AminoglycosidesAminoglycosides

IntroIntro

Group of antibiotics used in the treatment of Group of antibiotics used in the treatment of bacteria infections aerobic G-vebacteria infections aerobic G-ve

Consists of 2 or more amino sugars and a Consists of 2 or more amino sugars and a hexose nucleushexose nucleus

Serious toxicity is a limiting factor for their Serious toxicity is a limiting factor for their applicationapplication

StreptomycinStreptomycin was the first to be discovered was the first to be discovered in 1943 by Schatz, Bugie and Waksmanin 1943 by Schatz, Bugie and Waksman

Other examples are:Other examples are:

Gentamicin*Gentamicin* StreptomycinStreptomycin AmikacinAmikacin NeomycinNeomycin Netilmicin*Netilmicin* TobramycinTobramycin KanamycinKanamycin Paromomycin+Paromomycin+*Not from *Not from Streptomyce sppStreptomyce spp (from (from Actinomycetes sppActinomycetes spp))+ Antiparasitic ( amoebiasis, cryptosporidiosis)+ Antiparasitic ( amoebiasis, cryptosporidiosis)

Families:Families: Determined by the type of amino sugar Determined by the type of amino sugar Neomycin – there are 3 amino sugars attached to Neomycin – there are 3 amino sugars attached to

2-deoxystreptamine e.g Neo B, Paromomycin2-deoxystreptamine e.g Neo B, Paromomycin Kanamycin family – 2 amino sugars attached to 2 Kanamycin family – 2 amino sugars attached to 2

deoxystreptamine. E.gs amikacin*. Kanamycin A & deoxystreptamine. E.gs amikacin*. Kanamycin A & B, tobramycinB, tobramycin

*a semisynthetic derivative of kanamycin A and *a semisynthetic derivative of kanamycin A and netilmicin is also semisyntheticnetilmicin is also semisynthetic

Aminoglycosides familyAminoglycosides family

Gentamicin family- Gentamicin family- – Gent Ci, Gent Ci, – Gent C1a and C2, Gent C1a and C2, – sisomicin and sisomicin and – Netilmicin (derivative of sisomicin)Netilmicin (derivative of sisomicin)

Streptomycin family Streptomycin family – Streptomycin and Streptomycin and – dihydrostreptomycin. dihydrostreptomycin. – Contains streptidine instead of deoxystreptamineContains streptidine instead of deoxystreptamine

Spectrum of activitySpectrum of activity Aerobic G-ve bacteria ( Citrobacter, Enterobacter, Aerobic G-ve bacteria ( Citrobacter, Enterobacter,

E. coli, proteus, Pseudomonas, Enterococci and E. coli, proteus, Pseudomonas, Enterococci and Staph aureus *)Staph aureus *)

Lack activity against most anaerobic or facultative Lack activity against most anaerobic or facultative bacteria and activity against G+ve# organisms is bacteria and activity against G+ve# organisms is limitedlimited

* in combination* in combination# Strept pyogenes is highly resistant# Strept pyogenes is highly resistant

Mechanism of ActionMechanism of Action BactericidalBactericidal antibiotics antibiotics Penetration involves active transportPenetration involves active transport Inhibition of protein synthesis by binding to Inhibition of protein synthesis by binding to

the 30S subunit of ribosomesthe 30S subunit of ribosomes Causes misreading and premature Causes misreading and premature

termination of protein synthesistermination of protein synthesis

Resistance-Resistance- May be plasmid mediated inactivation by May be plasmid mediated inactivation by

microbial enzymes or failure of drug microbial enzymes or failure of drug penetrationpenetration

Synthesis of metabolizing enzymesSynthesis of metabolizing enzymes Mutation may alter ribosomal binding site for Mutation may alter ribosomal binding site for

the aminoglycosidesthe aminoglycosides Cross resistance with other Cross resistance with other

aminoglycosides may occuraminoglycosides may occur

Absorption, Distribution and Absorption, Distribution and Elimination Elimination

