Hugo W.B., Russel A.D.(ed). Pharmaceutical Microbiology

Подождите немного. Документ загружается.

Fig. 5.15 Antifungal antibiotics: A, griseofulvin; B, nystatin; C, amphotericin (R = H) and its

methyl ester (R = CH

11.1

Synthetic antimicrobial agents

Sulphonamides

Sulphonamides were introduced by Domagk in 1935. It had been shown that a red azo

dye, prontosil (Fig. 5.16B), had a curative effect on mice infected with /3-haemolytic

streptococci; it was subsequently found that in vivo, prontosil was converted into

sulphanilamide. Chemical modifications of the nucleus of sulphanilamide (see Fig.

5.16A) gave compounds with higher antibacterial activity, although this was often

accompanied by greater toxicity. In general, it may be stated that the sulphonamides

Types of antibiotics 115

Fig. 5.16 A, some sulphonamides; B, prontosil rubrum; C, unsubstituted diaminobenzylpyrimidines;

D, trimethoprim; E, tetroxoprim; F, dapsone.

have a broadly similar antibacterial activity but differ widely in pharmacological

actions.

Bacteria which are almost always sensitive to the sulphonamides include Strep.

pneumoniae, /3-haemolytic streptococci, Escherichia coli and Proteus mirabilis; those

almost always resistant include Enterococcus faecalis, Ps. aeruginosa, indole-positive

Proteus and Klebsiella; whereas bacteria showing a marked variation in response include

Staph, aureus, gonococci, H. influenzae and hospital strains of E. coli and Pr. mirabilis.

The sulphonamides show a considerable variation in the extent of their absorption

into the bloodstream. Sulphadimidine and sulphadiazine are examples of rapidly

absorbed ones, whereas succinylsulphathiazone and phthalylsulphathiazole are poorly

absorbed and are excreted unchanged in the faeces.

From a clinical point of view, the sulphonamides are extremely useful for the

treatment of uncomplicated urinary tract infection caused by E. coli in domiciliary

practice. They have also been employed in treating meningococcal meningitis (a current

116 Chapter 5

problem is the number of sulphonamide-resistant meningococcal strains) and superficial

eye infections.

11.2 Diaminopyrimidine derivatives

Small-molecule diaminopyrimidine derivatives were shown in 1948 to have an antifolate

action. Subsequently, compounds were developed that were highly active against human

cells (e.g. the use of methotrexate as an anticancer agent), protozoa (e.g. the use of

pyrimethamine in malaria) or bacteria (e.g. trimethoprim: Fig. 5.16D). Unsubstituted

diaminobenzylpyrimidines (Fig. 5.16C) bind poorly to bacterial dihydrofolate reductase

(DHFR). The introduction of one, two or especially three methoxy groups (as in

trimethoprim) produces a highly selective antibacterial agent. A recent antibacterial

addition is tetroxoprim (2,4-diamino-5-(3',5'-dimethoxy-4'-methoxyethoxybenzyl)

pyrimidine; Fig. 5.16E) which retains methoxy groups at R

and R

and has a

methoxyethoxy group at R

. Trimethoprim and tetroxoprim have a broad spectrum of

activity but resistance can arise from a non-susceptible target site, i.e. an altered DHFR

(see Chapter 9).

11.3 Co-trimoxazole

Co-trimoxazole is a mixture of sulphamethoxazole (five parts) and trimethoprim

(one part). The reason for using this combination is based upon the in vitro finding

that there is a 'sequential blockade' of folic acid synthesis, in which the sulphonamide

is a competitive inhibitor of dihydropteroate synthetase and trimethoprim inhibits DHFR

(see Chapter 8, especially Fig. 8.5). The optimum ratio of the two components may not

be achieved in vivo and arguments continue as to the clinical value of co-trimoxazole,

with many advocating the use of trimethoprim alone. Co-trimoxazole is the agent of

choice in treating pneumonias caused by Pneumocystis carinii, a yeast (although it had

been classified as protozoa). Pneumocystis carinii is a common cause of pneumonia in

patients receiving immunosuppressive therapy and in those suffering from AIDS.

