaerobes
such as Bacteroides.
• Backup drug against G+ve cocci (it is active
against community-acquired strains of MRSA)
• Recommended for prophylaxis of
endocarditis in VHD pts who are allergic to
penicillin.
Clindamycin…
• Active against P. jiroveci and is used in combo
with pyrimethamine for AIDS-related
toxoplasmosis.
• Toxicity incl GIT irritation, skin rashes,
neutropenia, hepatic dysfunction, and
possible superinfections such as C. difficile
pseudomembranous colitis.
STREPTOGRAMINS
• Quinupristin-dalfopristin, a combo of 2
streptogramins, is bactericidal and has a
duration of antibacterial activity longer than
the t1/2 of the 2 cpds (postantibiotic effects).
• Antibacterial activity incl PRSP, MRSA and
VRSA, and resistant E. faecium
• E. faecalis is intrinsically resistant via an efflux
transport system
STREPTOGRAMINS…
• Admin. IV, the combo product may cause pain
and an arthralgia-myalgia syndrome.
• Potent inhibitors of CYP3A4 and ↑ plasma

levels of many drugs, incl. astemizole,
cisapride, cyclosporine, diazepam, NNRTIs,
and warfarin.
LINEZOLID
• 1st of a novel class of abx (oxazolidinones)
• Active against drug-resistant G+ve cocci, incl.
MRSA, PRSP and VRE
• Also active against L. monocytogenes and
corynebacteria.
• Binds to a unique site located on the 23S rRNA
of the 50S ribosomal subunit
• Currently there is no cross-resistance with
other PSIs.
LINEZOLID…
• Resistance involves a ↓ affinity of linezolid

for its binding site.
• Available in both oral and parenteral forms

and should be reserved for Rx of infns caused
by MDR G+ve bacteria.
LINEZOLID…
• Metabolized by the liver and has an
elimination t1/2 of 4–6 h.
• Thrombocytopenia and neutropenia occur,

most commonly in immunosuppressed pts.
• Has been implicated in the serotonin

syndrome when used in pts taking SSRIs.
Aminoglycosides
Aminoglycosides
• MODES OF ANTIBACTERIAL ACTION
• In the Rx of microbial infns with abx, multiple
daily dosage regimens traditionally have
been designed to maintain serum concs
above the MIC for as long as possible.
• However, the in vivo effectiveness of some
abx, incl. aminoglycosides (AGs), results from
a concentration-dependent killing action
Aminoglycosides…
• As the plasma level is ↑ above the MIC, AGs
kill an increasing proportion of bacteria and
do so at a more rapid rate.
• Many abx, incl. penicillins and cephalosporins,
cause time-dependent killing of microbes,
wherein their in vivo efficacy is directly
related to time above MIC and becomes
independent of conc. once the MIC has been
reached.
Aminoglycosides…
• AGs are also capable of exerting a postantibiotic
effect such that their killing action continues
when their Cp have ↓ below measurable levels.
• Consequently, AGs have greater efficacy when
admin. as a single large dose than when given as
multiple smaller doses.
• Toxicity (in contrast to the antibacterial efficacy)
of AGs depends both on a critical Cp and on the
time that such a level is exceeded.
Aminoglycosides…
• The time above such a threshold is shorter
with admin of a single large dose of an AG
than when multiple smaller doses are given.
• These concepts form the basis for once-daily
aminoglycoside dosing protocols, which can
be more effective and less toxic than
traditional dosing regimens. E.g. 160mg OD vs
80mg BD
Aminoglycosides…
• PKs
• Structurally related amino sugars attached by
glycosidic linkages.
• Polar cpds, not absorbed after oral admin, and
must be given IM or IV for systemic effect.
• Have limited tissue penetration and do not
readily cross the BBB.
• GF is the major mode of excretion, and plasma
levels of these drugs are greatly affected by ∆s in
renal function.
Aminoglycosides…
• Excretion of AGs is directly proportional to
creatinine clearance.
• With normal RF, the elimination t1/2 of AGs is 2–
3 h.
• Dosage adjustments must be made in renal
insufficiency to Px toxic accumulation.
• Monitoring of plasma levels of AGs is important
for safe and effective dosage selection and
adjustment.
Aminoglycosides…
• For traditional dosing regimens (2 or 3x/d),
peak serum levels are measured 30–60 min
after admin and trough levels just before the
next dose.
• With OD dosing, peak levels are less important

