Abstract
Interference of ANTIBACTERIAL AGENTS with immune and inflammatory systems, and the possible clinical implications, has long been a focus of attention worldwide. In particular, toxic effects with immunological implications (neutropenia, ALLERGY, INFLAMMATION, etc.) influence the development and clinical use of these drugs. However, favourable effects are also very important. Possible effects of ANTIBACTERIAL AGENTS on immune and inflammatory systems are shown in Table 29.1 and in sections on individual ANTIBACTERIAL AGENTS.
Final manuscript submitted on October 09, 2018.
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1 Introduction
Interference of ANTIBACTERIAL AGENTS with immune and inflammatory systems, and the possible clinical implications, has long been a focus of attention worldwide. In particular, toxic effects with immunological implications (neutropenia, ALLERGY, INFLAMMATION, etc.) influence the development and clinical use of these drugs. However, favourable effects are also very important. Possible effects of ANTIBACTERIAL AGENTS on immune and inflammatory systems are shown in Table 29.1 and in sections on individual ANTIBACTERIAL AGENTS.
ANTIBACTERIAL AGENTS may interact favourably with immune and inflammatory systems in three ways:
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ANTIBACTERIAL AGENTS stop the growth of, or kill, microorganisms which have initiated an acute excessive and/or chronic immunological or inflammatory state.
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ANTIBACTERIAL AGENTS may modify the actions of antibacterial host cells (MONOCYTES, NEUTROPHILS, etc.), which, together with the ANTIBACTERIAL AGENTS, combine to stop the growth of, or kill, the invading bacteria.
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ANTIBACTERIAL AGENTS may directly affect immune and inflammatory systems and modulate the inflammatory response or correct an immune dysfunction without direct effects on bacteria.
This chapter is concerned mainly with the third possibility with the particular aim of describing ANTIBACTERIAL AGENTS which are or may possibly be useful in the treatment of non-bacteriological immune or inflammatory diseases.
Several classes of ANTIBACTERIAL AGENTS may have activities within the third possibility, most importantly sulphones (dapsone) , macrolides , rifampicin , tetracyclines and their analogues. This chapter places emphasis on the basic pharmacology and clinical uses of these four drug groups in isolation from their mechanisms in causing bacteriostatic or bactericidal actions. Actions of other ANTIBACTERIAL AGENTS with less clear non-antibacterial effects are discussed in lesser detail.
The pharmacological effects of the ANTIBACTERIAL AGENTS have been studied widely both in in vitro and in vivo experimental systems. The results of in vitro studies depend, however, on the cell type, the technique, the cell activation status, the composition of the media and the concentration of the drug. Table 29.1 shows possible pathophysiological functions and mediators which may be inhibited to produce IMMUNOMODULATION or ANTI-INFLAMMATORY effects of ANTIBACTERIAL AGENTS.
In analysing the effects of any drug in vitro, it is important to compare the effective concentrations with the unbound plasma concentrations produced by therapeutic dosage. There are, however, several reasons why these correlations are often imprecise.
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The effects of the drug may be competitive and therefore depend upon the concentration of the agonist or stimulant of the system.
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The drug may be taken up avidly, even covalently, by the cells used in in vitro incubations. Consequently, the inhibitory activity may decrease with increasing cell densities in the in vitro incubations, as was demonstrated with the gold drug, auranofin, which is bound strongly to NEUTROPHILS [1].
In vivo experimental studies are the gold standard, but are subject to multiple pitfalls, such as species differences in the composition and functions of the IMMUNE SYSTEM [2], as well as ethical problems and interindividual variability in absorption, plasma concentrations, tissue distribution, metabolism and excretion. Furthermore, it is important to note that, within a particular group of ANTIBACTERIAL AGENTS, variable effects may be obtained. Thus, drugs within the one group of ANTIBACTERIAL AGENTS may have inconsistent pharmacological effects on mammalian systems. Despite these difficulties, major progress has been made in understanding the immune and ANTI-INFLAMMATORY effects of ANTIBACTERIAL AGENTS. Further, novel uses of these drugs and development of their analogues are potentially clinically important.
An early study suggested that the IMMUNOMODULATORY properties of ANTIBACTERIAL AGENTS could be predicted from their modes of action on microbial cells [3]. However, this hypothesis, in general, has not been confirmed.
