ANTIMICROBIAL GROUPS -anti-staphylococcal (penicillinase-resistant) PCN :

cloxacillin, nafcillin, flucloxacillin

Review: (methicillin and nafcillin – most stable; nafcillin-
Gram- Positive Bacterial Cell wall: Thicker peptidoglycan cell lower incidence of nephrotoxicity, may cause
wall neutropenia)
Gram-Negative Bacterial Cell Wall: Double membrane (with Spectrum:
outer membrane) -penicillinase -producing S. aureus
-other than gran positive cocci, but less
BETA-LACTAM ANTIMICROBIALS than PCN G
-with beta-lactam ring -Resistant are: Enterococcus, Neisseria spp.,
 Penicillins anaerobes, enterobacteria
 Cephalosporins
 Monobactams -aminopenicillins (broad spectrum),: ampicillin,
 Carbapenems amoxicillin, bacampicillin
 Cephamycins - have amino group (NH2) that enhances their
uptake through bacterial porin channels able
 Beta-lactamase inhibitors
to cross the lipopolysaccharide layer more easily;
helps make aminopenicillins have greater activity
against gram negative bacteria
Spectrum:
-similar to natural PCNs
-Enterococci
-Listeria monogytogenes
-Haemophilus spp
-E. coli
-Proteus mirabilis
-Salmonella
-Resistant are: Proteus vulgaris, klebsiella,
Enterobacter, serratia, yersinia

-anti-pseudomonal penicillin: ticarcillin,

Bacterial cell wall carbenicillin, mezlocillin, piperacillin
-protects against noxious outside influences
-prevents rupture of the plasma membrane from a high
internal osmotic pressure Benzyl Pen G: parent compound of the group,
-structural stability is due to mainly to the murein obtained from fungi, particularly Penicillium
(peptidoglycan) lattice notatum
- consists of basic building blocks linked together to
form a large macromolecule MOA: binds to penicillin-binding proteins
- each basic unit contains the two linked - Natural analogs of the D-ala-D-ala terminal
aminosugars N-acetylglucosamine and N- sequence to which PBPs bind to catalyze
acetylmuramyl acid crosslinking with a peptide
-transpeptidase enzyme cross-links the peptide chains of - inhibits peptidoglycan synthesis by inhibiting
adjacent aminosugar chains the transpeptidase enzyme