since they will naturally be high.
Aminoglycosides…
• MoA
• AGs are bactericidal PSIs.
• Penetration thr’ the bacterial cell envelope is
partly dependent on oxygen-dependent active
transport, and they have min activity against
strict anaerobes.
• AG transport can be enhanced by CWS
inhibitors, which may be the basis of
antimicrobial synergism.
Aminoglycosides…
• Inside the cell, AGs bind to the 30S RS and
interfere with PS in at least 3 ways:
– they block formation of the initiation
complex;
– they cause misreading of the code on the
mRNA template; and
– they inhibit translocation.
• AGs may also disrupt polysomal structure,
resulting in nonfunctional monosomes.
Aminoglycosides…
• MECHANISMS OF RESISTANCE
• Streptococci, incl S. pneumoniae, and
enterococci are relatively resistant to
gentamicin and most other AGs owing to
failure of the drugs to penetrate into the cell.
• However, the 10 mechanism of resistance to
AGs, especially in G-ve bacteria, involves the
plasmid-mediated formation of inactivating
enzymes.
Aminoglycosides…
• These enzymes are grp transferases that
catalyze the acetylation of amine functions
and the transfer of phosphoryl or adenylyl grps
to the oxygen atoms of hydroxyl grps on the AG.
• Individual AGs have varying susceptibilities to
such enzymes.
• For e.g. transferases produced by enterococci
can inactivate amikacin, gentamicin, and
tobramycin but not streptomycin.
Aminoglycosides…
• However, amikacin is often resistant to many
enzymes that inactivate gentamicin and
tobramycin.
• In addition, resistance to streptomycin, which is

common, appears to be due to ∆s in the
ribosomal binding site.
Aminoglycosides…
• CLINICAL USES
• Main differences among the individual AGs lie
in their activities against specific organisms,
particularly G-ve rods.
• Gentamicin, tobramycin, and amikacin are
important drugs for the Rx of serious infns
caused by aerobic G-ve bacteria, incl E. coli and
Enterobacter, Klebsiella, Proteus, Providencia,
Pseudomonas, and Serratia species.
Aminoglycosides…
• These AGs also have activity against strains of H.
influenzae, M. catarrhalis, and Shigella species,
although they are not DoC for infns caused by
these organisms.
• In most cases, AGs are used in combination
with a β-lactam abx.
• When used alone, AGs are not reliably effective
in the Rx of infns caused by G+ve cocci.
Aminoglycosides…
• Antibacterial synergy may occur when AGs
are used in combo with CWSIs.
• E.g. incl. their combined use with penicillins in
the Rx of pseudomonal, listerial, and
enterococcal infns.
• Streptomycin in combo with penicillins is
often more effective in enterococcal carditis
than regimens that incl other AGs.
Aminoglycosides…
• This combo is also used in the Rx of TB, plague,
and tularemia.
• Other AGs are usually effective in these
conditions.
• MDR-TB that are resistant to streptomycin
may be susceptible to amikacin.
• Becoz of the risk of ototoxicity, streptomycin
should not be used when other drugs will
serve.
Aminoglycosides…
• Owing to their toxic potential, neomycin and

