Antibacterial Drugs Drugs for Treating Bacterial Infections When bacteria overcome the cutaneous or mucosal barriers and penetrate body tissues, a bacterial infection is present. Frequently the body succeeds in remov- ing the invaders, without outward signs of disease, by mounting an immune re- sponse. If bacteria multiply faster than the body’s defenses can destroy them, infectious disease develops with inflam- matory signs, e.g., purulent wound in- fection or urinary tract infection. Appro- priate treatment employs substances that injure bacteria and thereby prevent their further multiplication, without harming cells of the host organism (1). Apropos nomenclature: antibiotics are produced by microorganisms (fungi, bacteria) and are directed “against life” at any phylogenetic level (prokaryotes, eukaryotes). Chemotherapeutic agents originate from chemical synthesis. This distinction has been lost in current us- age. Specific damage to bacteria is partic- ularly practicable when a substance interferes with a metabolic process that occurs in bacterial but not in host cells. Clearly this applies to inhibitors of cell wall synthesis, because human and ani- mal cells lack a cell wall. The points of attack of antibacterial agents are sche- matically illustrated in a grossly simpli- fied bacterial cell, as depicted in (2). In the following sections, polymyx- ins and tyrothricin are not considered further. These polypeptide antibiotics enhance cell membrane permeability. Due to their poor tolerability, they are prescribed in humans only for topical use. The effect of antibacterial drugs can be observed in vitro (3). Bacteria multi- ply in a growth medium under control conditions. If the medium contains an antibacterial drug, two results can be discerned: 1. bacteria are killed—bacte- ricidal effect; 2. bacteria survive, but do not multiply—bacteriostatic effect. Al- though variations may occur under therapeutic conditions, different drugs can be classified according to their re- spective primary mode of action (color tone in 2 and 3). When bacterial growth remains un- affected by an antibacterial drug, bacte- rial resistance is present. This may oc- cur because of certain metabolic charac- teristics that confer a natural insensitiv- ity to the drug on a particular strain of bacteria (natural resistance). Depending on whether a drug affects only a few or numerous types of bacteria, the terms narrow-spectrum (e.g., penicillin G) or broad-spectrum (e.g., tetracyclines) antibiotic are applied. Naturally sus- ceptible bacterial strains can be trans- formed under the influence of antibac- terial drugs into resistant ones (acquired resistance), when a random genetic al- teration (mutation) gives rise to a resist- ant bacterium. Under the influence of the drug, the susceptible bacteria die off, whereas the mutant multiplies un- impeded. The more frequently a given drug is applied, the more probable the emergence of resistant strains (e.g., hos- pital strains with multiple resistance)! Resistance can also be acquired when DNA responsible for nonsuscepti- bility (so-called resistance plasmid) is passed on from other resistant bacteria by conjugation or transduction. 266 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 267 A. Principles of antibacterial therapy Selective antibacterial toxicity Bacteria Body cells Cell membrane Cell wall Bacterium DNA RNA Protein 1 day Antibiotic Insensitive strain Sensitive strain with resistant mutant Selection 3. 2. 1. Immune defenses Anti- bacterial drugs Bacterial invasion: infection Penicillins Cephalosporins "Gyrase-inhibitors" Nitroimidazoles Bacitracin Vancomycin Polymyxins Tyrothricin Rifampin Tetracyclines Chloramphenicol Erythromycin Clindamycin Aminoglycosides Sulfonamides Trimethoprim Tetrahydro- folate synthesis Resistance Bacteriostatic Bactericidal Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of Cell Wall Synthesis In most bacteria, a cell wall surrounds the cell like a rigid shell that protects against noxious outside influences and prevents rupture of the plasma mem- brane from a high internal osmotic pressure. The structural stability of the cell wall is due mainly to the murein (peptidoglycan) lattice. This consists of basic building blocks linked together to form a large macromolecule. Each basic unit contains the two linked aminosug- ars N-acetylglucosamine and N-acetyl- muramyl acid; the latter bears a peptide chain. The building blocks are synthe- sized in the bacterium, transported out- ward through the cell membrane, and assembled as illustrated schematically. The enzyme transpeptidase cross-links the peptide chains of adjacent amino- sugar chains. Inhibitors of cell wall synthesis are suitable antibacterial agents, be- cause animal and human cells lack a cell wall. They exert a bactericidal action on growing or multiplying germs. Mem- bers of this class include !