1. PENICILLINS Penicillin Binding Proteins

a. Natural (antibiotic) penicillins -virtually all bacteria contain PBPs
-Pen G (injection) -different bacteria have different amounts and different types
-Pen V (PO) of PBPs
-benzathine PCN G - different PBPs have different affinities for B-lactams -> will
-procaine PCN G demonstrate different sensitivities
Spectrum:
-aerobes Absorption:
-anaerobes (except penicillinase-producing bacteria) - PCN G- inactivated by gastric acid, which cleaves
-N.meningitidis the beta-lactam ring
-spirochetes (T.pallidum, Leptospira, Borrelia spp.) - Methicillin-acid labile (destroyed in acid
-enterococci (bacteriostatic effect) environment)
b. Semisynthetic penicillins - Nafcillin – erratic
 - Benzathine and procaine PCN – formulated to
delay absorption
- Amoxicillin – good absorption
Distribution:
- For meningitis – 18- 24 mU/day of PCN,
meninges inflamed
- Combination of penicillin with sodium,
potassium, procaine, and benzathine
- Inc. stability
- Regulates absorption
- Food interference (except amoxicillin):
give PCN 2 hrs before or 2 hrs after
meals
Clearance:
- PCN G – rapid renal elimination, mainly
unchanged (80% clearance within 4 hours)
- Probenecid – inhibits secretion of PCN
- Competes with PCN in the organic acid
transporter in the kidney  dec PCN
clearance
- Nafcillin – biliary
- Oxacillin, dicloxacillin, cloxacillin- both biliary
and renal
General Spectrum:
-gram positive organisms (mainly) except those with added
spectrum
-anaerobes except Bacteroides fragilis
-extended spectrum (may cover for Pseudomonas)
Adverse drug reactions (ADRs) – most important
- Hypersensitivity; anaphylaxis (in 0.01%)
- Neurotoxicity – mostly convulsions due to GABA
antagonism
- Other: Nausea and vomiting, diarrhea, stinging in the
vein if given IV
Specific ADRs
- Nafcillin- neutropenia
- Oxacillin – hepatitis
- Methicillin – interstitial nephritis
Mechanisms of resistance:
- B-lactamase enzyme production
- Modification of target PBPs
- Impaired penetration of a drug for target PBPs (i.e.
impenetrable gram negative cell wall)
- Efflux pump
2. CEPHALOSPORINS
 Similar in mechanism of action and in toxicity to PCNs
-5% cross sensitivity with PCN
 More stable than PCNs to many beta-lactamases
 Generations- classified according to spectrum of clinical
activity
First generation:
-alternative to anti-staphylococcal penicillins
-cephalexin (Ceporex, Keflex, Oneflex)
-cefazolin
Spectrum:
-Gram-positive cocci (except enterococci and MRSA)
-some gram negative organisms like E.coli and Klebsiella
pneumoniae
True second generations:
-Cefuroxime
-cefaclor
-cefamandole
-cefotiam
-carbacephem: loracarbef
-cephamycins: cefocitin, cefotetan
Spectrum:
-similar activity against Gram-positive cocci
-inc.activity against gram-negative bacilli
-enhanced anaerobic bacterial coverage (including
Bacteroides fragilis)
-cefuroxime: effective for CAP, crosess BBB but not as
effective as ceftriaxone or cefotaxime
-cefaclor: more susceptible to beta-lactamase hydrolysis
-carbacephem: Gram (+) cocci including S. aureus, S.
pneumoniae, and other streptococci, modest activity vs. H.
influenzae and M. catarrhalis
-cephamycins: same as second gen cephalosphorins but with
good anaerobic activity
-cefoxitin: effective against Bacteroides
-cefuroxime, cefaclor, cefamandole: effective against H
influenzae
Third generation cephalosporins:
-greater activity vs a wider range of gram-negatives
A. agents with anti-pseudomonal activity
o Ceftazidime- often 1st drug given to pseudomonas
o Cefoperazone
B. agents with no anti-pseudomonal activity
o Ceftriaxone - good coverage for typhoid fever,
salmonella, used for gonorrhea
o Cefotaxime –better gram pos. coverage (except
enterococci) also w/ gram neg
o Cefixime – has oral prep
o Ceftizoxime
Fourth generation cephalosporins:
o Cefepime: effective vs bacteria resistant to many
cephalosporins because of
-more rapid penetration of bacteria
-ability to target multiple PBPs
-lower affinity for several B-lactamases
 Caution: assoc. with higher all-cause mortality than -tachycardia
are other B-lactam antibiotics, possibly because of -arrythmias
drug-induced encephalopathy -confusion

Fifth generation cephalosporins: 3. MONOBACTAMS

o Ceftobiprole: powerful anti pseudomonal -Aztreonam is the prototype
characteristics, appears to be less susceptible to MOA: binds to penicillin-binding proteins  ultimately
development of resistance interfering with cell wall synthesis
o Ceftaroline: effective against MRSA, drug-resistant Pharmacokinetics: not absorbed orally
pneumococci, common gram-negative pathogens, no
anti-pseudomonal or VRE (vancomycin-resistant Advantages over the aminoglycosides and cephalosporins:
enterococcus) coverage -not nephrotoxic
o Ceftolozone -remains cidal under anaerobic conditions

REMEMBER: Spectrum: narrow

Pharmacokinetics: -only for aerobic gram-negative rods, including Pseudomonas
-excreted via biliary mechanisms: - beta lactamase resistant gram-negative rods
o Cefamandole - inactive against gram positives and anaerobes
o Cefoperazone
o Ceftriaxone Safety: may be safely administered to patients who had a
previous anaphylactic reaction to penicillin
ADRs
-allergy 4. CARBAPENEMS
-hematologic: bone marrow suppression WBC count -Structural feature: presence of a carbapenem
-nephrotoxicity: occasional interstitial nephritis and tubular nucleus
necrosis Preparations:
-pseudomembranous colitis o Imipenem
-cross-allergenicity with PCN is not absolute: has different o Meropenem
chemical nucleus, avoid if with history of anaphylaxis to PCNs o Ertapenem
o Doripenem
ADRs secondary to the presence of methylthiotetrazole side
chain: disulfiram-like reactions AND hypoprothrombinemia MOA: binds to penicillin-binding proteins preferentially to
(from inhibition of Vitamin-K dependent factors) -PBP 1: responsible for maintaining the bacterial wall’s
o Cefamandole constant diameter
o cefoperazone - PBP 2- responsible for extending the bacterial cell wall in
o cefotetan any direction  ultimately leads to rapid lysis of bacteria
o moxalactam - resistant to most beta-lactamases
o cefmenoxime Pharmacokinetics: absorption: very poor
o latamoxef -metabolism: readily inactivated by renal dihydropeptidases
 low urinary concentrations
o cefmetazole
Spectrum: ultra-broad
- gram positive cocci (except MRSA and Enterococcus
faecium)
- gram negative bacilli including Pseudomonas (except
Stenotrophomonas maltophilia)
-anaerobes

Clinical uses: drug of choice for Enterobacter spp.