kanamycin are usually restricted to topical or
oral use (e.g. to eliminate bowel flora).
• Gentamicin is also available for topical use.
• Netilmicin has been used for Rx of serious
infns caused by organisms resistant to the
other AGs.
Aminoglycosides…
• Spectinomycin
• an aminocyclitol related to the AGs.
• Sole use is as a backup drug, admin. IM as a
single dose for the Rx of gonorrhea, most
commonly in pts allergic to β-lactams.
• There is no cross-resistance with other drugs
used in gonorrhea.
• May cause pain at the injection site.
Aminoglycosides…
• TOXICITY
• A. Ototoxicity
• Auditory or vestibular damage (or both) may
occur with any AG and may be irreversible.
• Auditory impairment is more likely with
amikacin and kanamycin;
• Vestibular dysfunction is more likely with
gentamicin and tobramycin
Aminoglycosides…
• Ototoxicity risk is proportional to the Cp and
thus is especially high if dosage is not approp.
modified in a pt with renal dysfunction.
• Ototoxicity may be ↑ by the use of loop
diuretics.
• Becoz ototoxicity has been reported after fetal
exposure, the AGs are CI in pregnancy unless
their potential benefits outweigh risk.
Aminoglycosides…
• B. Nephrotoxicity
• Renal toxicity usually takes the form of acute
tubular necrosis.
• This AE, which is often reversible, is more
common in elderly pts and in those
concurrently receiving amphotericin B,
cephalosporins, or vancomycin.
• Gentamicin and tobramycin are the most
nephrotoxic.
Drugs with nephrotoxic potential
• ACE inhibitors, • Methicillin
• acetazolamide, • methoxyflurane,
• aminoglycosides, • NSAIDs,
• aspirin, • pentamidine,
• amphotericin B • sulfonamides,
• cyclosporine, • tetracyclines
• furosemide, (degraded),
• gold salts, • thiazides, and
• lithium, • triamterene
Aminoglycosides…
• C. Neuromuscular Blockade
• Though rare, a curare-like block may occur at
high doses of AGs and may result in
respiratory paralysis.
• Usually reversible by Rx with calcium and
neostigmine, but ventilatory support may be
required.
Aminoglycosides…
• D. Skin Reactions
• Allergic skin rxns may occur in pts, and
contact dermatitis may occur in personnel
handling the drug.
• Neomycin is the agent most likely to cause

this adverse effect.
Sulfonamides,
Trimethoprim,
& Fluoroquinolones
Sulfonamides, Trimethoprim,
& Fluoroquinolones…
• Sulfonamides and trimethoprim are
antimetabolites selectively toxic to microbes
becoz they interfere with folic acid synthesis.
• Sulfonamides continue to be used selectively as
individual antimicrobial agents, although
resistance is common.
• The combo of a sulfonamide with trimethoprim
causes a sequential blockade of folic acid
synthesis.
• This results in a synergistic action against a
wide spectrum of microorganisms; resistance
occurs but has been relatively slow in
development.
• Fluoroquinolones, which selectively inhibit
microbial nucleic acid metabolism, also have
a broad spectrum of antimicrobial activity that
includes many common pathogens.
• Resistance has emerged to the older abx in
this class but has been offset to some extent
by the introduction of newer fluoroquinolones
with expanded activity against common
pathogenic organisms.
ANTIFOLATE DRUGS
• The antifolate drugs used in the Rx of infectious
diseases are
– the sulfonamides, which inhibit microbial
enzymes involved in folic acid synthesis, and
– trimethoprim, a selective inhibitor of

dihydrofolate reductase.
ANTIFOLATE DRUGS…
• 1. Sulfonamides
• Weakly acidic cpds that have a common
chemical nucleus resembling p-aminobenzoic
acid (PABA).
• Members differ mainly in their PK properties