-lactam anti- biotics such as the penicillins and cepha- losporins, in addition to bacitracin and vancomycin. Penicillins (A). The parent sub- stance of this group is penicillin G (ben- zylpenicillin). It is obtained from cul- tures of mold fungi, originally from Pen- icillium notatum. Penicillin G contains the basic structure common to all peni- cillins, 6-amino-penicillanic acid (p. 271, 6-APA), comprised of a thiazolidine and a 4-membered !-lactam ring. 6- APA itself lacks antibacterial activity. Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacte- ria are in their growth and replication phase, penicillins are bactericidal; due to cell wall defects, the bacteria swell and burst. Penicillins are generally well toler- ated; with penicillin G, the daily dose can range from approx. 0.6 g i.m. (= 10 6 international units, 1 Mega I.U.) to 60 g by infusion. The most important ad- verse effects are due to hypersensitivity (incidence up to 5%), with manifesta- tions ranging from skin eruptions to anaphylactic shock (in less than 0.05% of patients). Known penicillin allergy is a contraindication for these drugs. Be- cause of an increased risk of sensitiza- tion, penicillins must not be used local- ly. Neurotoxic effects, mostly convul- sions due to GABA antagonism, may oc- cur if the brain is exposed to extremely high concentrations, e.g., after rapid i.v. injection of a large dose or intrathecal injection. Penicillin G undergoes rapid renal elimination mainly in unchanged form (plasma t 1/2 ~ 0.5 h). The duration of the effect can be prolonged by: 1. Use of higher doses, enabling plas- ma levels to remain above the minimal- ly effective antibacterial concentration; 2. Combination with probenecid. Re- nal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of 6-APA). The acid probenecid (p. 316) competes for this route and thus retards penicillin elimination; 3. Intramuscular administration in depot form. In its anionic form (-COO - ) penicillin G forms poorly water-soluble salts with substances containing a posi- tively charged amino group (procaine, p. 208; clemizole, an antihistamine; benzathine, dicationic). Depending on the substance, release of penicillin from the depot occurs over a variable inter- val. 268 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 269 A. Penicillin G: structure and origin; mode of action of penicillins; methods for prolonging duration of action Bacterium Cell wall Cell membrane Cell wall building block Amino acid chain Cross-linked by transpeptidase Sugar Penicillin G Fungus Penicillium notatum Human Penicillin allergy Neurotoxicity at very high dosage Plasma concentration 3 x Dose Minimal bactericidal concentration Time Increasing the dose Anion secretory system Combination with probenecid Depot preparations ~1 ~7-28 ~2 Inhibition of cell wall synthesis Probenecid Penicillin Pr ocaine Penicillin + - Clemizole Penicillin + - Benzathine 2 Penicillins + - + Duration of action (d) Antibody Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Although very well tolerated, peni- cillin G has disadvantages (A) that limit its therapeutic usefulness: (1) It is inac- tivated by gastric acid, which cleaves the !-lactam ring, necessitating paren- teral administration. (2) The !-lactam ring can also be opened by bacterial en- zymes (!-lactamases); in particular, penicillinase, which can be produced by staphylococcal strains, renders them re- sistant to penicillin G. (3) The antibacte- rial spectrum is narrow; although it en- compasses many gram-positive bacte- ria, gram-negative cocci, and spiro- chetes, many gram-negative pathogens are unaffected. Derivatives with a different sub- stituent on 6-APA possess advantages (B): (1) Acid resistance permits oral ad- ministration, provided that enteral ab- sorption is possible. All derivatives shown in (B) can be given orally. Penicil- lin V (phenoxymethylpenicillin) exhib- its antibacterial properties similar to those of penicillin G. (2) Due to their penicillinase resistance, isoxazolylpen- icillins (oxacillin dicloxacillin, flucloxacil- lin) are suitable for the (oral) treatment of infections caused by penicillinase- producing staphylococci. (3) Extended activity spectrum: The aminopenicillin amoxicillin is active against many gram- negative organisms, e.g., coli bacteria or Salmonella typhi. It can be protected from destruction by penicillinase by combination with inhibitors of penicilli- nase (clavulanic acid, sulbactam, tazo- bactam). The structurally close congener am- picillin (no 4-hydroxy group) has a simi- lar activity spectrum. However, because it is poorly absorbed (<50%) and there- fore causes more extensive damage to the gut microbial flora (side effect: diar- rhea), it should be given only by injec- tion. A still broader spectrum (including Pseudomonas bacteria) is shown by car- boxypenicillins (carbenicillin, ticarcillin) and acylaminopenicillins (mezclocillin, azlocillin, piperacillin). These substanc- es are neither acid stable nor penicilli- nase resistant. Cephalosporins (C). These !