-responsible for many nosocomial infections, and less
commonly community-acquired infections (UTI, respiratory
infections, soft tissue infections, osteomyelitis, and
endocarditis, etc)
Disulfiram reactions include: -treatment of in-hospital life-threatening infection
-flushing, hypotension o Imipenem – effective only against intracellular
-nausea bacteria
-headache o Ertapenem – given OD
-vomiting o Meropenem – more active vs Enterobacteriacea and
-sweating Pseudomonas aeruginosa
 - all strains of Staphylococci (including MRSA) and PCN-
Adverse effects: resistant pneumococci
-nausea and vomiting - Corynebacterium diphtheriae
-Fever - Clostridiodes difficile
-GI distress -Listeria
-skin rashes
-neurotoxicity at very high levels (confusion, encephalopathy, Indications:
seizures) -drug of choice for serious drug resistant gram positive
-reactions at infusion sites organisms, including MRSA, penicillin-resistant pneumococci,
and C. difficile; lacks penetration through gram negative cell
Mechanisms of resistance: membranes
-production of B-lactamases -synergistic with aminoglycosides if used for serious
-efflux pumps enterococcal infections
-mutations
Adverse effects- encountered frequently
5. BETA-LACTAMASE INHIBITORS -most reactions minor and reversible
MOA: overcome resistance caused by B-lactamase  by -irritating to tissue  phlebitis in injections
merely binding to B-lactamase -chills and fever may occur
-negligible antibacterial activity -nephrotoxicity (known)
-“suicide inhibitors” -ototoxicity – very rare
-added to another antimicrobial = more effective - red man syndrome (common) = flushing (sec to histamine
o Clavulanic acid, sulbactam, tazobactam and release), may dec BP – administer slowly over 1 hr, not an
avibactam allergy but a predictable response to rapidly administered
vancomycin
o Coamoxiclav = amoxicillin + clavulanic acid
o Sultamicillin = ampicillin + sulbactam AMINOGLYCOSIDES
o Piperacillin + Tazobactam MOA: inhibits protein synthesis at the 30S subunit
o Ticarcillin + clavulanic acid -its polycationic antibiotic molecules create fissures in outer
o Ceftazidime + avibactam cell membrane by combining with the negatively charged wall
polysaccharide and penetrating through an active transport
Clinical uses: effective against plasmid-encoded beta- system  lysis of cell envelope
lactamases produced by Pharmacokinetics: not absorbed from the GIT (give
-gonococci parenterally)
-streptococci -low protein binding
-E.coli -does not penetrate the CNS and bone
-high conc in the renal cortex* and inner ear
*all aminoglycosides conc in the renal cortex
GLYCOPEPTIDES Route of administration: IV or IM, topical for wounds, oral
o Vancomycin -for gut decontamination (hepatic encephalopathy)
o Teicoplanin
o Amikacin- most stable aminoglycoside against R-
o Lipoglycopeptides
plasmid mediated enzymes
-dalbavancin
-oritavancin
for aerobic and facultative gram-negative bacteria
-telavancin
-effective only against aerobes
-transport into bacteria is oxygen-dependent
MOA: (vancomycin)
-inhibits cell wall synthesis by binding firmly to the d-ala-d-ala
Spectrum: intermediate
terminus of nascent peptidoglycan pentapeptide  inhibits
-gram negative bacilli, including: enterobacteria, P.
the transglycosylase  prevents further elongation of
aeruginosa
peptidoglycan and cross-linking  weakens peptidoglycan 
-Mycobacterium tuberculosis and some atypical mycobacteria
cell becomes susceptible to lysis
(amikacin, streptomycin, kanamycin)
Pharmacokinetics: absorption: poor not absorbed orally
-good distribution except in CNS
Clinically useful in
-excretion: renal, solely by glomerular filtration
-combination treatment of serious gram-negative bacteria
Spectrum: narrow
-synergism with beta lactam vs streptococci and enterococci
- gram positive aerobes
- anaerobes
Adverse effects:
- enterococci
-ototoxicity (most vestibulotoxic- balance: streptomycin, -gram positive cocci and bacilli
gentamicin; most toxic to cochlea/hearing: neomycin, -Mycoplasma pneumoniae
kanamycin, amikacin) -Legionella
-nephrotoxicity- gentamicin, tobramycin, neomycin (used -Chlamydia
topically, too toxic for systemic use) -gram negative organisms
-neurotoxic (neuromuscular paralysis) -Bordetella pertussis
-hypersensitivity reaction -Haemophilus
-Moraxella
-Pasteurella
-Brucella

