General Outline for Antibiotics Chemistry –MIP Chemistry –MIP Effect on microbes - MIP Effect on microbes - MIP Spectrum of coverage Spectrum of coverage

General Outline for General Outline for AntibioticsAntibiotics• Chemistry –MIPChemistry –MIP

• Effect on microbes - MIPEffect on microbes - MIP• Spectrum of coverageSpectrum of coverage• Mechanism(s) of actionMechanism(s) of action• Mechanism(s) of resistanceMechanism(s) of resistance

• Pharmacology of antibiotic Pharmacology of antibiotic class – mostly new infoclass – mostly new info• AbsorbanceAbsorbance• Fate after absorptionFate after absorption• ExcretionExcretion

• Pharmacology of select Pharmacology of select agents – mostly new infoagents – mostly new info

• Therapeutic uses – Therapeutic uses – somewhat new infosomewhat new info

• Toxicity/contraindications – Toxicity/contraindications – mostly new infomostly new info• Common (> 10%)Common (> 10%)• Uncommon (1-9%)Uncommon (1-9%)• Rare (< 1%)Rare (< 1%)

Sir Alexander Sir Alexander FlemingFleming

SulfonamidesSulfonamides• Analogues of PABAAnalogues of PABA• Broad spectrumBroad spectrum• Competitive inhibitors Competitive inhibitors

of dihydropteroate of dihydropteroate synthase – needed for synthase – needed for folic acid synthesisfolic acid synthesis

• Cidal in urineCidal in urine• Mechanisms of Mechanisms of

resistanceresistance• Altered affinity of Altered affinity of

enzyme for drugenzyme for drug• Decreased permeability Decreased permeability

or active effluxor active efflux• New pathway of folic acid New pathway of folic acid

synthesissynthesisGerhard Domagk gets Gerhard Domagk gets a Nobel for Medicine, a Nobel for Medicine, 1939.1939.

SulfonamidesSulfonamides• Mostly absorbed from Mostly absorbed from

GI tractGI tract• Binds variably to Binds variably to

serum albumin serum albumin • Wide tissue Wide tissue

distribution, including distribution, including transplacentallytransplacentally

• Variably inactivated in Variably inactivated in liver by acetylation liver by acetylation and then excreted in and then excreted in urineurine

• Some agents can Some agents can precipitate in acid precipitate in acid urineurine

Rapidly Absorbed and Rapidly Absorbed and Eliminated SulfonamidesEliminated Sulfonamides

• Sulfisoxazole, Sulfisoxazole, sulfamethoxazole, sulfamethoxazole, sulfadiazinesulfadiazine

• Bind extensively Bind extensively to plasma proteinsto plasma proteins

• Highly Highly concentrated in concentrated in urine (cidal)urine (cidal)

• Sulfamethoxazole Sulfamethoxazole combined with combined with trimethoprim trimethoprim (Bactrim) is widely (Bactrim) is widely used to treat a variety used to treat a variety of infections (esp. UTI)of infections (esp. UTI)

Poorly Absorbed Poorly Absorbed SulfonamidesSulfonamides

• SulfasalazineSulfasalazine• Poorly absorbed in Poorly absorbed in

GI tractGI tract• Used to treat Used to treat

ulcerative colitis ulcerative colitis and irritable bowel and irritable bowel syndromesyndrome

• Gut flora metabolize Gut flora metabolize drug into 2 drug into 2 compounds, 1 toxic, compounds, 1 toxic, 1 therapeutic (5-1 therapeutic (5-aminosalicylate)aminosalicylate)

Ulcerative Colitis

Sulfonamides for Topical Sulfonamides for Topical UseUse

• SulfacetamideSulfacetamide• Good penetration Good penetration

in eyein eye• Non-irritating Non-irritating

• Silver Silver sulfadiazinesulfadiazine• Prevention and Prevention and

treatment of treatment of burn wound burn wound infections infections

Bacterial corneal Bacterial corneal infectioninfection

Long Acting Long Acting SulfonamideSulfonamide

• SulfadoxineSulfadoxine• Serum half-life Serum half-life

is measured in is measured in days rather days rather than minutes or than minutes or hourshours

• Combined with Combined with pyirethamine to pyirethamine to treat malariatreat malaria Plasmodium Plasmodium

vivaxvivax

Therapeutic Uses Therapeutic Uses of Sulfonamidesof Sulfonamides

• Urinary tract Urinary tract infectionsinfections

• NocardiosisNocardiosis• ToxoplasmosiToxoplasmosi

s (avoid using s (avoid using in pregnant in pregnant women)women)

