Aminoglycosides

100

Practical Urology: EssEntial PrinciPlEs and PracticE

amino group. The activity is enhanced if the

bacterial cell is induced.53 The structure-prop-

same primed sugar is not hydroxylated, thus

erty relationships of the different substituents

gentamicins are generally more active than

corresponding to the pharmacophore show the

kanamycins.49 In parallel, the more active sub-

following aspects53: Elements that enhance activ-

stances, however, are better substrates for inacti-

ity and reduce resistance selection include a

vating nucleotidyltransferases. Because of the

cyclopropyl at position 1, a methoxy at position

aminocyclitol ring the aminoglycosides are

8,a pyrrolidine or substituted piperazine at posi-

basic molecules and have a high degree of solu-

tion 7, and a fluor substituent at position 6.53

bility in water and poor solubility in lipids. They

Moieties or elements that enhance the volume of

are therefore poorly absorbed and distributed

distribution are a cyclopropyl at position 1, and

in the tissues and they must be actively trans-

those that enhance half-life and central nervous

ported across the bacterial cell membrane.

system penetration are a bulky side chain at

Aminoglycosides are almost exclusively excreted

position 7.53 Fluoroquinolones work mainly in a

in the urine by glomerular filtration, but approx-

concentration-dependent manner and exert a

imately 5% of the administered dose is retained

marked post-antibiotic effect. The antibacterial

in the epithelial cells lining the S1 and S2 seg-

activity in urine however is reduced, because

ments of the proximal tubules.51 The aminogly-

fluoroquinolones form antibacterially inactive/

cosides thus accumulate in the lysosomes of the

less active complexes with divalent cations.54

tubular cells. This accumulation in renal tubular

Most fluoroquinolones show excellent bio-

cells renders aminoglycosides suitable for treat-

availability (60–100%) and a high volume of dis-

ment of pyelonephritis, but eventually also

tribution. Penetration into the prostate tissue is

causes the lysosomes to rupture above a certain

better than any other antibiotic substance. The

cut-off concentration. The highly concentrated

serum levels are usually low.53 The urinary excre-

aminoglycoside together with the lysosomal

tion of fluoroquinolones differs widely between

enzymes are then released into the cytosol and

substances. A high urinary excretion (³75%) can

eventually lead to cell damage and is the reason

be observed with levofloxacin (84%), lomefloxa-

for nephrotoxicity.

cin (75%), and ofloxacin (81%). An intermediate

excretion rate (40–74%) is seen with ciprofloxa-

Fluoroquinolones

cin (43%), enoxacin (53%), fleroxacin (67%), and

a low excretion rate (<40%) is seen with moxi-

Fluoroquinolones can be classified according to

floxacin (20%) and norfloxacin (20%).55

antibacterial spectrum and activity and the

main indications into four groups.52 Among the

agents frequently used for the treatment of UTI,

Trimethoprim, Cotrimoxazole

the first group comprises agents such as norflox-

acin, with indications essentially limited to UTI.

Cotrimoxazole is the combination of trimethop-

The second group encompasses agents such as

rim (TMP) and sulfamethoxazole (SMX) in the

ofloxacin and ciprofloxacin with broad indica-

ratio of 1:5. Both substances inhibit different

tions for systemic use and predominant Gram-

steps in the folic acid biosynthetic pathway. SMX

negative activity. The third group comprises

is a structural analogue of p-aminobenzoic acid,

agents such as levofloxacin with good Gram-

the basic building block used by bacteria to syn-

negative activity and, in addition, improved

thesize dihydrofolic acid, the first step in the

activity against Gram-positive and atypical

reaction leading to folic acid. SMX competitively

pathogens, and the fourth group comprises

inhibits this step. TMP competitively prevents

agents with good Gram-negative activity and, in

the conversion of dihydrofolic acid to tetrahy-

addition, further improved activity against

drofolic acid, the metabolically active cofactor

Gram-positive and atypical and anaerobic bac-

for synthesis of purines.56 Of all sulfonamides,

teria, such as moxifloxacin.

SMX was paired with TMP because of similar

Fluoroquinolones form ternary complexes

absorptive and pharmacodynamic properties.

between DNA and the bacterial topoisomerases

Each drug is well absorbed. Approximately 85%

II and IV, which play a critical role in the organi-

of total SMX is recovered in the urine, 30% as

zation of the bacterial DNA. Thus the DNA

free drug and the rest as acetylated metabolite.

destabilizes and consequently apoptosis of the

Similarly, most of TMP is not metabolized and is