Indications:
-alternative drug to beta-lactam allergy
-drug of choice:
o Campylobacter
o Mycoplasma
o Legionella
-adjunct in treatment of gastroparesis
MACROLIDES
o Erythromycin
FYI: GASTROPARESIS
o Clarithromycin
-literally, “stomach paralysis” ; stomach motility either
o Roxithromycin abnormal or absent
o Azalide subgroup o Erythromycin
-azithromycin -binds to “motilin” receptors in the small intestine
o Ketolide subgroup and stomach  stimulates these receptors 
-telithromycin results in contraction and improved stomach
emptying
MOA: -short lived effect due to tolerance
-binds to the p-site of the 50S ribosomal subunit to inhibit -best used for a worsening of symptoms or used on
bacterial protein synthesis an intermittent basis
Mode of action: primarily bacteriostatic
Pharmacokinetics:
o Clarithromycin
-absorption
-more stable than erythromycin
o Erythromycin base is destroyed by stomach acid 
-BID dosing
tablet must be enteric coated
o Azithromycin
o Food interferes with absorption
-OD dosing, shorter duration of treatment
o Stearate and ethylsuccinate formulations are fairly
-high distribution in tissues and phagocytes than in
acid-resistantc and better absorbed plasma
o Erymthromycin lactobionate – IV -also indicated for prophylaxis of Mycobacterium
o Clarithromycin – improved acid stability and oral avium intracelullare complex
absorption compared with erythromycin o Ketolides (prototype: telithromycin)
o Azithromycin – rapidly absorbed and well tolerated -limited clinical use
orally -semisynthetic macrolides
-distribution -effectivity for resistant strains :
o Good intracellular concentration - poor substrates foe efflux-pump mediated
o Widely distributed, except to the brain and CSF resistance
o Poor concentration in the CNS even in the presence -higher affinity for ribosomes than other
of inflammation macrolides
o Azithromycin – penetrates into most tissues, slowly -OD dosing
released from tissues (tissue half-life of 2-4 days) -ADR: hepatotoxicity, prolongs QT interval
-excretion
o Erythromycin – primarily in bile, not removed by Adverse reactions:
dialysis -GIT- anorexia, nausea, vomiting, diarrhea
o Clarithromycin – urine and bile -liver toxicity (erythromycin estolate, telithromycin)
o Azithromycin – unchanged in bile -may prolong QT interval
o Ketolides – urine and bile
Drug interactions:
Spectrum -metabolized cy Cytochrome P450 enzymes (isoform CYP3A)
-BFAD Blackbox warning for Erythromycin: -Vibrio cholera
-concomitant use of CYP3A inhibitors like nitroimidazole -rickettsia
can cause inc. serum levels of erythromycin  probably inc -Borrelia
risk of cardiac arrythmia -Chlamydia
- concurrent use of diltiazem of verapamil should -Mycoplasma
probably be avoided by persons at risk for heart -Leptospirosis (alternative agent)
abnormalities or those with long QT manifestations -syphilis (alternative agent)
-Actinomyces (alternative agent)
Mechanisms of resistance -melloidosis (alternative agent)
-reduced membrane permeability or efflux -glander (alternative agent)
-esterases
-modification of ribosomal binding sites Indications:
*cross resistance among macrolides is complete -Drug of choice for atypical conditions
-Mycoplasma
TETRACYCLINES -Chlamydia
-Conventional Tetracyclines -Rickettsia
o Chlortetracycline -Vibrios
o Demethylchlortetracycline -Secondary use: syphilis, respiratory infections, leptospirosis,
o Ocytetracycline (terramycin) acne
o Tetracycline -Sclerosant solution for pleurodesis
-Second generation
o Doxycycline (vibramycin, doxin) Adverse effects:
o Minocycline (minocin) - GIT disturbances
o Lymecycline -Photosensitivity – esp demeclocycline (not listed in MIMS)
-Third generation (Glycylcylcline) -hepatotoxicity – esp if given in high doses to pregnant
o Tigecycline (minocycline analog) patients with impaired liver function (may lead to hepatic
necrosis)
-bone and dentine tissue defects
MOA:
-nephrotoxicity
-bind reversibly th=o the 16S subunit of the 30S ribosomal
-spontaneously degraded over time: degradation products
subunit  inhibit translation (protein synthesis)  weakens
are nephrotoxic  can cause Fanconi syndrome
the ribosome-tRNA interaction  prevents addition of amino
-superinfection
acids to the growing peptide
-hypersensitivity rxn
Pharmacokinetics:
-vestibular toxicity – vertigo (dose-dependent, reversible)
-first generation: characterized by poor absorption after food
noted with minocycline
intake
-second generation: more reliably absorbed orally
Resistance:
-third generation: parenteral
-widespread; plasmid-mediated
-ALL: absorption impaired by:
-enhanced by use in animal feeds
-presence of food
-milk
Mechanisms of resistance
-divalent and trivalent ions (calcium, iron, aluminum)