and clinical uses.
ANTIFOLATE DRUGS…
• 1. Sulfonamides…
• PK features incl modest tissue penetration,
hepatic metabolism, and excretion of both
intact drug and acetylated metabolites in the
urine.
• Solubility may be ↓ in acidic urine, resulting
in precipitation of the drug or its metabolites.
ANTIFOLATE DRUGS…
• Becoz of the solubility limitation, a combo of 3
separate sulfonamides (triple sulfa) has been
used to ↓ the likelihood that any one drug will
precipitate.
• Sulfonamides may be classified as
– short-acting (eg, sulfisoxazole),
– intermediate-acting (eg, sulfamethoxazole), and
– long-acting (eg, sulfadoxine).
• Sulfonamides bind to plasma proteins at sites
shared by bilirubin and by other drugs.
ANTIFOLATE DRUGS…
• 2. Trimethoprim
• Structurally similar to folic acid.
• A weak base and is trapped in acidic
environments, reaching high concs in prostatic
and vaginal fluids.
• A large % of trimethoprim is excreted
unchanged in the urine.
• The t1/2 of this drug is similar to that of
sulfamethoxazole (10–12 h).
ANTIFOLATE DRUGS…
• High-Yield Terms:
• Antimetabolite: A drug that, through chemical
similarity, is able to interfere with the role of
an endogenous cpd in cellular metabolism
• Sequential blockade: The combined action of
2 drugs that inhibit sequential steps in a
pathway of bacterial metabolism
ANTIFOLATE DRUGS…
• High-Yield Terms:
• DNA gyrase: Bacterial topisomerase responsible
for -ve supercoiling of double-stranded DNA that
balances the positive supercoiling of DNA
replication and acts as a “swivel,” preventing
damage to the DNA strand
• Topoisomerase IV: Bacterial topisomerase
initiating decatenation, the mechanism by which
2 daughter DNA molecules are separated at the
conclusion of DNA replication
ANTIFOLATE DRUGS…
• Mechanisms of Action
• 1. Sulfonamides
• Are bacteriostatic inhibitors of folic acid
synthesis.
• As antimetabolites of PABA, they are
competitive inhibitors of dihydropteroate
synthase.
ANTIFOLATE DRUGS…
• 1. Sulfonamides…
• Also act as substrates for this enzyme, resulting
in the synthesis of nonfunctional forms of folic
acid.
• Selective toxicity of sulfonamides results from
the inability of mammalian cells to synthesize
folic acid; they must use preformed folic acid that
is present in the diet.
ANTIFOLATE DRUGS…
• 2. Trimethoprim
• Trimethoprim is a selective inhibitor of bacterial
dihydrofolate reductase that Px formation of the
active tetrahydro form of folic acid.
• Bacterial dihydrofolate reductase is 4–5 orders

of magnitude more sensitive to inhibition by
trimethoprim than the human enzyme.
ANTIFOLATE DRUGS…
• 3. Trimethoprim plus sulfamethoxazole
• When the 2 drugs are used in combo,
antimicrobial synergy results from the sequential
blockade of folate synthesis
• The drug combo is bactericidal against

susceptible organisms
ANTIFOLATE DRUGS…
• Resistance
• Bacterial resistance to sulfonamides is common
and may be plasmid-mediated.
• Can result from
– ↓ IC accumulaòn of the drugs,
– ↑ producòn of PABA by bacteria, or
– a ↓ in the sensi`vity of dihydropteroate

synthase to the sulfonamides.
ANTIFOLATE DRUGS…
• Clinical resistance to trimethoprim most