There are two notable concerns with all ANTIBACTERIAL AGENTS, which may be used clinically for their non-antibacterial activities, possibly for long periods. The concerns are the possibilities of bacterial resistance and changes in gastrointestinal flora. In particular, many ANTIBACTERIAL AGENTS cause pseudomembranous colitis due to an overgrowth of Clostridium difficile in the colon. Symptoms range from mild diarrhoea to potentially life-threatening.
Some ANTIBACTERIAL AGENTS have been investigated in attempts to develop analogues which are not antibacterial but have retained their IMMUNOMODULATORY or ANTI-INFLAMMATORY actions. In particular, efforts have been made to synthesise macrolides and tetracyclines with ANTI-INFLAMMATORY actions without significant antibacterial actions (see sections on individual drug groups).
2 Aminoglycosides
Aminoglycosides interfere with bacterial protein synthesis by acting on the 30S ribosomal subunit. Although they are considered to be extracellular ANTIBACTERIAL AGENTS, they accumulate slowly in host cells (over days in MACROPHAGES) by fluid-phase pinocytosis.
The aminoglycosides are excreted unchanged to a very large extent, and, consequently, their dosage is reduced in renal impairment in line with their plasma concentrations.
Conflicting data exist on the in vitro inhibitory effect of aminoglycosides (at therapeutic concentrations) on the function of NEUTROPHILS. Inhibition of the respiratory burst is the most common observed effect [4, 5]. Suggested underlying mechanisms include binding to negatively charged membrane phospholipids (leading to membrane disturbances), specific binding to inositol biphosphate (resulting in phospholipase C inhibition) and protein kinase C (PKC) inhibition. Interstingly, amikacin at low concentrations (contrary to other aminoglycosides) enhances the respiratory burst of NEUTROPHILS in vitro,whereas supratherapeutic concentrations (> 1 g/l are inhibitory [5].
Most of the non-bacterial clinical interest in the aminoglycosides has been associated with their effects on congenital muscular dystrophic disease. Several trials on the use of aminoglycosides in cystic fibrosis have given encouraging results [6]. However, the need for pharmacokinetic monitoring to avoid toxicity may limit the possible use of aminoglycosides for long-term treatment of congenital muscular dystrophic disease or inflammatory diseases unless they are shown to be extremely beneficial.
3 Beta-Lactams
Five groups comprise the beta (β)-lactam, namely, penams (penicillins and β-lactamase inhibitors), penems (faropenem), carbapenems (imipenem, meropenem), cephems (cephalosporins, cephamycins, oxa- and carbacephems) and monobactams (aztreonam), all of which bind to various enzymes (penicillin-binding proteins) and the transpeptidase enzyme involved in the synthesis of PEPTIDOGLYCAN backbone which is normally responsible for the strength of bacterial cell walls.
Cefodizime , a cephalosporin, was the subject of worldwide interest in the 1990s and was referred to as an immune response modifier (IRM) antibiotic. Cefodizime showed a greater effect on Enterobacteriaceae infections than that expected from its in vitro antibacterial effects, even more so in immunocompromised animals [7]. Cefodizime demonstrates pleiotropic effects on immune and inflammatory parameters such as enhanced phagocyte function, B LYMPHOCYTE repressiveness and delayed HYPERSENSITIVITY and it may restore phagocytic activity and activity of NATURAL KILLER (NK) cells, as well as IL-1 and IFN-Y production, in immunocompromised patients and animals. Cefodizime also stimulates the proliferative response of LYMPHOCYTES, increases the phagocytic and bactericidal activity of NEUTROPHILS and downregulates the production of INFLAMMATORY CYTOKINES by stimulated MONOCYTES [7,8,9]. Another cephalosporin, cefaclor , is considered to “normalise” the immune and inflammatory systems during bacterial infections and may be useful in the clinical treatment of patients with immune disorders leading to chronic INFLAMMATION [10].
There is now little interest in the IRM activity of cefodizime, but further work on the non-antibacterial effects of cephalosporins and other beta-lactams on host cells is still required.
4 Fluoroquinolones
The fluoroquinolones are synthetic antibacterial drugs whose activity is due to their inhibition of bacterial TOPOISOMERASE II and thus on DNA replication. Mammalian cells also contain an TOPOISOMERASE II, but it is unclear if an interaction with the enzyme is responsible for any of the therapeutic or adverse effects of fluoroquinolones.
The best-known fluoroquinolone is ciprofloxacin (Fig. 29.1) which is eliminated by both excretion of the unchanged drug and metabolism. Its TERMINAL HALF-LIFE is approximately 4 h, and it is usually administered twice daily. Peak concentrations of unbound ciprofloxacin in plasma are approximately 1800 μg/L (5–6 μmol/L).