-intracellular accumulation due to:
-alkaline pH
-efflux pump (active transport)
-widely distributed to all tissue and fluids, limited penetration
-impaired influx
into CNS
-ribosomal protection prevents binding
-crosses placental barrier
-enzymatic inactivation
-bound and stored in many tissues including dentine and
enamel of unerupted teeth
Resistance:
o Doxycycline: concentrates strongly in prostatic fluid,
-Proteus and Pseudomonas constitutively produce and efflux
useful for prostatitis
pump – all tetracyclines are substrates; universally resistant
-agents with highest plasma protein binding
to tetracyclines
o Doxycycline
-Tigecycline – overcomes the ff mechanisms of resistance:
o Minocycline
efflux pump (active transport) , ribosomal protection
-metabolized to varying degrees
-excretion mainly renal; doxycycline excreted in feces
LINCOSAMIDES
MOA:
Spectrum: broad
-Aerobic gram positives (except enterococcus)
-gram negatives
-inhibits protein synthesis by binding to the 23S portion of the o Clindamycin – used with pyrimethamine to treat
50S ribosomal subunit  premature dissociation of the toxoplasmosis; more effective and lesser side effects
peptidyl-tRNA from the ribosome compared to lincomycin
Spectrum:
-gram positive cocci: Adverse effects:
-Staphylococcus -GIT disturbances
-Streptococcus -pseudomembranous colitis/superinfection
-Many anaerobic gram positive and gram-negative bacteria -hypersensitivity reaction/skin rashes
(including B. fragilis) -hepatic dysfunction
*Clostridiodes difficile is resistant
*not effective for Enterococcus Mechanism of resistance:
-mainly recommended for anaerobes -mutation of ribosomal receptor sites
-Peptococcus -modification of receptor by methylase
-Veilonella -enzymatic inactivation
-Bacteroides
-Clostridium perfringes OXAZOLIDINONES
-Actinomyces o Linezolid
-gram positive organisms such as o Eperozolid
-S. pyogenes o Torezolid
-S. Pneumoniae o Radezolid
-S. viridans
-S. bovis MOA:
-C. diphtheriae -inhibits protein synthesis by preventing formation of
-Bacillus anthracis ribosome complex that initiates protein synthesis
-Nocardia spp. -binding site = 23S ribosomal RNA of the 50S subunit
-protozoa Mode of activity: primarily static, cidal for streptococci
-Toxoplasma
-Babesia Spectrum: wide variety of gram positives including
-Plasmodium vivax -staphylococci including MRSA
-streptococci
Pharmacokinetics: -enterococci
-well- absorbed -gram positive anaerobic cocci
-good distribution except in the CNS even in the presence of -gram positive rods such as corynebacterial, Nocardia sp., and
inflammation L.monocytogenes
-good levels in bone, fibrous connective tissue -Mycobacterium tuberculosis
-can enter alveolar macrophages
-90-94% bound to plasma proteins Clinical uses- approved for
-eliminated partly by metabolism and partly by biliary and -vancomycin-resistant E. faecium infections
renal excretion -health care-associated pneumonia
-community-acquired pneumonia
Indications: -complicated and uncomplicated skin and soft tissue gram
-mainly for anaerobes (like Bacteroides), especially intestinal positive infections
and vaginal infections
-osteomyelitis Adverse Drug Reactions:
-acne -reversible and generally mild hematologic ADRs 9reversible,
-alternative to PCN for gram (+) cocci mild myelosuppression) – most common is thrombocytopenia
-role in prophylaxis for patients with valvular diseases who -ADRs related to linezolid-induced inhibition of mitochondrial
will have dental extraction protein synthesis; optic and peripheral neuropathy, lactic
-commonly used in infections in and around the oral cavity acidosis
-high preponderance of anaerobic bacteria causing these -serotonin syndrome – if taken with serotonergic drugs
infections (SSRIs)
-toxic shoxk syndrome – secondary to Staphylococcus and - (serious but rare) hyperlactatemia and metabolic acidosis:
Streptococcus lactate is produced by the cells that cannot undergo aerobic
-necrotizing fasciitis (ie flesh eating dse)- sec to grp A metabolism because of mitochondrial suppression
Streptococcus
-also active vs. Pneumocyctis jiroveci (formerly P. carinii) and Mechanism of resistance:
Toxoplasma gondii -mutation of binding site on the 23s ribosomal RNA
-linezolid was approved in 2000
 -resistance was first reported in 2001 Mode of action: generally, bacteriostatic; cidal for
Pneumococcus
STREPTOGRAMINS
-identified almost 50 yrs ago Spectrum: broad
-recently found clinical use as a consequence of the inc -ineffective against Chlamydia
multidrug-resistant bacteria
o Quinipristin- Dalfopristin: a combination of 2 Pharmacokinetics:
streptogramins, in a fixed 70:30 ratio; synergistic -absorption: well absorbed orally
MOA: -distribution: very well distributed in tissues, including the
