Urinary antiseptics

Urinary antiseptics:
• Produce effective bactericidal concentration in urine, no
systemic antibacterial effect but may be toxic.
• Often administered with acidifying agents (low pH in itself is
inhibitor of bacterial growth in urine).
• Used for recurrent or chronic UTI - sustain sterility.

Drugs:
1. Nitrofurantoin
2. Methenamine
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 Nitrofurantoin
• Mechanism of action.
• Undergoes reduction: 5 nitroÆ nitro anion, superoxide and
other oxygen radicalsÆ bacterial toxicity. Affect
biochemical processes (RNA and DNA and protein
synthesis).
Antimicrobial activity.
• Is bactericidal for most urinary pathogens.
• Effective against many strains of E. coli and Enterococci-
resistance develops slowly.
• Not effective against proteus and pseudomonas and
many of enterobacter and klebsiella.
• Antibacterial activity high at pH <5.5.

Therapeutic uses
• Used for the treatment and prevention of UTI.
• Long term prophylaxis of lower UTI caused by susceptible
bacteria.
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• Used prophylactically post intercourse in women with chronic
UTI
 Nitrofurantoin- contd.
Adverse effects
• Nausea, vomiting, diarrhea.
• Hemolytic anemia (in patients deficient in G6PD)
• Pulmonary hypersensitivity reactions
– Acute pneumonitis.
– Subacute reactions- acute respiratory distress syndrome ( pulmonary
infiltration, effusion- fever and eosinophilia may occur- resolution may occur.
– Chronic reactions- more than 6 months therapy- chronic desquamative
interstitial pneumonitis with fibrosis (resolution does not occur).
• Intrahepatic cholestasis, hepatocellular damage- fatal.
• Neurological disorders - headache, vertigo, drowsiness, muscular aches and
nystagmus, neuropathies.

Contraindications
- Pregnant women at term, nursing mothers.
- Infants less than 1 month and nursing infants- cellular damage and anemia.
- Impaired renal function (creatinine clearance <40 ml/min).

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 Methenamine
Decomposes in an acidic pH (< 6) to ammonia & formaldehyde- alkylating
agent-
denatures protein- bactericidal. Used as salt of mandelic or hippuric acid.

Antimicrobial activity
• Most urinary pathogens are sensitive to formaldehyde & acidification
helps formaldehyde dependent antibacterial action.
• Most effective for E. coli but also for S aureus and S. epidermidis
• Enterobacter and proteus vulgaris are resistant. Proteus releases ammonia-
strongly alkaline urine.

Adverse reactions
• Gastric distress, nausea, vomiting.
• Bladder irritation (dysuria, polyuria, hematuria, albuminuria, urgency).
• Rashes.
• Mandelic salt may crystallize in urine if urine flow is inadequate- not given in
patient with renal failure. Don’t give with sulfonamides- insoluble
complexes may form.
• Acute hepatic failure in patients with preexisting hepatic insufficiency-
(due to ammonia formed).

Therapeutic uses:
• Long term prophylaxis or suppressive therapy of recurring UTI. Keep 4
the pH of urine below 5.5
 Aminoglycosides
• A group of bactericidal antibiotics sharing antimicrobial,
pharmacological and toxic characteristics; differ in
antibacterial activity; show variable cross resistance,
synergise with bacterial cell wall synthesis inhibitors. They
contain aminosugars.

General characteristics:
• Polycations, used as sulfate salts, ionize in solution in polar
substances, not adequately absorbed after oral
administration, achieve poor concentration in
cerebrospinal fluid, readily excreted by glomerular
filtration.

• Effective against aerobic gram-negative enteric bacilli

and inhibit protein synthesis by acting on 30s ribosomes
and are bactericidal, more active at alkaline pH.
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• Have relatively narrow margin of safety - ototoxic and

 Aminoglycosides
Classification: group consists of
Streptomycin, gentamicin, tobramycin, amikacin, netilmicin
Neomycin, kanamycin
Paromomycin
Spectinomycin.
Gentamicin and tobramycin and amikacin are most widely used.
Neomycin is used topically.

Mechanism of action: Irreversible inhibitors of protein synthesis.

• First -passive diffusion via porin channels across the outer membrane.
• Next- active transport across the cell mem. into the cytoplasm by an oxygen
dependent process. Low extracellular pH and anaerobic conditions inhibit transport
and transport is enhanced by β lactams.
• Once inside they bind to 30 S subunit of ribosomal protein.
• Protein synthesis is inhibited in 3 ways:
– Interference of initiation complex of peptide formation
– Induction of misreading of mRNA which causes incorporation of wrong amino acids
into the peptide chain, resulting in nonfunctional or toxic protein.
– Breaking up of polysomes into nonfunctional monosomes
These actions occur more or less simultaneously. Overall effect is irreversible and is lethal to
cell.
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 Aminoglycosides
Antibacterial activity of aminoglycosides
• Aerobic G-ve (including Enterobacteriaecae, e.g. E. coli,
Enterobacter, Klebsiella, Proteus, P.aeruginosa, Serratia).