-lac- tam antibiotics are also fungal products and have bactericidal activity due to in- hibition of transpeptidase. Their shared basic structure is 7-aminocepha- losporanic acid, as exemplified by cephalexin (gray rectangle). Cephalo- sporins are acid stable, but many are poorly absorbed. Because they must be given parenterally, most—including those with high activity—are used only in clinical settings. A few, e.g., cepha- lexin, are suitable for oral use. Cephalo- sporins are penicillinase-resistant, but cephalosporinase-forming organisms do exist. Some derivatives are, however, also resistant to this !-lactamase. Cephalosporins are broad-spectrum antibacterials. Newer derivatives (e.g., cefotaxime, cefmenoxin, cefoperazone, ceftriaxone, ceftazidime, moxalactam) are also effective against pathogens re- sistant to various other antibacterials. Cephalosporins are mostly well tolerat- ed. All can cause allergic reactions, some also renal injury, alcohol intolerance, and bleeding (vitamin K antagonism). Other inhibitors of cell wall syn- thesis. Bacitracin and vancomycin interfere with the transport of pepti- doglycans through the cytoplasmic membrane and are active only against gram-positive bacteria. Bacitracin is a polypeptide mixture, markedly nephro- toxic and used only topically. Vancomy- cin is a glycopeptide and the drug of choice for the (oral) treatment of bowel inflammations occurring as a complica- tion of antibiotic therapy (pseudomem- branous enterocolitis caused by Clos- tridium difficile). It is not absorbed. 270 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 271 C. Cephalosporin A. Disadvantages of penicillin G B. Derivatives of penicillin G 6-Aminopenicillanic acid Penicillin G Penicillinase Staphylococci E. coli Salmonella typhi Gonococci Pneumococci Streptococci Narrow-action spectrum Active Not active H + Cl - Resis- tant Resistant, but sensitive to cephalosporinase Broad Cefalexin Penicillin V Oxacillin Amoxicillin Resis- tant Resis- tant Resis- tant Sensitive Resistant Resistant Narrow Narrow Broad PenicillinaseAcid Spectrum Concentration needed to inhibit penicillin G- sensitive bacteria Gram-positive Gram-negative Acid sensitivity Penicillinase sensitivity Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of Tetrahydrofolate Synthesis Tetrahydrofolic acid (THF) is a co-en- zyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihy- drofolate reductase. DHF is made from folic acid, a vitamin that cannot be syn- thesized in the body, but must be taken up from exogenous sources. Most bacte- ria do not have a requirement for folate, because they are capable of synthesiz- ing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and tri- methoprim. Sulfonamides structurally resem- ble p-aminobenzoic acid (PABA), a pre- cursor in bacterial DHF synthesis. As false substrates, sulfonamides competi- tively inhibit utilization of PABA, hence DHF synthesis. Because most bacteria cannot take up exogenous folate, they are depleted of DHF. Sulfonamides thus possess bacteriostatic activity against a broad spectrum of pathogens. Sulfon- amides are produced by chemical syn- thesis. The basic structure is shown in (A). Residue R determines the pharma- cokinetic properties of a given sulfon- amide. Most sulfonamides are well ab- sorbed via the enteral route. They are metabolized to varying degrees and eliminated through the kidney. Rates of elimination, hence duration of effect, may vary widely. Some members are poorly absorbed from the gut and are thus suitable for the treatment of bacte- rial bowel infections. Adverse effects may include, among others, allergic re- actions, sometimes with severe skin damage, displacement of other plasma protein-bound drugs or bilirubin in neo- nates (danger of kernicterus, hence con- traindication for the last weeks of gesta- tion and in the neonate). Because of the frequent emergence of resistant bacte- ria, sulfonamides are now rarely used. Introduced in 1935, they were the first broad-spectrum chemotherapeutics. Trimethoprim inhibits bacterial DHF reductase, the human enzyme be- ing significantly less sensitive than the bacterial one (rarely bone marrow de- pression). A 2,4-diaminopyrimidine, tri- methoprim, has bacteriostatic activity against a broad spectrum of pathogens. It is used mostly as a component of co- trimoxazole. Co-trimoxazole is a combination of trimethoprim and the sulfonamide