-inhibits ribosomal protein synthesis at the 50S subunit CNS
(similar to macrolides) -metabolism: conjugation with glucuronic acid, inactivated by
o Dalfopristin blocks an early step in protein synthesis  hepatic glucuronosyltransferase
forms a bond with a ribosome  prevents elongation of -excretion: tubular secretion (major route), small amount in
the peptide chain bile or feces, excretion in neonates is very poor
o Quinupristin blocks a later step prevents the
extension od peptide chains  causes incomplete Indications:
chains to be released -bactericidal against
Mode of action: cidal -pneumococci
-H. influenzae
Pharmacokinetics: -N. meningitidis
-absorption: poor -Bacteroides
-active metabolites contribute to the antimicrobial activity -rickettsiosis
-elimination: principally renal -Salmonella infections
-Significant pharmacodynamic properties - topical ophthalmic antibiotic
-rapidly cidal for Enterococcus faecium
-prolonged post-antibiotic effect (up to 10 hrs for Adverse effects:
staphylococci) -hematologic- bone marrow depression
-aplastic anemia
Spectrum: gram positive cocci, including -simple anemia
-MDR strains of streptococci -gray baby syndrome
-PCN-resistant strains of S. pneumoniae -results from inability of the liver to glucoronidate
-methicillin-susceptible and resistant strains of staphylococci chloramphenicol effectively (immature liver unable to
-E. faecium (but not Enterococcus faecalis) produce enough UDP-glucoronyltransferase enzyme, needed
to metabolize chloramphenicol)
Adverse effects: -hypersensitivity reaction
-infusion-related events, such as pain at the infusion site -GIT effects
-arthralgia-myalgia syndrome
Drug interactions:
Clinical use: -potent inhibitor od CYP450 isoform CYP2C19 and CYP3A4
-Staphylococcal infections -antagonism with cidal drugs as penicillins and
-vancomycin-resistant strains of Enterococcus ‘faecium aminoglycosides
-ineffective for Enterococcus fecalis because of an efflux
type resistant mechanism Resistance: inactivation by acetyltransferase and, in some
cases, phosphotransferase enzymes
Mechanism of resistance:
-due to modification of quinupristin binding site NITROIMIDAZOLES
-enzymatic inactivation of dalfopristin o Prototype: Metronidazole
-efflux
MOA:
AMPHENICOL -target organisms preferentially reduce the 5-nitro group on
o Chloramphenicol the molecule, creating active metabolites that disrupt the
helical structure of DNA  prevents nucleic acid synthesis 
MOA: eventually leads to cell death
-binds to the 23S rRNA on the 50S subunit of bacterial -its nitro group is chemically reduced in anaerobes and
ribosome  prevents protein chain elongation by inhibiting sensitive protozoans  reactive reduction products appear to
the peptidyl transferase activity  prevents formation of a be responsible for antiprotozoal and antibacterial activity
peptide bond
Pharmacokinetics:
-absorption: good
-distribution: very well distributed, low protein binding o Tinidazole
-excretion: renal -Has greater efficacy then metronidazole vs. most
susceptible pathogens
Spectrum: -produces a higher cure rate in a shorter period of
-Helicobacter pylori time than
- E. coli -active vs some metronidazole-resistant strains
-Proteus
-Klebsiella FLUOROQUINOLONES (QUINOLONES)
-Anaerobes MOA: fluoroquinolones bind to and inhibit:
-protozoa such as -DNA gyrase (also known as topoisomerase II)
- Trichomonas vaginalis - Topoisomerase IV
-Entamoeba histolytica
- Giardia lamblia Spectrum: broad
-Balantidium coli -1st and 2nd generation- selectively inhibit the topoisomerase II
ligase domain
Indications: -3rd and 4th generation – more selective for the topoisomerase
-drug of choice: IV ligase domain  enhanced gram-positive coverage
-extraluminal amoebiasis
-giardiasis DNA Gyrase
-trichomoniasis -DNA Is normally supercoiled = under too much tension to be
-anaerobic infections separated
-combination treatment for H. pylori in PUD -an extra step is required before replication and transcription
-Clostridiodes difficile superinfection can occur
- DNA gyrase relaxes supercoiled DNA  cuts it  allows
Adverse effects: rotation to occur  then reattaches it
-Common: nausea, headache, dry mouth, metallic taste
-infrequent: vomiting, diarrhea, insomnia, weakness, MOA 1: inhibit DNA gyrase in gram-negative organisms
dizziness, thrush, rash, dysuria, dark urine, vertigo, -prevent reattachement from occurring
paresthesias, encephalopathy, and neutropenia -at high doses, this leads to the release of these broken
-rare: pancreatitis and severe CNS toxicity (ataxia, segments of DNA
encephalopathy, seizures) -it is thought that the accumulation of these DNA fragments
-disulfiram-like effect leads to cell death