• Gentamicin, tobramycin, netilmicin and amikacin: active against

aerobic gram-negative bacilli (Pseudomonas, Proteus, Enterobacter,
Klebsiella, Serratia, acinetobacter, citrobacter).

• Streptomycin and gentamicin- active against enterococci and

Strep.viridans – adm.with penicillin.

• Gentamicin and tobramycin: Staph. aureus and Staph.

epidermidis.

• Tobramycin- more active against Pseudomonas aeruginosa and

Proteus species.

• Amikacin and netilmicin: Organisms resistant to genta and

tobramycin. Used for nosocomial infection caused by organisms
producing aminoglycoside-inactivating enzymes.
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 Aminoglycosides contd.
Microbial resistance to aminoglycosides

• Microorganism may produce transferase

enzyme or enzymes that cause inactivation of
drug by adenylation, phosphorylation,
acetylation of hydroxyl or amino groups (plasmid
mediated.

• Low permeability of antibiotic.

• Low affinity of drug to 30 S bacterial ribosome

due to mutation.

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 Aminoglycosides contd.
ADME
Absorption
• Highly polar cations- poorly abs. from GIT - eliminated in feces.
• Rapid abs. occurs from serosal surfaces,,wounds, burns and toxicity may occur .
• These are administered as IV infusion or IM, topical or IT (meningitis).
Distribution
• Excluded from most cells, CNS, and eye. Vd is equal to volume of extra cellular
fluid.
• Low protein binding 10-50%.
• High conc. in the renal cortex, and endolymph and perilymph of inner ear.
• Conc. In CSF <10% but in meningitis 25%- inadequate for negative aerobic
bacillary meningitis in adults and so IT (intrathecal) or intraventricular adm.
needed. In neonate with poor BBB- there is no need for intrathecal administration,
systemic administration is quite enough.
• They cross placenta. Streptomycin may cause hearing loss in children born to
women who receive the drug during pregnancy.
Elimination
• Occurs by glomerular filtration. Half life is 2-3 hours- increased to 24-48 hours
in renal impairment. Adjust the doses in renal impairment- decrease the dose or
increase the dosing interval or both. Measure plasma concentrations at least twice
weekly .
• Single daily dose is less ototoxic and nephrotoxic than divided dose regimens
and as effective (concentration dependent killing with post antibiotic effect). 9
 Untoward effects of aminoglycosides

Factors which increase toxicity:

• Duration of treatment >5 days.
• Sustained concentration
• Repeated doses.
• Higher doses, total amount
• Elderly persons
• Hypotension
• Dehydration
• Renal insufficiency
• Concurrent use with loop diuretics, other
nephrotoxic drugs (vancomycin, amphotericin B,
cisplatin, cyclosporin, some cephalosporins)
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 Toxicity of aminoglycosides

1. Ototoxicity: may occur with all. Largely

irreversible.
– Auditory: tinnitus, later hearing loss- due to
progressive accumulation of these drugs in
perilymph and endolymph of inner earÆ
progressive destruction of vestibular, cochlear
sensory cells.
Neomycin, kanamycin and amikacin are more
ototoxic.

– Vestibular toxicity- motion related headache,

dizziness, or nausea; later ataxia, loss of balance.
Streptomycin and gentamicin are more
vestibulotoxic.

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 Toxicity of aminoglycosides contd
2. Nephrotoxicity: usually reversible
• Leads to reduced excretion of the drug, which in
turn leads to further ototoxicity.

• Monitor plasma conc. particularly during

prolonged and /or high dose therapy.

• Neomycin is most nephrotoxic followed by

gentamicin and tobramycin .

• Streptomycin is least nephrotoxic.

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 Toxicity of aminoglycosides. contd..
3. Neuromuscular blockade
• Acute neuromuscular blockade and apnea.
• Neomycin most likely to produce this.

• Intrapleural or intraperitoneal instillation of

aminoglycoside - more toxic than after IV or IM injection.

• Myasthenic patients – more prone to this adverse effect.

• General anesthetics, hypocalcemia, hypermagnesemia

also effect NMB.

• Neuromuscular blockade is treated by IV calcium or

edrophonium/ neostigmine.
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 Toxicity of aminoglycosides. contd
4.Other effects on NS
• Optic neuritis with streptomycin.
• Peripheral neuritis and paresthesia mostly
perioral but also of hands and face- with
streptomycin.
• Radiculitis- on intraventricular or intrathecal
gentamicin.