11.4 Dapsone

Dapsone (diaminodiphenylsulphone; Fig. 5.16F) is used specifically in the treatment

of leprosy. However, because resistance to dapsone is unfortunately now well known,

it is recommended that dapsone be used in conjunction with rifampicin and clofazimine.

11.5 Antitubercular drugs

The three standard drugs used in the treatment of tuberculosis were streptomycin

(considered above), ^-aminosalicylic acid (PAS) and isoniazid (isonicotinylhydrazide,

INH; synonym, isonicotinic acid hydrazine, INAH). The tubercle bacillus rapidly

becomes resistant to streptomycin, and the role of PAS was mainly that of preventing

this development of resistance. The current approach is to treat tuberculosis in two

phases: an initial phase where a combination of three drugs is used to reduce the bacterial

level as rapidly as possible, and a continuation phase in which a combination of

Types of antibiotics 117

two drags is employed. Front-line drags are isoniazid, rifampicin, streptomycin

and ethambutol. Pyrazinamide, which has good meningeal penetration, and is thus

particularly useful in tubercular meningitis, may be used in the initial phase to produce

a highly bactericidal response.

Isoniazid has no significant effect against organisms other than mycobacteria. It is

given orally. Cross-resistance between it, streptomycin and rifampicin has not been

found to occur.

When bacterial resistance to these primary agents exists or develops, treatment

with the secondary antitubercular drugs has to be considered. The latter group comprises

capreomycin, cycloserine, some of the newer macrolides (azithromycin, clarithromycin),

4-quinolones (e.g. ciprofloxacin, ofloxacin) and prothionamide (no longer marketed in

the UK). Prothionamide, pyrazinamide and ethionamide are, like isoniazid, derivatives

of isonicotinic acid. The British National Formulary no longer lists ethionamide

as being a suitable antitubercular drug. Chemical structures of the above, and of

thiacetazone (not nowadays used because of its side-effects) are presented in Fig. 5.17.

There has, unfortunately, been a global resurgence of tuberculosis in recent years.

Multiple drug-resistant M. tuberculosis (MDRTB) strains have been isolated in which

resistance has been acquired to many drugs used in the treatment of this disease.

Fig. 5.17 Antitubercular compounds (see text also for details of antibiotics): A, PAS; B, isoniazid;

C, ethionamide; D, pyrazinamide; E, prothionamide; F, thiacetazone; G, ethambutol.

11.6

Nitrofuran compounds

The nitrofuran group of drugs (Fig. 5.18) is based on the finding over 40 years ago that

a nitro group in the 5 position of 2-substituted furans endowed these compounds with

antibacterial activity. Many hundreds of such compounds have been synthesized, but

only a few are in current therapeutic use. In the most important nitrofurans, an

azomethine group, —CH=N—, is attached at C-2 and a nitro group at C-5. Less

"important nitrofurans have a vinyl group, —CH=CH—, at C-2.

Biological activity is lost if:

1 the nitro ring is reduced;

2 the —CH=N— linkage undergoes hydrolytic decomposition; or

3 the —CH=CH— linkage is oxidized.

The nitrofurans show antibacterial activity against a wide spectrum of micro-

organisms, but furaltadone has now been withdrawn from use because of its toxicity.

Furazolidone has a very high activity against most members of the Enterobacteriaceae,

and has been used in the treatment of diarrhoea and gastrointestinal disturbances of

bacterial origin. Nitrofurantoin is used in the treatment of urinary tract infections; anti-

bacterial levels are not reached in the blood and the drug is concentrated in the urine. It

is most active at acid pH. Nitrofurazone is used mainly as a topical agent in the treatment

of burns and wounds and also in certain types of ear infections. The nitrofurans are

believed to be mutagenic.

Fig. 5.18 A, furan; B, 5-nitrofurfural; C-F, nitrofuran drugs: respectively C, nitrofurazone, D,

nitrofurantoin, E, furazolidone and F, furaltadone.