Some drugs which exhibit Disulfiram-like effects First generation

o Metronidazole o Nalidixic acid
o Tolbutamide o Oxolinic acid
o Cefoperazone o Pipemidic acid
o Cefotetan Spectrum: for UTI and diarrheal diseases only; resistant to P.
o Cefamandole aeruginosa and gram positives
o Moxalactam
o Cefmenoxime Second generation:
o Latamoxef o Ciprofloxacin
o Cefmetazole o Enoxacin
o Lomefloxacin
Drug interactions (Metronidazole) o Norfloxacin
-potentiates the anticoagulant effect of coumarin-type o Ofloxacin
anticoagulants o Pefloxacin
-phenytoinn and phenobarbital may accelerate its elimination Spectrum:
-Cimetidine may dec its plasma clearance -Enterobacteria
-inc lithium toxicity -Neisseria
-Haemophilus
Relative contraindications: -staphylococcus
-best avoided during pregnancy and lactation women -Corynobacteria
-metronidazole and its metabolites are mutagenic in bacteria -Streptococcus (Moderate activity)
and tumorigenic in mice - Listeria (Moderate activity)
-congenital abnormalities have not clearly been associated -Mycoplasma (Moderate activity)
with use in humans -Chlamydia (Moderate activity)
-Rickettsia (Moderate activity) Drug interactions:
-M. tuberculosis, M. fortuitum (Moderate activity) -with NSAIDS  fluoroquinolones may potentiate CNS
*resistant to anaerobes toxicity and cause seizures
-with theophylline  they will inc theophylline levels and inc
MOA 2: inhibit topoisomerase IV in gram positive organisms risk of the theophylline toxicity
-interferes with separation of replicated chromosomal DNA -Probenecid – blocks its excretion
into the respective daughter cells during cell division  halts
cell division Resistance:
-point mutation in binding region of the target enzymes:
Third generation (active vs. Streptococci) -primarily DNA gyrase (topoisomerase II)
o levofloxacin -secondarily topoisomerase IV
o sparfloxacin
o balofloxacin OTHERS…
o pazufloxacin
Spectrum: enhanced activity vs. gram positive pathogens SULFONAMIDES
-intracellular pathogens MOA: inhibits folic acid synthesis by competitive inhibition of
-some gram positive and gram-negative aerobes dihydropteroate synthetase
-mycobacteria (sparfloxacin)
*resistant to Enterococcus