5. Hypersensitivity reactions
• Rare. These include skin rashes, eosinophilia, fever,
angioedema, exfoliative dermatitis, stomatitis,
anaphylactic shock.

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 Individual drugs
1. Streptomycin
Uses
– Secondary line drug for tuberculosis; used in combination
with 2 or 3 other drugs.

– Bacterial endocarditis:given with penicillin to produce a

synergistic bactericidal effect against Strep. viridans and
Strep. faecalis. Gentamicin- preferred because of irreversible
vestibular toxicity produced by streptomycin.

– Tularemia

– Plague- all types.

– Brucellosis- doxycycline and rifampin are the drugs of choice.

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 2. Gentamicin
USES:
I. Urinary tract infection (UTI): In severe pyelonephritis: alone or in combination with
a beta lactam antibiotic- empirical therapy.

II. Pneumonia: With G-ve organisms in hospitalized patients, used along with penicillin
or cephalosporin. Not for CAP

III. Meningitis– not recommended, 3rd generation cephalosporins are preferred .

IV. Bacterial endocarditis:

Enterococcal endocarditis: ampicillin/penicillin + aminoglycoside.
Staph endocarditis: nafcillin + gentamicin or tobramicin

V. Other infections:
Empirical therapy of sepsis in immunocompromised patients: gentamicin + β
lactam+metronidazole
Serious gram –ve septicemia- DOC
Acute salpingitis- (PID), intraabdominal infection secondary to penetrating
trauma, diverticulitis, cholangitis, appendicitis, peritonitis, post surgical wound
infection- polymicrobial infection with –ve and anaerobes.

vi. Topical applications: infected burns, wounds, skin lesions, ophthalmic infections

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 Tobramycin, amikacin
3. Tobramycin
Uses:
• Similar to gentamicin- preferred for pseudomonas infection used
with antipseudomonal penicillin or ceftazidime.
Tobramycin is less nephrotoxic than gentamicin, but is expensive.

– Tobramycin inhalation decreases pseudomonas/enterobacteriacae in

cystic fibrosis

4. Amikacin
• Has broadest antimicrobial activity as it is resistant to
aminoglycoside inactivating enzymes, hence used in
infections due to gentamicin or tobramycin resistant
strains.
Uses:
– Initial treatment of serious nosocomial gram-negative bacillary
infection.
– For Mycobacterium tuberculosis resistant to streptomycin and for
disseminated atypical mycobacterial infection (avium, kansasii) in17
AIDS patients.
 Netilmicin
• Latest of the group.

• Antimicrobial activity similar to amikacin except

for myco. tuberculosis.

• Least ototoxic and nephrotoxic.

• Uses are similar to amikacin.

• Effective against serious infections due to gram

negative bacilli and certain gentamicin resistant
pathogens except enterococci.

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 Neomycin and Kanamycin
Neomycin kanamycin belong to same group, have similar properties.
6.. Neomycin
Uses
i. Topical: .
• For infections of skin or mucous membranes, i.e., infected burns, wounds, ulcers and
infected dermatoses,
• May be used alone or with other antibiotics like polymyxin B for continuous irrigation of bladder
to prevent bacteriuria and bacteremia associated with indwelling catheters.

ii. Oral
• Neomycin with erythromycin is given orally for 1- 2 days for preparation of bowel for
surgery – reduces aerobic bowel flora, reduces rate of postoperative wound infection.
• As an adjunct to therapy of hepatic coma- to destroy coliform bacteria to prevent ammonia
formation- nowadays lactulose is preferred .

Adverse reactions
• Hypersensitivity reactions- skin rashes- on topical application- cross reactivity with others
• Ototoxicity and nephrotoxicity on parenteral use- hence not used by this route.
• Neuromuscular blockade with respiratory paralysis- after irrigation of wounds or serosal
cavities.
• On oral administration - a sprue like malabsorption syndrome and superinfection with
overgrowth of yeasts in the intestine may occur

7. Kanamycin
• It may be used as a 2nd line treatment of tuberculosis.
• Orally it is used as adjunctive therapy in hepatic coma for 36-72 hours-as effect in intestinal
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microorganism may not be sustained
 Paromomycin , spectinomycin

8. Paromomycin
Uses:
– Intestinal amebiasis.
– Leishmaniasis

9. Spectinomycin
• Used in the treatment of gonococcal infection in
patients allergic to penicillin and those infected with β-
lactamase producing gonococci.
• Administered by IM- single inj.
Adverse reactions:
• Rash, fever, pain, nausea, nephrotoxicity, anemia.
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