commonly results from the production of
dihydrofolate reductase that has a ↓ affinity
for the drug.
ANTIFOLATE DRUGS…
• Clinical Use
• 1. Sulfonamides
• Are active against G+ve and G-ve organisms,
Chlamydia, and Nocardia.
• Specific members of the sulfonamide grp are
used by the foll. routes for the conditions
indicated:
• a. Simple UTIs—Oral (eg, triple sulfa,
sulfisoxazole).
ANTIFOLATE DRUGS…
• b. Ocular infections—Topical (eg,
sulfacetamide).
• c. Burn infections—Topical (eg, mafenide, silver
sulfadiazine)
• d. Ulcerative colitis, rheumatoid arthritis—Oral
(eg, sulfasalazine).
• e. Toxoplasmosis—Oral sulfadiazine plus
pyrimethamine (a dihydrofolate reductase
inhibitor) plus folinic acid.
ANTIFOLATE DRUGS…
• 2. Trimethoprim-sulfamethoxazole (TMP-
SMZ)
• This drug combo is effective PO in the Rx of
UTIs and in respiratory, ear, and sinus infns
caused by H. influenzae and M. catarrhalis.
• In the immunocompromised pt, TMP-SMZ is
used for infns due to Aeromonas hydrophila
and is the DoC for Px and Rx of pneumocystis
pneumonia.
ANTIFOLATE DRUGS…
• An IV formulation is available for pts unable to
take the drug PO and is used for Rx of severe
pneumocystis pneumonia and for G-ve sepsis.
• TMP-SMZ is also the drug of choice in
nocardiosis,
• A possible backup drug for cholera, typhoid
fever, and shigellosis, and has been used in
the Rx of infns caused by MRSA and Listeria
monocytogenes.
Toxicity of Sulfonamides…
• 1. Hypersensitivity
• Allergic rxns, incl. skin rashes and fever, occur
commonly.
• Cross-allergenicity btn the individual
sulfonamides should be assumed and may also
occur with chemically related drugs (eg, oral
hypoglycemics, thiazides).
• Exfoliative dermatitis, polyarteritis nodosa, and
Stevens-Johnson syndrome have occurred rarely.
• 2. Gastrointestinal
• Nausea, vomiting, and diarrhea occur
commonly.
• Mild hepatic dysfunction can occur, but
hepatitis is uncommon.
• 3. Nephrotoxicity
• Sulfonamides may precipitate in the urine at
acidic pH, causing crystalluria and hematuria
• 4. Hematotoxicity
• Although such effects are rare, sulfonamides
can cause granulocytopenia
thrombocytopenia, and aplastic anemia.
• Acute hemolysis may occur in persons with

glucose-6-phosphate dehydrogenase
deficiency.
• 5. Drug interactions
• Competition with warfarin and methotrexate for
plasma protein binding transiently ↑ the plasma
levels of these drugs.
• Sulfonamides can displace bilirubin from plasma
proteins, with the risk of kernicterus in the
neonate if used in the 3rd trimester of
pregnancy.
Toxicity of Trimethoprim
• Trimethoprim may cause the predictable AEs of
an antifolate drug, incl.
– megaloblastic anemia,
– leukopenia, and granulocytopenia.
• These effects are usually ameliorated by

supplementary folinic acid.
Toxicity of Trimethoprim
• The combo of TMP-SMZ may cause any of the
AEs a/c the sulfonamides.
• AIDS pts given TMP-SMZ have a high incidence

of AEs, incl
– fever,
– rashes,
– leukopenia, and diarrhea

FLUOROQUINOLONES
• Classification
• Generationwise based on their spectrum of
activity.
• Norfloxacin, a 1st-G FQ derived from nalidixic

acid, has activity against the common
pathogens that cause UTIs.
FLUOROQUINOLONES
• Classification…
• Ciprofloxacin and ofloxacin (2nd-G FQs) have
greater activity against G-ve bacteria and are
also active against the gonococcus, many G+ve
cocci, mycobacteria, and agents of atypical
pneumonia (M. pneumoniae, Chlamydophila
pneumoniae).
FLUOROQUINOLONES…
• 3rd-G FQs (levofloxacin, gemifloxacin, and

moxifloxacin) are slightly less active than
ciprofloxacin and ofloxacin against G-ve’s but
have greater activity against G+ve cocci, incl S
pneumoniae and some strains of enterococci
and MRSA.
FLUOROQUINOLONES…
• 3rd-G drugs are commonly referred to as