sul- famethoxazole. Since THF synthesis is inhibited at two successive steps, the antibacterial effect of co-trimoxazole is better than that of the individual com- ponents. Resistant pathogens are infre- quent; a bactericidal effect may occur. Adverse effects correspond to those of the components. Although initially developed as an antirheumatic agent (p. 320), sulfasala- zine (salazosulfapyridine) is used main- ly in the treatment of inflammatory bowel disease (ulcerative colitis and terminal ileitis or Crohn’s disease). Gut bacteria split this compound into the sulfonamide sulfapyridine and mesala- mine (5-aminosalicylic acid). The latter is probably the anti-inflammatory agent (inhibition of synthesis of chemotactic signals for granulocytes, and of H 2 O 2 formation in mucosa), but must be present on the gut mucosa in high con- centrations. Coupling to the sulfon- amide prevents premature absorption in upper small bowel segments. The cleaved-off sulfonamide can be ab- sorbed and may produce typical adverse effects (see above). Dapsone (p. 280) has several thera- peutic uses: besides treatment of lepro- sy, it is used for prevention/prophylaxis of malaria, toxoplasmosis, and actino- mycosis. 272 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 273 A. Inhibitors of tetrahydrofolate synthesis (Vitamin) DHF-Reductase R determines pharmacokinetics Duration of effect Dosing interval Sulfasalazine (not absorbable) Cleavage by intestinal bacteria Mesalamine Sulfapyridine (absorbable) Bacterium Human cell Synthesis of purines Thymidine Sulfonamidesp-Aminobenzoic acid Combination of Trimethoprim and Sulfamethoxazole Co-trimoxazole = Dihydro- folic acid (DHF) Tetrahydro- folic acid Folic acid Trimethoprim Sulfisoxazole 6 hours Sulfamethoxazole 12 hours Sulfalene 7 days Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of DNA Function Deoxyribonucleic acid (DNA) serves as a template for the synthesis of nucleic ac- ids. Ribonucleic acid (RNA) executes protein synthesis and thus permits cell growth. Synthesis of new DNA is a pre- requisite for cell division. Substances that inhibit reading of genetic informa- tion at the DNA template damage the regulatory center of cell metabolism. The substances listed below are useful as antibacterial drugs because they do not affect human cells. Gyrase inhibitors. The enzyme gy- rase (topoisomerase II) permits the or- derly accommodation of a ~1000 µm- long bacterial chromosome in a bacteri- al cell of ~1 µm. Within the chromoso- mal strand, double-stranded DNA has a double helical configuration. The for- mer, in turn, is arranged in loops that are shortened by supercoiling. The gy- rase catalyzes this operation, as illus- trated, by opening, underwinding, and closing the DNA double strand such that the full loop need not be rotated. Derivatives of 4-quinolone-3-car- boxylic acid (green portion of ofloxacin formula) are inhibitors of bacterial gy- rases. They appear to prevent specifical- ly the resealing of opened strands and thereby act bactericidally. These agents are absorbed after oral ingestion. The older drug, nalidixic acid, affects exclu- sively gram-negative bacteria and at- tains effective concentrations only in urine; it is used as a urinary tract anti- septic. Norfloxacin has a broader spec- trum. Ofloxacin, ciprofloxacin, and enoxacin, and others, also yield system- ically effective concentrations and are used for infections of internal organs. Besides gastrointestinal problems and allergy, adverse effects particularly involve the CNS (confusion, hallucina- tions, seizures). Since they can damage epiphyseal chondrocytes and joint car- tilages in laboratory animals, gyrase in- hibitors should not be used during preg- nancy, lactation, and periods of growth. Azomycin (nitroimidazole) deriv- atives, such as metronidazole, damage DNA by complex formation or strand breakage. This occurs in obligate an- aerobes, i.e., bacteria growing under O 2 exclusion. Under these conditions, con- version to reactive metabolites that at- tack DNA takes place (e.g., the hydroxyl- amine shown). The effect is bactericidal. A similar mechanism is involved in the antiprotozoal action on Trichomonas va- ginalis (causative agent of vaginitis and urethritis) and Entamoeba histolytica (causative agent of large bowel inflam- mation, amebic dysentery, and hepatic abscesses). Metronidazole is well ab- sorbed via the enteral route; it is also given i.v. or topically (vaginal insert). Because metronidazole is considered potentially mutagenic, carcinogenic, and teratogenic in the human, it should not be used longer than 10 d, if possible, and be avoided during pregnancy and lactation. Timidazole may be considered equivalent to metronidazole. Rifampin inhibits the bacterial en- zyme that catalyzes DNA template-di- rected RNA transcription, i.e., DNA-de- pendent RNA polymerase. Rifampin acts bactericidally against mycobacteria (M. tuberculosis, M. leprae), as well as many gram-positive and gram-negative bac- teria. It is well absorbed after oral inges- tion. Because resistance may develop with frequent usage, it is restricted to the treatment of tuberculosis and lepro- sy (p. 280). Rifampin is contraindicated in the first trimester of gestation and during lactation. Rifabutin resembles rifampin but may be effective in infections resistant to the latter. 