Fourth generation: (inhibits topo IV and II- slows

development of resistance
o Moxifloxacin
o Sitafloxacin
o Prulifloxacin
Spectrum: same of third gen
-anaerobes
Pharmacokinetics:
Pharmacokinetics: -rapid and complete absorption from GIT
-well absorbed from GIT -variable protein binding
- food delays absorption -good distribution
- >50% bioavailability following oral intake -metabolism: hepatic
-high lipid solubility -excretion: renal
-high concentration in most tissues
-renal excretion ; exception: moxifloxacin (hepatic) Clinical uses:
-uncomplicated UTI
Adverse effects: -Malaria
-GIT- nausea, vomiting, diarrhea (most common) -Toxoplasmosis
-CNS- headache, restlessness -Pneumocistis jiroveci (cotrimoxazole)
-skin – rashes, photosensitivity
-arthropathy (tendon ruptures – Achilles, shoulder) Adverse effects:
-Hypersensitivity reaction
Contraindications: -GIT
-not used in children less than 18 (arthropathy and -hematologic (agranulocytosis, hemolytic anemia)
chondrotoxicity in immature animals) -skin rashes
-pregnant or breastfeeding women -drug fever
-Boxed warning 1 with systemic use (for all ages) -Stevens-Johnson syndrome
-tendinitis -vasculitis
-tendon rupture -renal-crystalluria
-Inc risk in: Predictable ADR: antifolate effects (megaloblastic anemia,
-patient over 60 y/o leukopenia and granulocytopenia)
-concomittant corticosteroid intake -sulfas are cross-allergenic
-kidney, heart, lung transplants
-Boxed warning 2 with systemic use (due to NM blocking Contraindications:
activity) -infants less than 2 months old
– exacerbation of muscle weakness in patients with -pregnant and lactating others
myasthenia gravis
 -distributed into the extravascular space
-crosses BBB and placenta
-plasma protein binding: 90%
-not metabolized by hepatic CYP enzymes
-excretion: renal

Indications:
-complicated skin infections
-multi-drug resistant gram positive bacteria

Adverse effects:
-eosinophilic pneumonia
DIAMINOPYRIMIDINES -resumably due to its binding to surfactant
MOA: inhibits folic acid synthesis by selective inhibition of -reversible myopathy  monitor creatine kinase levels
bacterial dihydrofolate reductase
POLYPEPTIDES
o Actinomycin
o Bacitracin
o Colistin
o Polymixin B

MOA: attach and disrupt bacterial cell membrane

-bind and inactivate endotocin

Pharmacokinetics: Mode of action: cidal for many gram negative rods, including
-almost complete absorption from GIT Pseudomonas
-45% bound to plasma proteins
-good distribution Pharmacokinetics:
-60-80% excreted unchanged in the urine -not absorbed from GIT
-75 % protein bound
Adverse effects: -poor CSF concentration
-Hypersensitivity reaction -renal excretion
-GIT – nausea, vomiting
-antifolate effects (megaloblasttosis, thrombocytopenia and Adverse effects:
granulocytopenia) -substantial nephrotoxicity
-substantial neurotoxicity
Clinical uses: -hypersensitivity reaction
-uncomplicated UTI (trimethoprim)
-blood schizonticide against P. falciparum (Pyrimethamine) Indications:
-Toxoplasmosis (Pyrimethamine + sulfadiazine) -only for topical agents
-no longer used systematically because of adverse effects
Spectrum- cotrimoxazole
-good activity of cotrimoxazole against gram positivesa and
MUPIROCIN (PSEUDOMONIC ACID)
Enterobacteriaceae
-a natural substance produced by Pseudomonas fleuorescens
-minimal activity against anaerobes
MOA: inhibits staphylococcal isoleucyl tRNA synthetase
Cyclic Lipopeptide: DAPTOMYCIN
MOA: disrupts the cytoplasmic membrane  causes rapid Pharmacokinetics: rapidly inactivated after absorption 
depolarization of membrane due to K+ efflux and associates systemic levels are undetectable
disruption of DNA, RNA, and protein synthesis  rapid
concentration -dependent bacterial deaths Spectrum:
-active against gram-positive cocci, including methicillin-
susceptible and MRSA

Indications:
-topical treatment of minor skin infections, such as impetigo
Pharmacokinetics: (ointment)
-administered IV
FIDAXOMICIN
MOA: inhibits bacterial protein synthesis by binding to the
sigma subunit of RNA polymerase

Pharmacokinetics: administered orally.

Spectrum: narrow
-active against gram-positive aerobes and anaerobes only

Indications:
-C. difficile infection in adults (as effective as oral vancomycin)

RIFAXIMIN
-derivative of rifampicin
MOA: inhibits bacterial protein synthesis by binding to the
beta subunit of DNA-dependent RNA polymerase

Pharmacokinetics: administered orally.

-systemic absorption is <0.5%, but fecal concentrations are
high
-not thought to be associated with cytochrome P450-
mediated drug interactions due to its limited absorption

Spectrum:
-active against gram-positive and gram negative aerobes and
anaerobes

Indications:
-Originally approved for travelers’ diarrhea
-now used in themanagement of hepatic encephalopathy,
irritable bowel syndrome with diarrhea and occasionally, as
an adjunct in cases of recurrent refractory difficile infection in
adults

FOSFOMYCIN
MOA: inhibits very early stage of bacterial cell wall synthesis
(inhibits cytoplasmic enolpyruvate)

Spectrum: gram positive and gram negative organisms

Appears safe in pregnancy