Polar agents with poor oral absorptionPolar agents with poor oral absorption Usual routes: IM or I.VUsual routes: IM or I.V Cmax achieved within 30-90 of IMCmax achieved within 30-90 of IM Absorption increases in inflammationAbsorption increases in inflammation No significant amount in breast milkNo significant amount in breast milk Plasma protein binding is minimalPlasma protein binding is minimal Vd approximates 25% of lean body weightVd approximates 25% of lean body weight

Abs, Distr and EliminationAbs, Distr and Elimination

Penetration of CNS: 10-25% of plasma levelPenetration of CNS: 10-25% of plasma level Accumulates in the perilymph and endolymph as Accumulates in the perilymph and endolymph as

well as renal cortexwell as renal cortex Vd increases in – leukaemia Vd increases in – leukaemia Clearance increases and T1/2 reduces in cystic Clearance increases and T1/2 reduces in cystic

fibrosisfibrosis T1/2 for most; 2-3 hoursT1/2 for most; 2-3 hours Elimination is by glomerular filtrationElimination is by glomerular filtration Both haemo- and peritoneal dialysis remove Both haemo- and peritoneal dialysis remove

aminoglycosidesaminoglycosides

Unwanted effectsUnwanted effects

Ototoxicity: netilmicin is reputed to be mildest on Ototoxicity: netilmicin is reputed to be mildest on both Vest and Audi. Functions*both Vest and Audi. Functions*

Nephrotoxicity#Nephrotoxicity# Other neurotoxic effects – optic neuritis, peripheral Other neurotoxic effects – optic neuritis, peripheral

neuritis, neuromuscular blockadeneuritis, neuromuscular blockade Others: angioedema, skin rash, blood dyscrasia, Others: angioedema, skin rash, blood dyscrasia,

eosinophilia, fever, stomatitis, anaphylaxiseosinophilia, fever, stomatitis, anaphylaxis

*Neo/Amk/kan affect Audi more than others while Str/Gen tend to affect Vest fn *Neo/Amk/kan affect Audi more than others while Str/Gen tend to affect Vest fn moremore

# Gen/Tob/Neo are relatively more nephrotoxic than the others# Gen/Tob/Neo are relatively more nephrotoxic than the othersNB: Nephrotoxic effects occurs in 5-10% of patientsNB: Nephrotoxic effects occurs in 5-10% of patients

Therapeutic drug monitoringTherapeutic drug monitoring

Necessary in:Necessary in: Patients with life threatening infectionsPatients with life threatening infections Renal impairmentRenal impairment 24 hours into new regimen24 hours into new regimen NeonatesNeonates Samples usually taken just before and 30 Samples usually taken just before and 30

minutes after a doseminutes after a dose

Caution in:Caution in:

PregnancyPregnancy Myasthenia gravis (MG)Myasthenia gravis (MG) Renal impairmentRenal impairment Parkinson’s dxParkinson’s dx 88thth cranial nerve disease cranial nerve disease

StreptomycinStreptomycin

Usual dosage: 15-25 mg per Kg body wt IMUsual dosage: 15-25 mg per Kg body wt IM

Therapeutic applications in: Therapeutic applications in: Bacterial endocarditis from enterococcal and Bacterial endocarditis from enterococcal and

group D Strep group D Strep TularemiaTularemia PlaguePlague TuberculosisTuberculosis

GentamicinGentamicin

Inexpensive and reliable efficacyInexpensive and reliable efficacy Usual dose; 3-5 mg per Kg body wt in 3 Usual dose; 3-5 mg per Kg body wt in 3

divided doses dailydivided doses daily Therapeutic Applications: UTI, Pneumonia Therapeutic Applications: UTI, Pneumonia

(nosocomial), Peritonitis, meningitis and (nosocomial), Peritonitis, meningitis and sepsissepsis

TetracyclinesTetracyclines

TetracyclinesTetracyclines

Broad spectrum antibiotics Broad spectrum antibiotics (incl: Legionella spp, (incl: Legionella spp, Ureaplasma, Mycoplasma, chlamydia plasmodium and rickettsial Ureaplasma, Mycoplasma, chlamydia plasmodium and rickettsial infections)infections)

Origin: Origin: Streptomyces sppStreptomyces spp Examples: Chlortetracycline, demeclocyline, Examples: Chlortetracycline, demeclocyline,

oxytetracycline, doxycline*, tetracycline*, oxytetracycline, doxycline*, tetracycline*, minocycline*minocycline*

* semisynthetic* semisynthetic

Mechanism of action:Mechanism of action: Binding of the 30S subunit of ribosome, preventing Binding of the 30S subunit of ribosome, preventing

the access of aminoacyl tRNA to the acceptor site the access of aminoacyl tRNA to the acceptor site on the mRNA-ribosome complexon the mRNA-ribosome complex

ResistanceResistance Plasmid mediated decrease accumulation of the Plasmid mediated decrease accumulation of the

drugdrug Blockade of access by ribosome protecting protein Blockade of access by ribosome protecting protein Enzymatic inactivation of TCNEnzymatic inactivation of TCN

ABS, DISTR and ELIMINATIONABS, DISTR and ELIMINATION

Most are incompletely absorbed when taken orally*Most are incompletely absorbed when taken orally* Abs occurs mainly in the stomach and upper small intestineAbs occurs mainly in the stomach and upper small intestine Fasting improves abs while presence of food or divalent Fasting improves abs while presence of food or divalent

cations reducecations reduce Peak conc ~ 2-4 hrPeak conc ~ 2-4 hr T1/2: 6-12 hrs+T1/2: 6-12 hrs+ Widely distributed Widely distributed (incl: RE cells in spleen, liver and bone marrow; also (incl: RE cells in spleen, liver and bone marrow; also

synovial and sinuses bone and dentine and prostate)synovial and sinuses bone and dentine and prostate)

*Chlortetracycline is worst; minocycline and doxy are best*Chlortetracycline is worst; minocycline and doxy are best+ half life of mino and doxy very long 16-18 hr+ half life of mino and doxy very long 16-18 hr

Undergoes entero-hepatic cyclingUndergoes entero-hepatic cycling Most tetracyclines are excreted in urine Most tetracyclines are excreted in urine

(doxicycline, an exception)(doxicycline, an exception) Clinical usesClinical uses Wide range of bacteria diseasesWide range of bacteria diseases++

– Ricketsial infectionsRicketsial infections– MycoplasmaMycoplasma– ChlamydiaChlamydia

++ Use often precluded by resistance Use often precluded by resistance

Unwanted effectsUnwanted effects

GI upset including abd pain, nausea, vomiting diarrheaGI upset including abd pain, nausea, vomiting diarrhea PhotosensitivityPhotosensitivity HepatotoxicityHepatotoxicity Renal toxicityRenal toxicity Teeth and bone discolourationTeeth and bone discolouration Skin rashesSkin rashes Pseudomembraneous colitisPseudomembraneous colitis Thrombophlebitis (IV)Thrombophlebitis (IV) Pseudo-tumour cerebriPseudo-tumour cerebri Leukopenia, Thrombocytopenic purpuraLeukopenia, Thrombocytopenic purpura

ChloramphenicolChloramphenicol

ChloramphenicolChloramphenicol

Broad spectrum antibiotic (MIC for sensitive strains < 8 Broad spectrum antibiotic (MIC for sensitive strains < 8 ug/ml)ug/ml)

Antimicrobial spectrum: Rickettsial, Antimicrobial spectrum: Rickettsial, salmonella infectionssalmonella infectionsMechanismMechanism Inhibition of protein synthesis via 50S subunit of ribosome** Inhibition of protein synthesis via 50S subunit of ribosome** ResistanceResistance Plasmid mediated elaboration of inactivating enzymes Plasmid mediated elaboration of inactivating enzymes

(acetyl transferase)(acetyl transferase)

** Other 50S: erythromycin Clindamycin** Other 50S: erythromycin Clindamycin

ChloramphenicolChloramphenicol

Introduced to clinical practice in 1949Introduced to clinical practice in 1949 BacteriostaticBacteriostatic Fallen out favour in western countries cos it Fallen out favour in western countries cos it

causes aplastic anaemiacauses aplastic anaemia Main use restricted as eye ointment/dropsMain use restricted as eye ointment/drops Poorly dissolves in water requiring that IV is given Poorly dissolves in water requiring that IV is given

as succinate ester.as succinate ester. The succinate ester is incompletely hydrolysed The succinate ester is incompletely hydrolysed