Types of antibiotics 119

11.7

4-quinolone antibacterials

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic

acid is regarded as the progenitor of the new quinolones. It has been used for

several years as a clinically important drug in the treatment of urinary tract infections.

Since its clinical introduction, other 4-quinolone antibacterials have been synthesized,

some of which show considerably greater antibacterial potency. Furthermore, this

means that many types of bacteria not susceptible to nalidixic acid therapy may be

sensitive to the newer derivatives. The most important development was the introduction

of a fluorine substituent at C-6, which led to a considerable increase in potency and

spectrum of activity compared with nalidixic acid. These second-generation quinolones

are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin

(Fig. 5.19).

Nalidixic acid is unusual in that it is active against several different types of Gram-

negative bacteria, whereas Gram-positive organisms are resistant. However, the newer

fluoroquinolone derivatives show superior activity against Enterobacteriacease and

Ps. aeruginosa, and their spectrum also includes staphylococci but not streptococci.

Extensive studies with norfloxacin have demonstrated that its broad spectrum, high

urine concentration and oral administration make it a useful drug in the treatment of

urinary infections. Ciprofloxacin may be used in the treatment of organisms resistant

to other antibiotics; it can also be used in conjunction with a /3-lactam or aminoglycoside

antibiotic, e.g. when severe neutropenia is present.

The third and most recently developed generation of quinolones has maintained many

of the properties of the second generation; examples are lomefloxacin, sparfloxacin (both

difluorinated derivatives) and temafloxacin (a trifluorinated derivative). Lomefloxacin

has a sufficiently long half-life to allow once-daily dosing, but adverse photosensitivity

reactions are now being recognized. Sparfloxacin retains high activity against Gram-

negative bacteria but has enhanced activity against Gram-positive cocci and anaerobes.

Temafloxacin has, unfortunately, been withdrawn from clinical use because of unex-

pected severe haemolytic and nephrotoxic reactions.

11.8 Imidazole derivatives

The imidazoles comprise a large and diverse group of compounds with properties

encompassing antibacterial (metronidazole), antiprotozoal (metronidazole), antifungal

(clotrimazole, miconazole, ketoconazole, econazole) and anti-anthelmintic (mebendazole)

activity: see Table 5.4. Metronidazole (Fig. 5.20A) inhibits the growth of pathogenic

protozoa, very low concentrations being effective against the protozoa Trichomonas

vaginalis, Entamoeba histolytica and Giardia lamblia. It is also used to treat bacterial

vaginosis caused by Gardnerella vaginalis. Given orally, it cures 90-100% of sexually

transmitted urogenital infections caused by T. vaginalis. It has also been found that

metronidazole is effective against anaerobic bacteria, for example B.fragilis, and against

facultative anaerobes grown under anaerobic, but not aerobic, conditions. Metronidazole

is administered orally or in the form of suppositories.

Other imidazole derivatives include clotrimazole (Fig. 5.20B), miconazole (Fig.

5.20C) and econazole (Fig. 5.20D), all of which possess a broad antimycotic spectrum

120 Chapter 5

Table 5.4 Antimicrobial imidazoles

Antimicrobial

or other activity Examples

Antibacterial Metronidazole, tinidazole: anaerobic bacteria only

Antiprotozoal Metronidazole, tinidazole

Anthelmintic Mebendazole

Antifungal Clotrimazole, miconazole, econazole, ketoconazole

Newer imidazoles: fluconazole, itraconazole

with some antibacterial activity and are used topically. Miconazole is used topically

but can also be administered by intravenous or intrathecal injection in the treatment of

severe systemic or meningeal fungal infections. Newer imidazoles are (a) ketoconazole

(Fig. 5.20E) which is used orally for the treatment of systemic fungal infections (but

not when there is central nervous system involvement or where the infection is life-

threatening), (b) fluconazole (Fig. 5.20F), which is given orally or by intravenous

infusion in the treatment of candidiasis and cryptococcal meningitis. Itraconazole is

well absorbed when given orally after food.

11.9 Flucytosine

Flucytosine (5-fluorocytosine; Fig. 5.20G) is a narrow-spectrum antifungal agent

with greatest activity against yeasts such as Candida, Cryptococcus and Torulopsis.