Nocardia Nocardia asteroidesasteroides

Toxicity/Contraindications Toxicity/Contraindications

of Sulfonamides - UTof Sulfonamides - UT• Crystallization Crystallization

in acid urinein acid urine• Common to Common to

uncommon uncommon depending on depending on drugdrug

• Alkalize urine or Alkalize urine or increase increase hydrationhydration


of Sulfonamides - bloodof Sulfonamides - blood• Acute hemolytic anemia Acute hemolytic anemia

• Rare to extremely rareRare to extremely rare• Associated with glucose-6-Associated with glucose-6-

phosphate dehydrogenase activity phosphate dehydrogenase activity in RBCin RBC

• Agranulocytosis (extremely rare)Agranulocytosis (extremely rare)• Aplastic anemia (extremely rare)Aplastic anemia (extremely rare)


of Sulfonamides - immuneof Sulfonamides - immune• Hypersensitivity reactions Hypersensitivity reactions

((common to uncommoncommon to uncommon))• Skin and mucous membrane Skin and mucous membrane

manifestations (rashes)manifestations (rashes)• Serum sicknessSerum sickness• Focal or diffuse necrosis of the Focal or diffuse necrosis of the

liver (rare)liver (rare)

Toxic Epidermal Toxic Epidermal Necrolysis (TEN)Necrolysis (TEN)


of Sulfonamides - of Sulfonamides - miscellaneousmiscellaneous• Nausea, anorexia, Nausea, anorexia,

vomiting (vomiting (commoncommon))• Kernicterus Kernicterus

• Displacement of Displacement of bilirubin from plasma bilirubin from plasma albumin to brain albumin to brain resulting in resulting in encephalopathyencephalopathy

• Never give sulfa drugs Never give sulfa drugs to a pregnant or to a pregnant or lactating womanlactating woman

• Potentiation of oral Potentiation of oral coagulants, sulfonylurea coagulants, sulfonylurea hypoglycemic drugs, hypoglycemic drugs, and hydrantoin and hydrantoin anticonvulsantsanticonvulsants

Bilirubin deposits in Bilirubin deposits in neonatal brainneonatal brain

The QuinolonesThe Quinolones• Naladixic acid was a Naladixic acid was a

byproduct of byproduct of chloroquine synthesischloroquine synthesis

• Current drugs are Current drugs are fluoridated 4-fluoridated 4-quinolonesquinolones

• Broad coverage (some Broad coverage (some broader than others)broader than others)

• Targets DNA gyrase Targets DNA gyrase (G-) and topoisomerase (G-) and topoisomerase IV (G+)IV (G+)

• Resistance due to efflux Resistance due to efflux and mutations in and mutations in targetstargets

QuinolonesQuinolones• Favorable Favorable

pharmacological pharmacological attributesattributes• Orally administered, quickly Orally administered, quickly

absorbed, even with a full absorbed, even with a full stomachstomach

• Excellent bioavailability in a Excellent bioavailability in a wide range of tissues and body wide range of tissues and body fluids (including inside cells)fluids (including inside cells)

• Mostly cleared by the Mostly cleared by the kidneyskidneys• Exceptions are pefloxacin and Exceptions are pefloxacin and

moxifloxacin which are moxifloxacin which are metabolized by liver metabolized by liver

• Ciprofloxacin, ofloxacin, Ciprofloxacin, ofloxacin, and pefloxacin are and pefloxacin are excreted in breast milkexcreted in breast milk

““Got Got Cipro?”Cipro?”

Therapeutic Uses Therapeutic Uses of Quinolonesof Quinolones

• Urinary tract Urinary tract infectionsinfections

• ProstatitisProstatitis• STD’sSTD’s

• ChlamydiaChlamydia• ChancroidChancroid• NotNot syphilis or syphilis or

gonorrhea (due gonorrhea (due to increased to increased resistance)resistance)


• GI and abdominal GI and abdominal • Travelers Travelers

diarrheadiarrhea• ShigellosisShigellosis• Typhoid feverTyphoid fever

• Respiratory tractRespiratory tract• All work well All work well

against atypicalsagainst atypicals• New agents for New agents for

strep. pneumoniastrep. pneumonia


• Bone, joint, soft Bone, joint, soft tissuetissue• Ideal for chronic Ideal for chronic

osteomylitisosteomylitis• Resistance developing Resistance developing

in in S. aureus, P. S. aureus, P. aeruginosaaeruginosa, and , and S. S. marcesensmarcesens