274 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 275 Indication: TB Streptomyces species A. Antibacterial drugs acting on DNA RNA Twisting by opening, underwinding, and closure of DNA strand 1 2 3 4 Gyrase Gyrase inhibitors 4-Quinolone- 3-carboxylate- derivates, e. g. DNA-double helix Damage to DNA DNA-dependent RNA polymerase Anaerobic bacteria Nitroimidazole e. g., metronidazole Trichomonas infection Amebic infection Rifampicin Bacterial chromosome ofloxacin Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. [...]... acid tRNA Insertion of incorrect amino acid Aminoglycosides Peptide chain Tobramycin Chloramphenicol Peptide synthetase Chloramphenicol Erythromycin Erythromycin Streptomyces species A Protein synthesis and modes of action of antibacterial drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 278 Antibacterial Drugs Tetracyclines... Flucytosine A Antifungal drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 283 284 Antiviral Drugs Chemotherapy of Viral Infections Viruses essentially consist of genetic material (nucleic acids, green strands in (A) and a capsular envelope made up of proteins (blue hexagons), often with a coat (gray ring) of a phospholipid (PL)... polymerase O O Inhibition of uncoating C O O P O Foscarnet Amantadine O B Inhibitor of DNA polymerase: B Foscarnet C Prophylaxis for viral flu Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 287 288 Antiviral Drugs Drugs for the Treatment of AIDS Replication of the human immunodeficiency virus (HIV), the causative agent of AIDS, is susceptible... induction p-Aminobenzoic acid Dapsone Hemolysis Clofazimine Folate synthesis Mycobacterium leprae Skin discoloration A Drugs used to treat infections with mycobacteria (1 tuberculosis, 2 leprosy) Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 282 Antifungal Drugs Drugs Used in the Treatment of Fungal Infections Infections due to fungi... (ototoxicity, in part irreversible) Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license Antibacterial Drugs Tetracyclines Chloramphenicol Inactivation by chelation of Ca2+, Al3+ etc Advantage: good penetration through barriers Antibacterial effect on gut flora C he la tio n Irritation of mucous membranes Absorption 279 Disadvantage:... required for the eradication of dermatophytes corresponds to the renewal period of skin, hair, or nails Griseofulvin may cause uncharacteristic adverse effects The need for prolonged administration (several months), the incidence of side effects, and the availability of effective and safe alternatives have rendered griseofulvin therapeutically obsolete Lüllmann, Color Atlas of Pharmacology © 2000 Thieme... Transport system Bacterium Nephrotoxicity No absorption "bowel sterilization" A Aspects of the therapeutic use of tetracyclines, chloramphenicol, and aminoglycosides Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 280 Antibacterial Drugs Drugs for Treating Mycobacterial Infections Mycobacteria are responsible for two diseases:... treatment with two or more drugs Combination therapy prevents the emergence of resistant mycobacteria Because the antibacterial effects of the individual substances are additive, correspondingly smaller doses are sufficient Therefore, the risk of individual adverse effects is lowered Most drugs are active against only one of the two diseases Antitubercular Drugs (1) Drugs of choice are: isoniazid, rifampin,... semisynthetic chloro analogue of lincomycin, which derives from a Streptomyces species Taken orally, clindamycin is better absorbed than lincomycin, has greater antibacterial efficacy and is thus preferred Both penetrate well into bone tissue Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license Antibacterial Drugs 277 mRNA Tetracyclines... of severe herpes simplex infection Before the introduction of the better tolerated acyclovir, vidarabine played a major part in the treatment of herpes simplex encephalitis Among virustatic antimetabolites, acyclovir (A) has both specificity of the highest degree and optimal tolerability, Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of . 266 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial. 270 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial