ANTIBIOTICS AND ANTIBIOTICS AND ANTISEPTICS FOR URINARY ANTISEPTICS FOR URINARY

TRACT INFECTIONSTRACT INFECTIONS

Rianto SetiabudyRianto SetiabudyS-1 lecture, FMUIS-1 lecture, FMUI

Regular Class, June 24, 2008Regular Class, June 24, 2008Internat. Class, June 23, 2008Internat. Class, June 23, 2008

INTRODUCTION (1)INTRODUCTION (1)UTIs are very commonly found in medical UTIs are very commonly found in medical practicepracticeGram (–) pathogens, especially Gram (–) pathogens, especially E. coliE. coli, are the , are the most prevalent etiologymost prevalent etiologyUTIs include acute uncomplicated cystitis, UTIs include acute uncomplicated cystitis, acute and chronic pyelonephritis, acute and acute and chronic pyelonephritis, acute and chronic prostatitischronic prostatitisIn acute stage with signs of systemic In acute stage with signs of systemic infections infections →→ use systemic antimicrobial use systemic antimicrobial agents agents

INTRODUCTION (2)INTRODUCTION (2)To prevent recurrent infection To prevent recurrent infection →→ use urinary use urinary antisepticsantisepticsUrinary antiseptics may be effective to cure Urinary antiseptics may be effective to cure uncomplicated lower UTI, but not for UTIs with uncomplicated lower UTI, but not for UTIs with signs of systemic infectionssigns of systemic infections

OBJECTIVESOBJECTIVES

To understand the difference between To understand the difference between urinary antiseptics and antibiotics used urinary antiseptics and antibiotics used for UTIfor UTITo understand the indications, To understand the indications, mechanism of action, pharmacokinetics, mechanism of action, pharmacokinetics, side effects, contra- indications, side effects, contra- indications, precautions, and interactions of precautions, and interactions of antimicrobial agents commonly used for antimicrobial agents commonly used for the treatment of UTIthe treatment of UTI

ANTIBIOTICS COMMONLY ANTIBIOTICS COMMONLY USED IN UTIUSED IN UTI

Antimicrobials for systemic infections:Antimicrobials for systemic infections:1.1. Trimethoprim-sulfamethoxazoleTrimethoprim-sulfamethoxazole2.2. Fluoroquinolones Fluoroquinolones 3.3. Betalactams: Penicillins and CephalosporinsBetalactams: Penicillins and Cephalosporins4.4. AminoglycosidesAminoglycosides

Urinary antiseptics:Urinary antiseptics:1.1. NitrofurantoinNitrofurantoin2.2. MethenamineMethenamine3.3. FosfosmycinFosfosmycin

ANTIMICROBIALS ANTIMICROBIALS COMMONLY USED FOR UTIs COMMONLY USED FOR UTIs

WITH SYSTEMIC INFECTIONSWITH SYSTEMIC INFECTIONS

TRIMETHOPRIM –TRIMETHOPRIM –SULFAMETHOXAZOLESULFAMETHOXAZOLE

(COTRIMOXAZOLE)(COTRIMOXAZOLE)

COTRIMOXAZOLE (1)COTRIMOXAZOLE (1)

pteridine + PABA

dihydrofolic acid

tetrahydrofolic acid

synthesis of amino acids, purines, and pyrimidines

Mechanism of action:

Enz. dihydrofolate reductaseEnz. dihydrofolate reductase

sulfonamidessulfonamides

trimethoprimtrimethoprim

Enz. dihydropteroate Enz. dihydropteroate synthetasesynthetase

Spectrum: wide, mainly active against Gram (-) pathogens Pharmacokinetics:– Rapidly absorbed– High tissue concentration in prostate

I: UTI, typhoid fever, shigellosis, typhoid fever, lower respiratory tract infection, Pneumocystis carinii infectionSE: hypersensitivity reactions, Stevens-Johnson’s syndrome, bone marrow depression, hemolytic anemia, crystalluria

COTRIMOXAZOLE (2)COTRIMOXAZOLE (2)

FLUOROQUINOLONESFLUOROQUINOLONES

FLUOROQUINOLONES (1)FLUOROQUINOLONES (1)

MA:MA:1.1. Inhibits topoisomerase II (= DNA gyrase) Inhibits topoisomerase II (= DNA gyrase)

which plays a role in the relaxation of the which plays a role in the relaxation of the supercoiled DNA during transcription supercoiled DNA during transcription

2.2. Inhibits topoisomerase IV which plays a Inhibits topoisomerase IV which plays a role during the separation of the newly role during the separation of the newly formed chromosomal DNA after the formed chromosomal DNA after the replicationreplication

FLUOROQUINOLONES (2)FLUOROQUINOLONES (2)Derivatives: ciprofloxacin, ofloxacin, Derivatives: ciprofloxacin, ofloxacin, levofloxacin, norfloxacin, moxifloxacinlevofloxacin, norfloxacin, moxifloxacinPharmacokinetics: Pharmacokinetics: – Effective for systemic infectionsEffective for systemic infections– Long TLong T1/21/2

Interactions:Interactions:– Absorption through gastrointestinal tract is Absorption through gastrointestinal tract is

reduced by antacids reduced by antacids – fluoroquinolones inhibit metabolism of fluoroquinolones inhibit metabolism of

theophyllinetheophylline

The ‘respiratory quinolones’ (moxifloxacin, The ‘respiratory quinolones’ (moxifloxacin, levofloxacin):levofloxacin):– active against pathogens causing lower active against pathogens causing lower

respiratory tract infections (including Gram respiratory tract infections (including Gram positive bacteria and ‘atypical’ pathogens), positive bacteria and ‘atypical’ pathogens), i.e.: i.e.: S. pneumoniae, H. influenzae, M. S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, M. pneumoniae, C. catarrhalis, S. aureus, M. pneumoniae, C. pneumoniaepneumoniae

FLUOROQUINOLONES (3)FLUOROQUINOLONES (3)

Spectrum:Spectrum:– Mainly Gram (-) pathogensMainly Gram (-) pathogens– P. aeruginosaP. aeruginosa (only ciprofloxacin) (only ciprofloxacin)– Less active against Gram (+) (except moxi-Less active against Gram (+) (except moxi-

floxacin)floxacin)– Inactive against anaerobes Inactive against anaerobes SE: gastro-intestinal and CNS, phototoxicity, SE: gastro-intestinal and CNS, phototoxicity, prolongation of QT interval prolongation of QT interval →→ Torsades de Torsades de pointespointes, tendinitis, hepatotoxicity, tendinitis, hepatotoxicityCI: pregnant women and children CI: pregnant women and children →→ possible possible joint damagejoint damage

FLUOROQUINOLONES (4)FLUOROQUINOLONES (4)

PENICILLINSPENICILLINS

PENICILLINSPENICILLINS (1)(1)Structure:Structure:

Betalactamase (penisillinase) breaks the Betalactamase (penisillinase) breaks the betalactam ring betalactam ring →→loss of antibacterial activity loss of antibacterial activity

R R — N — N SS

AA BB

CC

CCNN

OO COOHCOOH

Betalactam ringThiazolidine ring

MA:MA:– Binds to the Penicillin-binding proteins Binds to the Penicillin-binding proteins

(PBPs), i.e. transpeptidases (PBPs), i.e. transpeptidases blocks the blocks the cross-linking process in the synthesis of cell cross-linking process in the synthesis of cell wallwall

– This is followed by the activation of This is followed by the activation of autolysin autolysin cell lysis cell lysis

PENICILLINS (2)PENICILLINS (2)

PENICILLINS (3)PENICILLINS (3) Classification based on antibacterial spectrum:Classification based on antibacterial spectrum:1.1. Natural penicillin: penicillin G, fenoksimetil-Natural penicillin: penicillin G, fenoksimetil-

penisilinpenisilin2.2. Aminopenicillin: Aminopenicillin: amoxicillin, ampicillin amoxicillin, ampicillin

(commonly used in UTI, often in combination (commonly used in UTI, often in combination with a betalactamase inhibitor)with a betalactamase inhibitor)

3.3. Anti-staphylococcal penicillin: dicloxacillin, Anti-staphylococcal penicillin: dicloxacillin, flucloxacillinflucloxacillin

4.4. Anti-pseudomonal penicillin: ticarcillinAnti-pseudomonal penicillin: ticarcillin5.5. Ureidopenicillin: piperacillinUreidopenicillin: piperacillin

Mechanism of resistance:Mechanism of resistance:o production of betalactamaseproduction of betalactamaseo modification of PBPmodification of PBPo reduction of cell wall permeabilityreduction of cell wall permeability

SE:SE:o Hypersensitivity reactions: urticaria, skin rash, Hypersensitivity reactions: urticaria, skin rash,

asthma, fever, serum sickness, anaphylaxisasthma, fever, serum sickness, anaphylaxiso Toxic reactions: CNS stimulationToxic reactions: CNS stimulation

PENICILLINS (4)PENICILLINS (4)

Indications:Indications:

Infections due to susceptible Infections due to susceptible pathogens in:pathogens in:

Upper and lower respiratory tract Upper and lower respiratory tract infectionsinfections Urinary tract infectionsUrinary tract infections STD: syphillis, gonorrhoeSTD: syphillis, gonorrhoe Skin and soft tissue infectionsSkin and soft tissue infections Others: tetanus, anthrax, actinomycosis, Others: tetanus, anthrax, actinomycosis, clostridium, bacterial meningitis clostridium, bacterial meningitis

PENICILLINS (5)PENICILLINS (5)

Penicillins commonly used in UTI:Penicillins commonly used in UTI: Ampicillin:Ampicillin:

Oral ampicilin Oral ampicilin →→ for uncomplicated lower for uncomplicated lower UTIUTI

Intravenous ampicillin + an aminoglycoside Intravenous ampicillin + an aminoglycoside →→ for UTI with systemic infection for UTI with systemic infection

Amoxicillin-clavulanic acid and ampicillin-Amoxicillin-clavulanic acid and ampicillin-sulbactam:sulbactam: Indicated for UTI with systemic infections Indicated for UTI with systemic infections

caused by betalactamase-producing Gram caused by betalactamase-producing Gram (-) pathogens(-) pathogens

PENICILLINS (6)PENICILLINS (6)

CEPHALOSPORINSCEPHALOSPORINS

MA: see penicillinsMA: see penicillinsSpectrum:Spectrum:

Generation 1: mainly active against Generation 1: mainly active against Gram (+) pathogensGram (+) pathogensGeneration 2: mainly active against Generation 2: mainly active against Gram (-) pathogensGram (-) pathogensGeneration 3: active against Gram (-) Generation 3: active against Gram (-) and (+) pathogensand (+) pathogensGeneration 4: active against ESBL-Generation 4: active against ESBL-producing pathogensproducing pathogens

CEPHALOSPORINS (1)CEPHALOSPORINS (1)

Examples:Examples:– Gen 1: cefazolin, cephradine, cephalexin, Gen 1: cefazolin, cephradine, cephalexin,

cephadroxilcephadroxil– Gen 2: cefamandole, cefuroxime, cefoxitinGen 2: cefamandole, cefuroxime, cefoxitin– Gen 3: cefotaxime, ceftriaxone, Gen 3: cefotaxime, ceftriaxone,

ceftazidimeceftazidime– Gen 4: cefepimeGen 4: cefepimeNote: all generations can be used for UTI, Note: all generations can be used for UTI, but generation 1 has limited antibacterial but generation 1 has limited antibacterial activityactivity

CEPHALOSPORINS (2)CEPHALOSPORINS (2)

Indications: Indications: – Respiratory tract infectionsRespiratory tract infections– Urinary tract infectionsUrinary tract infections– Skin and soft tissue infectionsSkin and soft tissue infections– Nosocomial infectionsNosocomial infections– Intra-abdominal infectionsIntra-abdominal infections– Surgical prophylaxis (cefazolin)Surgical prophylaxis (cefazolin)– Gonorhea (ceftriaxone)Gonorhea (ceftriaxone)– Meningitis due to G (-) pathogens (only the Meningitis due to G (-) pathogens (only the

33rdrd generation cephalosporins) generation cephalosporins)

CEPHALOSPORINS (3)CEPHALOSPORINS (3)

SE:SE:– Hypersensitivity reactions: 5-10% cross-Hypersensitivity reactions: 5-10% cross-

hypersensitivity with penicillinshypersensitivity with penicillins– NephrotoxicityNephrotoxicity– Bleeding associated with Bleeding associated with

hypoprothrombinemia (associated with hypoprothrombinemia (associated with methyl thiotetrazole group, e.g. methyl thiotetrazole group, e.g. cefoperazone, cefamandole)cefoperazone, cefamandole)

– LeukopeniaLeukopenia– Superinfection Superinfection

CEPHALOSPORINS (4)CEPHALOSPORINS (4)

AMINOGLYCOSIDESAMINOGLYCOSIDES

AMINOGLYCOSIDES (1)AMINOGLYCOSIDES (1)Derivatives: Derivatives: – Gentamicin, tobramycin, amikacin, Gentamicin, tobramycin, amikacin,

kanamycin, streptomycinkanamycin, streptomycinMA: Inhibits protein synthesis (ribosome MA: Inhibits protein synthesis (ribosome subunit 30S) of bacteriasubunit 30S) of bacteriaBactericidalBactericidalCommonly combined with the betalactams in Commonly combined with the betalactams in the treatment of many serious infections caused the treatment of many serious infections caused by susceptible Gram (-) pathogensby susceptible Gram (-) pathogens

AMINOGLYCOSIDES (2)AMINOGLYCOSIDES (2)

Spectrum:Spectrum:– Active against Gram (-) pathogens such as: Active against Gram (-) pathogens such as:

P. aeruginosa, Klebsiella, Proteus, E. coliP. aeruginosa, Klebsiella, Proteus, E. coli– Streptomicin: not effective against Streptomicin: not effective against P. P.

aeruginosa. aeruginosa. Only indicated forOnly indicated for the treatment the treatment of tuberculosisof tuberculosis

– Amikacin: still effective for infections due to Amikacin: still effective for infections due to gentamicin-resistant Gram (-) pathogens.gentamicin-resistant Gram (-) pathogens.

AMINOGLYCOSIDES (3)AMINOGLYCOSIDES (3)

Mechanism of resistance:Mechanism of resistance:– To produce enzymes capable of destroying To produce enzymes capable of destroying

the drug (eg., acetyltransferase). This is the drug (eg., acetyltransferase). This is transferable via plasmidstransferable via plasmids

– To decrease drug uptakeTo decrease drug uptake– To modify the drug receptorTo modify the drug receptor

AMINOGLYCOSIDES (4)AMINOGLYCOSIDES (4)Pharmacokinetics:Pharmacokinetics:– Highly polar Highly polar →→ not absorbed via GI tract not absorbed via GI tract– Unable to penetrate the blood brain barrier Unable to penetrate the blood brain barrier – Highly concentrated in the kidneys and the Highly concentrated in the kidneys and the

inner part of ear inner part of ear →→ causing causing nephro-nephro- and and oto-oto-toxicitytoxicity

– Not metabolizedNot metabolized– Excretion: glomerular filtration. In renal Excretion: glomerular filtration. In renal

insufficiency insufficiency →→ drug accumulation drug accumulation →→ requiring dosage reductionrequiring dosage reduction

AMINOGLYCOSIDES (5)AMINOGLYCOSIDES (5)Indications: Indications: – Gentamicin, netilmycin, tobramycin, amikacin: Gentamicin, netilmycin, tobramycin, amikacin:

For serious infections by Gram (-) pathogens For serious infections by Gram (-) pathogens eg., UTI, sepsiseg., UTI, sepsis

– Streptomycin: for tuberculosis, brucellosis, Streptomycin: for tuberculosis, brucellosis, plague plague

SE: SE: – Ototoxicity: hearing loss, tinnitus, vertigoOtotoxicity: hearing loss, tinnitus, vertigo– NephrotoxicityNephrotoxicity– Respiratory paralisis due neuromuscular Respiratory paralisis due neuromuscular

blockade (rare)blockade (rare)

AMINOGLYCOSIDES (6)AMINOGLYCOSIDES (6)Caution:Caution:– The elderly and patients with renal The elderly and patients with renal

insufficiency insufficiency – Concomitant treatment with other ototoxic Concomitant treatment with other ototoxic

drugs (furosemide, ethacrinic acid)drugs (furosemide, ethacrinic acid)– Aminoglycosides are not indicated for Aminoglycosides are not indicated for

trivial infectionstrivial infectionsNote: blood level monitoring is required to Note: blood level monitoring is required to adjust dose in patient with impaired renal adjust dose in patient with impaired renal functionfunction

AMINOGLYCOSIDES (7)AMINOGLYCOSIDES (7)

Gentamicin (prototype)Gentamicin (prototype)– Effective for serious infections due to Gram-Effective for serious infections due to Gram-

negative pathogens ioncluding such as negative pathogens ioncluding such as P. P. aeruginosa, Proteus, Klebsiella, Serratia, E. aeruginosa, Proteus, Klebsiella, Serratia, E. coli, Enterobactercoli, Enterobacter

– A once-daily dose is more preferable than the A once-daily dose is more preferable than the divided dose. divided dose.

– Not recommended for topical use in hospital, Not recommended for topical use in hospital, except for burns except for burns

AMINOGLYCOSIDES (8)AMINOGLYCOSIDES (8)

Amikacin:Amikacin:– Is still effective against gentamicin-resistant Is still effective against gentamicin-resistant

pathogenspathogensTobramycin:Tobramycin:– Shares the same indication with gentamicinShares the same indication with gentamicinStreptomycin:Streptomycin:– Only indicated for tuberculosis, brucellosis, Only indicated for tuberculosis, brucellosis,

and plagueand plague

URINARY ANTISEPTICSURINARY ANTISEPTICS

NITROFURANTOIN (1)NITROFURANTOIN (1)

MA: damages the DNA of susceptible MA: damages the DNA of susceptible pathogenspathogens

Spectrum: Gram (+) and (-) pathogens.Spectrum: Gram (+) and (-) pathogens.

No cross resistance with other drugs but No cross resistance with other drugs but ineffective against ineffective against P. aeruginosaP. aeruginosa

Pharmacokinetics : Pharmacokinetics : – well absorbed through the GI tract well absorbed through the GI tract – metabolism and excretion are very rapid metabolism and excretion are very rapid →→

no systemic antibacterial actionno systemic antibacterial action– urine pH should be kept at < 5.5urine pH should be kept at < 5.5

Indication : - uncomplicated lower UTI (esp.in Indication : - uncomplicated lower UTI (esp.in women) and prophylaxis of cute exacerbation women) and prophylaxis of cute exacerbation in chronic UTI in chronic UTI

SE: gastric irritation, neuropathy, hemolytic SE: gastric irritation, neuropathy, hemolytic anemia (in G6PD-deficient patients). Rarely: anemia (in G6PD-deficient patients). Rarely: lung fibrosislung fibrosis

CI: renal insufficiencyCI: renal insufficiency

Interaction: antagonizes nalidixic acidInteraction: antagonizes nalidixic acid

NITROFURANTOIN (2)NITROFURANTOIN (2)

METHENAMINEMETHENAMINEAt pH < 5.5 methenamine At pH < 5.5 methenamine releases releases formaldehyde (antibacterial)formaldehyde (antibacterial)ProteusProteus splits urea splits urea releases ammonium releases ammonium hydroxide hydroxide pH pH ↑↑ methenamine losses its methenamine losses its activityactivitySE: gastric irritation, albuminuriaSE: gastric irritation, albuminuriaCI : impaired renal and/or hepatic fucntionCI : impaired renal and/or hepatic fucntionInteraction: sulfonamide should not be Interaction: sulfonamide should not be combined with methenamine because it may combined with methenamine because it may form insoluble compound with formaldehyde form insoluble compound with formaldehyde released by methenaminereleased by methenamine

FOSFOMYCINFOSFOMYCINMA: inhibits cell wall synthesis in the early stageMA: inhibits cell wall synthesis in the early stageSpectrum: Spectrum: E. coliE. coli and other Gram (+) and (–) and other Gram (+) and (–) pathogens, but not pathogens, but not P. aeruginosaP. aeruginosaSE: nausea, diarrhea, headacheSE: nausea, diarrhea, headacheI: uncomplicated lower UTII: uncomplicated lower UTIDose: 3 g in single administrationDose: 3 g in single administrationThis drug appears to be safe for use in This drug appears to be safe for use in pregnancypregnancy

THANK YOU