• Good against Good against polymicrobial polymicrobial infections like infections like diabetic foot ulcersdiabetic foot ulcers


• Ciprofloxacin for Ciprofloxacin for anthrax and anthrax and tuleremiatuleremia

• Combined with Combined with other drugs, other drugs, useful for atypical useful for atypical MycobacteriumMycobacterium sp. or for sp. or for prophylaxis in prophylaxis in neutropenic neutropenic patientspatients

Pulmonary Pulmonary AnthraxAnthrax


of Quinolonesof Quinolones• Nausea, vomiting, abdominal discomfort Nausea, vomiting, abdominal discomfort

((commoncommon))• Diarrhea and antibiotic-associated colitis Diarrhea and antibiotic-associated colitis

(uncommon to rare)(uncommon to rare)• CNS side effectsCNS side effects

• Mild headache and dizziness (Mild headache and dizziness (commoncommon to rare) to rare)• Hallucinations, delirium, and seizures (rare)Hallucinations, delirium, and seizures (rare)

• Arthropy in immature animals (Arthropy in immature animals (commoncommon))• Quinolones not given to children unless benefits Quinolones not given to children unless benefits

outweigh the risks outweigh the risks

• Leukopenia, eosinophila, heart arythmias Leukopenia, eosinophila, heart arythmias (rare)(rare)

The Beta-LactamsThe Beta-Lactams

PenicillinsPenicillins• Penicillium notatumPenicillium notatum

produces the only produces the only naturally occuring naturally occuring agent – penicillin G or agent – penicillin G or benzylpenicillinbenzylpenicillin

• Dosage and potency Dosage and potency based on IU (1 IU = based on IU (1 IU = 0.6 micrograms pure 0.6 micrograms pure penicillin G)penicillin G)

• P. chrysogenumP. chrysogenum produces 6-produces 6-aminopenicillanic aminopenicillanic acid, raw material for acid, raw material for semi-syntheticssemi-synthetics

• Dosage and potency Dosage and potency based on weightbased on weight

PenicillinsPenicillins

• Spectrum of activity based on R Spectrum of activity based on R groups added to 6-aminopenicillanic groups added to 6-aminopenicillanic acid coreacid core

• All are bactericidal and inhibit All are bactericidal and inhibit transpeptidasestranspeptidases

• Mechanisms of resistanceMechanisms of resistance• Alter affinity of transpeptidaseAlter affinity of transpeptidase• Enzymatically cleave the beta-lactam ringEnzymatically cleave the beta-lactam ring• Efflux pumpsEfflux pumps• Poor penetration into cellPoor penetration into cell

PenicillinsPenicillins

• Administered orally, Administered orally, intramuscularly, or intravenously intramuscularly, or intravenously depending on agentdepending on agent

• After oral dose, widely distributed After oral dose, widely distributed in tissues and secretions (except in tissues and secretions (except CNS, prostatic fluid, and the eye)CNS, prostatic fluid, and the eye)

• Do not kill intracellular pathogensDo not kill intracellular pathogens• Food interferes with adsorptionFood interferes with adsorption• Rapid elimination through kidney, Rapid elimination through kidney,

secreted in breast milksecreted in breast milk

Penicillins G and VPenicillins G and V

• Effective against aerobic G+ organisms except Effective against aerobic G+ organisms except StaphylococcusStaphylococcus, Pen G active against , Pen G active against Neisseria Neisseria and and anaerobesanaerobes

• 2/3 of oral Pen G destroyed by stomach acid, Pen V is 2/3 of oral Pen G destroyed by stomach acid, Pen V is more resistant so more is delivered to serummore resistant so more is delivered to serum

• Rapid elimination through kidney so probenecid, Rapid elimination through kidney so probenecid, procaine, of benzathine added to slow excretionprocaine, of benzathine added to slow excretion

• Most drug is bound to serum albumin but significant Most drug is bound to serum albumin but significant amounts show up in liver, bile, kidney, semen, joint amounts show up in liver, bile, kidney, semen, joint fluid, lymph, etc.fluid, lymph, etc.