Evidence has been presented which shows that, once inside the fungal cell, flucytosine

is deaminated ot 5-fluorouracil (Fig. 5.20H). This is converted by the enzyme

pyrophosphorylase to 5-fluorouridine monophosphate (FUMP), diphosphate (FUDP)

and triphosphate (FUTP), which inhibits RNA synthesis; 5-fluorouracil itself has

poor penetration into fungi. Candida albicans is known to convert FUMP to 5-

fluorodeoxyuridine monophosphate (FdUMP), which inhibits DNA synthesis by virtue

of its effect on thymidylate synthetase. Resistance can occur in vivo by reduced uptake

into fungal cells of flucytosine or by decreased accumulation of FUTP and FdUMP.

11.10 Synthetic allylamines

Terbinafine (Fig. 5.171), a member of the allylamine class of antimycotics, is an inhibitor

of the enzyme squalene epoxidase in fungal ergosterol biosynthesis. Terbinafine is

orally active, is fungicidal and is effective against a broad range of dermatophytes and

yeasts. It can also be used topically as a cream.

11.11 Synthetic thiocarbamates

The synthetic thiocarbamates, of which tolnaftate (Fig. 5.20J) is an example, also inhibit

squalene epoxidase. Tolnaftate inhibits this enzyme from C. albicans, but is inactive

against whole cells, presumably because of its inability to penetrate the cell wall.

Tolnaftate is used topically in the treatment or prophylaxis of tinea.

122 Chapter 5

Fig. 5.20 Imidazoles (A-F): A, metronidazole; B, clotrimazole; C, miconazole; D, econazole;

E, ketoconazole; F, fluconazole; G, flucytosine; H, 5-fluorouracil; I, terbinafine; J, tolnaftate.

Types of antibiotics 123

12 Antiviral drugs

Several compounds are known that are inhibitory to mammalian viruses in tissue

culture, but only a few can be used in the treatment of human viral infections. The main

problem in designing and developing antiviral agents is the lack of selective toxicity

that is normally possessed by most compounds. Viruses literally 'take over' the

machinery of an infected human cell and thus an antiviral drug must be remarkably

selectively toxic if it is to inhibit the viral particle without adversely affecting the human

cell. Consequently, in comparison with antibacterial agents, very few inhibitors can be

considered as being safe antiviral drugs, although the situation is improving. Possible

sites of attack by antiviral agents include prevention of adsorption of a viral particle to

the host cell, prevention of the intracellular penetration of the adsorbed virus, and

inhibition of protein or nucleic synthesis.

Genetic information for viral reproduction resides in its nucleic acid (DNA or RNA:

see Chapter 3). The viral particle (virion) does not possess enzymes necessary for its

own replication; after entry into the host cell, the virus uses the enzymes already present

or induces the formation of new ones. Viruses replicate by synthesis of their separate

components followed by assembly.

Antiviral drugs are considered below with a summary in Table 5.5.

12.1 Amantadines

Amantadine hydrochloride (Fig. 5.21A) does not prevent adsorption but inhibits

viral penetration. It has a very narrow spectrum and is used prophylactically against

infection with influenza A virus; it has no prophylactic value with other types of influenza

virus.

Table 5.5 Antiviral drugs and their clinical uses

Group

Nucleoside

analogues

Non-nucleoside

analogues

Antiviral

drug

Idoxuridine

Ribavirin (tribavirin)

Zidovudine

Didanosine (DDI)

Zalcitabine (DDC)

Acyclovir (aciclovir)

Famciclovir

Ganciclovir

Fascornet

Amantadines

Clinical uses

Skin including herpes labialis

Severe respiratory syncytial virus

bronchiolitis in infants and

children

AIDS treatment

r Herpes simplex and varicella zoster

Cytomegalovirus infections in

immunocompromised patients only

Cytomegalovirus retinitis in patients

with AIDS

Prophylaxis: influenza A outbreak

For further information, see the current issue of the British National Formulary.

124 Chapter 5