(70%); (70%); hence oral preferred to IVhence oral preferred to IV

ChloramphenicolChloramphenicol

Usual oral dose = 50 mg per kgUsual oral dose = 50 mg per kg IV usually 75 mg per kgIV usually 75 mg per kg Drug level to be monitored in neonates to < Drug level to be monitored in neonates to <

4 yrs old, elderly, renal impaired patients4 yrs old, elderly, renal impaired patients Recommended peak level 15-25 mg/ml Recommended peak level 15-25 mg/ml

(sample taken 1 hr after dose)(sample taken 1 hr after dose) Trough level < 15mg/kg (sample taken b4 Trough level < 15mg/kg (sample taken b4

next dose)next dose)

ABS DISTR EXCNABS DISTR EXCN

Well absorbed when given orally,Well absorbed when given orally, (IM not advised (IM not advised as it is poorly absorbed)as it is poorly absorbed)

Peak conc achieved within 2 hoursPeak conc achieved within 2 hours 60% of plasma found in CSF60% of plasma found in CSF T1/2 2 hoursT1/2 2 hours 10% unchanged in urine, the rest is 10% unchanged in urine, the rest is

inactivated by glucuronidation in the liverinactivated by glucuronidation in the liver

ADRsADRs Gray baby syndrome (consisting of: Gray baby syndrome (consisting of:

VDFlaccidityHypothermia Ashen-gray colour); VDFlaccidityHypothermia Ashen-gray colour); Gray syndromeGray syndrome

Jarisch_Hexheimer reactions when used in Jarisch_Hexheimer reactions when used in brucellosisbrucellosis

Bone marrow suppression: Bone marrow suppression: – presents with low Hb; presents with low Hb; – does not predict Aplastic anaemia, does not predict Aplastic anaemia, – dose dependent (>20g)dose dependent (>20g)

Risk of leukaemiaRisk of leukaemia

ADRs ADRs

Bone marrow aplasia* Bone marrow aplasia* – Not dose dependentNot dose dependent– UnpredictableUnpredictable– commonest with oral (1:24000, least with eye preps (1: commonest with oral (1:24000, least with eye preps (1:

~250000); ~250000); – may begin weeks after stopping drugmay begin weeks after stopping drug

Interactions: Phenytoin, phenobarb, Rifampicin, Interactions: Phenytoin, phenobarb, Rifampicin, chlorpropamide, dicoumarolchlorpropamide, dicoumarol

**Such effect unknown with Thiamphenicol (a methyl-sulphonyl analogue Such effect unknown with Thiamphenicol (a methyl-sulphonyl analogue of Chloramphenicol)of Chloramphenicol)

The QuinolonesThe Quinolones

IntroIntro

Group of broad spectrum antibioticsGroup of broad spectrum antibiotics Also known as DNA gyraseAlso known as DNA gyrase Generally bactericidalGenerally bactericidal May be broadly divided into two groupsMay be broadly divided into two groups

– FluoroquinolonesFluoroquinolones– Other quinolones: Nalidixic acid, the oldest Other quinolones: Nalidixic acid, the oldest

member, cinoxacinmember, cinoxacin

MechanismMechanism

Penetrates bacterial cell easilyPenetrates bacterial cell easily Inhibition of DNA gyrase Inhibition of DNA gyrase

– (in eukaroytes is called Topoisomerase II)(in eukaroytes is called Topoisomerase II) Prevents DNA replication Prevents DNA replication Blocks transcriptionBlocks transcription Resistance results from:Resistance results from:

– Increased efflux of drugIncreased efflux of drug– Altered DNA gyrase binding siteAltered DNA gyrase binding site