“respiratory FQs.”
• Most recently introduced drugs (eg,

gemifloxacin, moxifloxacin) are the broadest-
spectrum FQs introduced to date, with
enhanced activity against anaerobes.
FLUOROQUINOLONES…
• PKs
• All the FQs have good oral bioavailability
(antacids containing multivalent cations may
interfere) and penetrate most body tissues.
• However, norfloxacin does not achieve adequate
plasma levels for use in most systemic infns.
• Elimination of most FQs is thr’ the kidneys via
active tubular secretion, which can be blocked
by probenecid.
FLUOROQUINOLONES…
• Dosage reductions are usually needed in renal
dysfunction except for moxifloxacin which is
eliminated partly by hepatic metabolism and
also by biliary excretion.
• Use of moxifloxacin in UTIs is not
recommended.
• T1/2 of FQs are usually in the range of 3–8 h.
FLUOROQUINOLONES…
• MoA
• The FQs interfere with bacterial DNA synthesis
by inhibiting topoisomerase II (DNA gyrase),
especially in G-ve organisms and topoisomerase
IV, especially in G+ve organisms.
• They block the relaxation of supercoiled DNA
that is catalyzed by DNA gyrase, a step required
for normal transcription and duplication.
FLUOROQUINOLONES…
• Inhibition of topoisomerase IV by FQs interferes
with the separation of replicated chromosomal
DNA during cell division.
• FQs are usually bactericidal against susceptible
organisms.
• Like AGs, the FQs exhibit postantibiotic effects,
whereby bacterial growth continues to be
inhibited even after the Cp of the drug has
fallen below the MIC of the bacterium
FLUOROQUINOLONES…
• Resistance
• Has emerged rapidly in the case of 2nd-G FQs,
especially in C. jejuni and gonococci, but also
in G+ve cocci (eg, MRSA), P. aeruginosa and
Serratia spp.
• Mechanisms of resistance incl ↓ IC
accumulation of the drug via the production
of efflux pumps or ∆s in porin structure (in G-
ve bacteria).
FLUOROQUINOLONES…
• Efflux mechanisms appear to be responsible for
resistance in strains of M tuberculosis, S aureus,
and S pneumoniae.
• ∆s in the sensitivity of the target enzymes via
point mutations in the abx binding regions are
also established to confer resistance against
specific FQs.
• Mutations in the quinolone resistance
determining region of the gyrA gene that
encodes DNA gyrase is responsible for resistance
in gonococci.
FLUOROQUINOLONES…
• Clinical Use
• Effective in the Rx of infns of the urogenital
and GIT tracts caused by G-ve organisms, incl
gonococci, E. coli, K. pneumoniae, C. jejuni,
Enterobacter, P. aeruginosa, Salmonella, and
Shigella spp.
• Have been used widely for respiratory tract,
skin, and soft tissue infns, but their
effectiveness is now variable becoz of the
emergence of resistance.
FLUOROQUINOLONES…
• Ciprofloxacin and ofloxacin in single oral doses
have been used as alternatives to ceftriaxone
or cefixime in gonorrhea, but they are not
currently recommended becoz resistance is
now common.
• Ofloxacin eradicates C. trachomatis, but a 7-d
course of Rx is required.
• Levofloxacin has activity against most
organisms a/c CAP, incl. chlamydiae,
mycoplasma, and legionella species
FLUOROQUINOLONES…
• Gemifloxacin and moxifloxacin have the

widest spectrum of activity, which incl both
G+ve and G-ve organisms, atypical pneumonia
agents, and some anaerobic bacteria.
• FQs have also been used in the meningococcal
carrier state, in the Rx of TB, and in
prophylactic mgt of neutropenic pts.
FLUOROQUINOLONES…
• Toxicity
• GIT distress is the most common AE.
• May cause skin rashes, headache, dizziness,
insomnia, abnormal liver function tests,
phototoxicity, and both tendinitis and tendon
rupture.
FLUOROQUINOLONES…
• Toxicity…
• Opportunistic infns caused by C. albicans and
streptococci have occurred.
• The FQs are not recommended for children or

pregnant women becoz they may damage
growing cartilage and cause arthropathy.
FLUOROQUINOLONES…
• FQs may ↑ the plasma levels of theophylline
and other methylxanthines, enhancing their
toxicity.
• Newer FQs (gemifloxacin, levofloxacin,
moxifloxacin) prolong the QTc interval.
• Should be avoided in pts with known QTc
prolongation and those on certain
antiarrhythmic drugs or other drugs that ↑ the
QTc interval.
FLUOROQUINOLONES…
• Grepafloxacin was withdrawn from clinical
use becoz of serious cardiotoxicity.
• Currently available FQs are CI in pts taking
drugs that prolong the QT interval.
• What other drugs that have this characteristic
effect to ↑ the duraòn of the ventricular AP
include?
FLUOROQUINOLONES…
• Most important drugs that prolong the QT

interval are antiarrhythmics.
• These incl. drugs from class IA and class III,

incl. amiodarone, bretylium, disopyramide,
procainamide, quinidine, and sotalol.
FLUOROQUINOLONES…
• Although grp IA drugs are classified as Na+
channel blockers, they also block K+ channels
and prolong the duration of the ventricular AP.
• Other drugs implicated in QT prolongation incl.

erythromycin, mefloquine, pentamidine,
thioridazine and possibly other tricyclic
antidepressants, and ziprasidone.
Thanks for listening

Antibiotics - MAK25JUL17

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– prospective audit and feedback (PAF),

• In programs using preauthorization, approval

• Correcting an inaccurate abx allergy hx in the

Genus Species Disease

Ricketssiae Several spp. Tick- and insect

Salmonella S. typhimurium Food poisoning

β- Broad spectrum A wide range Bacteial CW

Antipseudomonal Selected G-ve

β-lactams CARBAPENEMSMany G-ve Bacterial

Polymixins Colistimethate, G-ve spp Bacterial

Tetracycline Demeclocycline Many G-ve Bacterial protein

Aminogycosides Amikacin, Many G-ve, Bacterial

Macrolides Azithromycin, Similar to Bacterial

Amphenicols Chloramphenicol G-ve and Bacterial

Antimycobacterials Capreomycin, Most used for Various unrelated

Miscellaneous Fusidic acid G+ve spp. Bacterial

Nitrofurantoin G-ve UTIs Damages

Methenamine G-ve UTIs Formaldehyd

• Selective toxicity of the drugs is mainly due to

• Bacteriostatic: An antimicrobial drug that

• β-lactam antibiotics: Drugs with structures

• This ring must be intact for antimicrobial

• β-lactam inhibitors: Potent inhibitors of some

• Ex. of β-lactamase inhibitors

• Brought about by drugs which exploit

4. Inhibition of nucleic acid synthesis. Affect

• What does the micro lab say?

• For deep IM admin. Absorption slow

• ↓ dose in Renal dysfn, Admin. Post dialysis

• Do not inject near artery or nerve (permanent

• Late (30 and latent syphilis with positive CSF):

• Neurosyphilis: 2.4 MU IM qDay x10-14 d;

• Procaine rxns: Immediate toxic rxns to procaine

• Avoid use in neonates; ↑ risk for sterile

2. PBP is unable to crosslink peptidoglycan chains

3. The bacteria is unable to synthesize a stable cell

4. The bacteria is lysed

• Have a wide spectrum of antibacterial activity

2nd Generation ↓Gram (+) and ↑Gram (-)

3rd Generation Gram(-), but also some GPC

4th Generation Gram (+) and Gram (-)

• Highly active against

– Enterobactericiae (E. coli, P. mirabilis,

• Useful alternative to Aminoglycosides in Rx of G-

– penicillin resistant gonorrhea,

– lyme disease involving CNS or joints,

– menengitis due to ampicillin resistant H.

• Ceftriaxone should not be reconstituted or

• Has higher affinity for PBP2a in oxacillin-

• Cephalosporins are bactericidal against

• Structural differences from penicillins render

• Resistance can also result from ↓ in

• MRSA are also resistant to cephalosporins.

• Min. activity against G-ve cocci, enterococci,

• Marked differences in activity occur among

– infns caused by the anaerobe B. fragilis

– sinus, ear, and respiratory infns caused by

• Have the ability to penetrate the BBB (except

• Less active against Enterobacter strains that

• Individual drugs also have activity against

• Likewise, in acute otitis media, a single inj. of

• All except ceftriaxone requires dose

• 3rd-G cephalosporins achieve more reliable