• Cautious use in neonates and infants because renal Cautious use in neonates and infants because renal function is not fully establishedfunction is not fully established

• Patients with renal failure clear the drugs through liver Patients with renal failure clear the drugs through liver although at a slow pacealthough at a slow pace

Penicillins G and VPenicillins G and VTherapeutic UsesTherapeutic Uses

• Streptococcus Streptococcus pneumoniaepneumoniae infections infections

• S. pyogenesS. pyogenes infections infections• Viridans strep Viridans strep

endocarditis (also given endocarditis (also given prophylactically)prophylactically)

• Anaerobes except Anaerobes except Bacteroides fragilisBacteroides fragilis groupgroup

• Meningococcal infectionsMeningococcal infections• Syphilis and other Syphilis and other

diseases caused by diseases caused by spirochetesspirochetes

Isoxazolyl PenicillinsIsoxazolyl Penicillins

• Oxacillin, cloxacillin, dicloxacillin, nafcillinOxacillin, cloxacillin, dicloxacillin, nafcillin• Designed to resist staphylococcal beta-Designed to resist staphylococcal beta-

lactamaseslactamases• Like Pen V, stable in stomach acid but Like Pen V, stable in stomach acid but

usually given parentally for serious staph usually given parentally for serious staph infectionsinfections

• MRSA not coveredMRSA not covered• Absorption and fate of drugs after Absorption and fate of drugs after

absorption, excretion similar to Pen G and absorption, excretion similar to Pen G and Pen VPen V

AminopenicillinsAminopenicillins

• Ampicillin and amoxicillinAmpicillin and amoxicillin• Broad spectrumBroad spectrum

• Not effective against beta-lactamase Not effective against beta-lactamase producersproducers

• Beta-lactamase inhibitors extend spectrumBeta-lactamase inhibitors extend spectrum

• Both are acid resistant but amoxicillin Both are acid resistant but amoxicillin is better absorbed, even with foodis better absorbed, even with food

• Don’t bind plasma proteins as much as Don’t bind plasma proteins as much as predecessorspredecessors

• Secreted through the kidney Secreted through the kidney

AminopenicillinsAminopenicillinsTherapeutic UsesTherapeutic Uses

• Upper Upper respiratory tract respiratory tract infectionsinfections

• Otitis mediaOtitis media• Uncomplicated Uncomplicated

UTIUTI• Acute bacterial Acute bacterial

meningitis in kidsmeningitis in kids• Typhoid feverTyphoid fever

A Carboxypenicillin and A Carboxypenicillin and a Ureidopenicillina Ureidopenicillin

• Ticarcillin and Ticarcillin and piperacillinpiperacillin

• Ticarcillin is anti-Ticarcillin is anti-PseudomonasPseudomonas drug drug

• Piperacillin + Piperacillin + tazobactam has the tazobactam has the broadest spectrum broadest spectrum

• Give parentallyGive parentally• Used for serious Used for serious

infectionsinfections


of Penicillinsof Penicillins• Hypersensitivity reactions (Hypersensitivity reactions (uncommonuncommon))

• Rash, fever, bronchospasm, vasculitis, Rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, SJS, serum sickness, exfoliative dermatitis, SJS, anaphylaxisanaphylaxis

• Drugs act as haptens when bound to serum Drugs act as haptens when bound to serum proteinsproteins

• Rashes will disappear when drug is Rashes will disappear when drug is withdrawn or can treat with antihistamineswithdrawn or can treat with antihistamines

• For patients with allergies, switch to a For patients with allergies, switch to a different class of antibiotics or try to different class of antibiotics or try to desensitizedesensitize


of Penicillinsof Penicillins• Pain and sterile Pain and sterile

inflammatory reaction at inflammatory reaction at injection site (dose-injection site (dose-related)related)

• Large doses given to Large doses given to patients with renal patients with renal failure can cause failure can cause lethargy, confusion lethargy, confusion twitching and seizurestwitching and seizures

• Sudden release of Sudden release of procaine can cause procaine can cause dizziness, tinnitus, dizziness, tinnitus, headache and headache and hallucinationshallucinations

• Pseudomembranous Pseudomembranous colitiscolitis

CephalosporinsCephalosporins• Base molecule is 7-Base molecule is 7-

aminocephalosporanic aminocephalosporanic acid produced by a acid produced by a Sardinian sewer moldSardinian sewer mold

• R groups determine R groups determine spectrum of activity spectrum of activity and pharmacological and pharmacological propertiesproperties

• Mechanism of Mechanism of action/resistance and action/resistance and class pharmacology class pharmacology essentially the same as essentially the same as penicillinspenicillins

First GenerationFirst GenerationCephalosporinsCephalosporins

• Cefazolin, cephalexin, Cefazolin, cephalexin, cephadroxilcephadroxil

• Excellent against Excellent against susceptible staph and susceptible staph and strepstrep

• Modest activity against Modest activity against G-G-

• Cefazolin given Cefazolin given parentally, others orallyparentally, others orally

• More than half of the More than half of the drug is bound to plasma drug is bound to plasma proteinsproteins

• Excreted by kidneys Excreted by kidneys unmetabolizedunmetabolized

• Good for staph and strep Good for staph and strep skin and soft tissue skin and soft tissue infections infections

Second GenerationSecond GenerationCephalosporinsCephalosporins

• Cefaclor, cefuroxime, cefprozilCefaclor, cefuroxime, cefprozil• Modest activity against G+, increased Modest activity against G+, increased

activity against G-, works against activity against G-, works against anaerobesanaerobes

• Cefaclor and cefprozil given orallyCefaclor and cefprozil given orally• Absorption and excretion same as first Absorption and excretion same as first

gen.gen.• Good for treating respiratory tract Good for treating respiratory tract

infections, intra-abdominal infections, infections, intra-abdominal infections, pelvic inflammatory disease, diabetic pelvic inflammatory disease, diabetic foot ulcersfoot ulcers

Third GenerationThird GenerationCephalosporinsCephalosporins

• Ceftaxime, ceftriaxzone, Ceftaxime, ceftriaxzone, cefoperazone, cefoperazone, cefpodoximecefpodoxime

• Broad spectrum killersBroad spectrum killers• Drugs of choice for Drugs of choice for

serious infectionsserious infections• No effect against No effect against ListeriaListeria

and beta-lactamase and beta-lactamase producing pneumococciproducing pneumococci

• Cefpodoxime given orally, Cefpodoxime given orally, others parentallyothers parentally

• Most excreted by kidneyMost excreted by kidney• Therapeutic uses Therapeutic uses

• Bacterial meningitis (2 Bacterial meningitis (2 exceptions)exceptions)

• Lyme diseaseLyme disease• Life-threatening G- Life-threatening G-

sepsissepsis

Fourth GenerationFourth GenerationCephalosporinCephalosporin

•CefepimeCefepime•Same antimicrobial spectrum Same antimicrobial spectrum

as third generation but as third generation but resists more beta-lactamasesresists more beta-lactamases

•Given parentally, excellent Given parentally, excellent penetration into CSFpenetration into CSF

•Good for nosocomial Good for nosocomial infectionsinfections


of Cephalosporinsof Cephalosporins• Hypersensitivity reactions Hypersensitivity reactions

(uncommon) essentially same as (uncommon) essentially same as for penicillinsfor penicillins

• Cross-reaction between 2 classesCross-reaction between 2 classes

CarbapenemsCarbapenems

•Beta-lactam ring is fused Beta-lactam ring is fused to a 5 member ring systemto a 5 member ring system

•Effect on microbes and Effect on microbes and pharmacology of pharmacology of carbapenems similar to carbapenems similar to penicillinspenicillins

Select CarbapenemsSelect Carbapenems

• ImipenemImipenem• Broad spectrum including anaerobes and Broad spectrum including anaerobes and

Pseudomonas aeruginosaPseudomonas aeruginosa• Parentally administeredParentally administered• Must be combined with cilastatin to be Must be combined with cilastatin to be

absorbedabsorbed• Excreted by kidneysExcreted by kidneys

• Meropenem, ertapenem, and doripenem Meropenem, ertapenem, and doripenem are similar to imipenem but don’t need are similar to imipenem but don’t need co-administration with cilastatinco-administration with cilastatin

Aztrenam – a Aztrenam – a monobactammonobactam

• Works only on G-, including Works only on G-, including Pseudomonas aeruginosaPseudomonas aeruginosa

• Useful for treating G- Useful for treating G- infections that require a beta-infections that require a beta-lactam because it does not lactam because it does not elicit hypersensitivity elicit hypersensitivity reactionsreactions


of Carbapenemsof Carbapenems• Nausea and vomiting (Nausea and vomiting (commoncommon))• Hypersensitivity reactions Hypersensitivity reactions

(uncommon)(uncommon)• Essentially the same as for Essentially the same as for

penicillins, exception is the penicillins, exception is the monobactammonobactam

• Cross-reactivity is possible, Cross-reactivity is possible, exception is the monobactamexception is the monobactam

The The End?End?

Nope.Nope.

Documents

General Outline for Antibiotics Chemistry –MIP Chemistry –MIP Effect on microbes - MIP Effect on microbes - MIP Spectrum of coverage Spectrum of coverage