Classes of quinolonesClasses of quinolones

4 generations (plus!)4 generations (plus!) Earlier generations have narrower spectrumEarlier generations have narrower spectrum 11stst generation: Nalidixic acid, cinoxacin, generation: Nalidixic acid, cinoxacin,

oxolinic acidoxolinic acid 22ndnd generation: ciprofoxacin, enoxacin, generation: ciprofoxacin, enoxacin,

ofloxacin, norfloxacinofloxacin, norfloxacin 33rdrd : sparfloxacin, levofloxacin : sparfloxacin, levofloxacin 44thth : gatifloxacin, sitafloxacin : gatifloxacin, sitafloxacin

ADMEADME

General good absorption profileGeneral good absorption profile Achieves peak plasma conc. 1-3 hrsAchieves peak plasma conc. 1-3 hrs Food may reduce rate but not extent of Food may reduce rate but not extent of

absorptionabsorption Bioavailability ranges from 50-90%Bioavailability ranges from 50-90% Kidneys involved in excretionKidneys involved in excretion

Clinical usesClinical uses

UTIUTI Travellers’ diarrhoeaTravellers’ diarrhoea Bone, joint soft tissues infectionsBone, joint soft tissues infections Respiratory infections esp. Respiratory infections esp.

– Legionella sppLegionella spp– MycoplasmaMycoplasma

Mycobacterium spp infectionsMycobacterium spp infections Other organisms: Chlamydia, BrucellaOther organisms: Chlamydia, Brucella

ADRsADRs

Peripheral neuropathyPeripheral neuropathy Tendonitis and tendon rupture can occurTendonitis and tendon rupture can occur RhabdomyolysisRhabdomyolysis SJSSJS Pseudomembranous colitisPseudomembranous colitis Prolongation of QT intervalProlongation of QT interval Not recommended in pre-pubertal b’cos of Not recommended in pre-pubertal b’cos of

tendency to cause arthropathytendency to cause arthropathy

The MacrolidesThe Macrolides

The macrolidesThe macrolides

Many membered lactone ring plus deoxy Many membered lactone ring plus deoxy sugarsugar

Bacteriostatic antibioticsBacteriostatic antibiotics Inhibits protein synthesis (50S)Inhibits protein synthesis (50S) Resistance is usually plasmid mediated Resistance is usually plasmid mediated

reduced reduced – ErythromycinErythromycin– AzithromycinAzithromycin– ClarithromycinClarithromycin

macrolidesmacrolides

Spectrum of antibacterial activitySpectrum of antibacterial activity Mostly Gram +veMostly Gram +ve DiphtheriaDiphtheria MycoplasmaMycoplasma LegionellaLegionella MycobacteriaMycobacteria BorreliaBorrelia

MacrolidesMacrolides

Erythromycin base is susceptible to gastric acid Erythromycin base is susceptible to gastric acid inactivationinactivation

Thus, it is usually presented in enteric formThus, it is usually presented in enteric form Poorly penetrates CNS but crosses placenta Poorly penetrates CNS but crosses placenta

barrierbarrier Plasma protein binding 70-90%Plasma protein binding 70-90% Half life is ~ 2 hoursHalf life is ~ 2 hours Clinical uses include: Toxoplasmosis and Clinical uses include: Toxoplasmosis and

cryptosporidiasis in HIV/AIDScryptosporidiasis in HIV/AIDS– Chlamydia, mycoplasma, pertusis, tetanus, syphilis, H. Chlamydia, mycoplasma, pertusis, tetanus, syphilis, H.

pylori pylori

Erythromycin Erythromycin

ADRsADRs Hypersensitivity reactionsHypersensitivity reactions Cholestatic jaundice*Cholestatic jaundice* Cardiac arrhythmiasCardiac arrhythmias Transient hearing lossTransient hearing loss* Likened to hypersensitivity rxn. Starts ~10 days; GI disturbance; * Likened to hypersensitivity rxn. Starts ~10 days; GI disturbance; ++ fever; fever;

leukocytosis; eosinophilia; elevated liver enzymes leukocytosis; eosinophilia; elevated liver enzymes Interactions include inhibition of metabolism of: Interactions include inhibition of metabolism of:

Digoxin, astemizole, carbamazepine, warfarinDigoxin, astemizole, carbamazepine, warfarin