Structure of ciprofloxacin in the unionised form. Like other fluoroquinolones, ciprofloxacin has both acidic (-COOH) and basic (amino group in the piperazine ring system). Consequently, the major species at physiological pH is the zwitterion with no net charge
To date, fluoroquinolones have not proven beneficial in inflammatory diseases. Interest in the potential immunostimulating properties of some fluoroquinolones is, however, growing. Ciprofloxacin , in combination with other drugs, such as pentoxifylline (a vasodilator), accelerates NEUTROPHIL recovery in breast cancer during or following chemotherapy [11].
4.1 Basic Immunomodulatory and Anti-inflammatory Pharmacology of Fluoroquinolones
It is difficult to categorise the in vitro pharmacological activities of the fluoroquinolones as they have a variety of effects (increase, decrease, no effect) on PHAGOCYTOSIS, adhesion, and respiratory burst of MONOCYTES and NEUTROPHILS. Their effects on the respiratory burst appear to depend on the animal species and the fluoroquinolone structure. High concentrations decrease levels of the INFLAMMATORY cytokines which have been induced by TNF-α in human cell lines (Table 29.2).
Stimulation of some immune or inflammatory systems in vitro has been reported (Table 29.2). These effects are inconsistent with suppression of immune or inflammatory systems. However, the potential value of fluoroquinolones as immune and ANTI-INFLAMMATORY agents is shown by increases in CYTOKINE responses in rats and mice in vivo (Table 29.2). The fluoroquinolones also decrease the severity of models of colitis in mice and rats where they probably have an ANTI-INFLAMMATORY effect in addition to their antibacterial actions. Further work on the IMMUNOMODULATORY and ANTI-INFLAMMATORY effects of this drug group is required.
4.2 Adverse Reactions of Fluoroquinolones
The adverse effects of the fluoroquinolones present a problem for their potential clinical use as non-ANTIBACTERIAL AGENTS. Adverse effects include low incidences of colitis, liver failure, tendon rupture and cardiac arrhythmias, particularly in combination with other drugs which may prolong QT INTERVAL (e.g. some anti-arrhythmics, tricyclic antidepressants and antipsychotic drugs). The Food and Drug Administration of the USA (FDA) recommends that patients should be checked for low blood sugar and adverse mental effects such as disorientation, memory impairment and delirium.
5 Fosfomycin
Fosfomycin (1-cis-1,2-epoxypropylphosphoric acid) (Fig. 29.2) is a broad-spectrum bactericidal antibiotic which interferes with bacterial cell wall biosynthesis by inhibiting pyruvate-uridine-diphosphate-N-acetylglucosamine transferase.
Structure of fosfomycin in the ionised form. Fosfomycin is a strong acid which is present as the anion at physiological pH values. It is available as its sodium and calcium salts and also a salt with an organic base
Fosfomycin is a highly ionised compound at physiological pH values which, not surprisingly, enters bacterial cells by a transporter. The glycerol-3-phosphate transporter in bacteria but its transporter into mammalian cells has not been recorded. It is accumulated twofold by NEUTROPHILS. Its availability is about 50% and has a TERMINAL HALF-LIFE of approximately 10 h which is extended in impairment of kidney function as it is excreted unchanged in urine.
Fosfomycin shows several potential immune and ANTI-INFLAMMATORY effects in in vitro and in vivo systems (Table 29.3). However, following the administration of bacterial LPS to human subjects, fosfomycin did not alter the levels of TNF-α, IL-1β or IL-6 proteins of mRNA [12]. Further work on the immune and ANTI-INFLAMMATORY effects of fosfomycin is required.
6 Fusidic Acid
Fusidic acid is a steroid derivative (Fig. 29.3) which is used mainly as an antistaphylococcal agent which interferes with bacterial biosynthesis of proteins. It has an oral BIOAVAILABILITY of about 50% and a TERMINAL HALF-LIFE of elimination of about 10 h after oral dosage.
Structure of fusidic acid in the ionised form. Fusidic acid is carboxylic acid which is available as its sodium salt
Fusidic acid has several ANTI-INFLAMMATORY effects in mice and rats in vivo, particularly by decreasing the release of TNF (Table 29.4). These effects require further study.
7 Isoniazid
Isoniazid is an antituberculous agent whose antimycobacterial activity has been attributed to its oxidative metabolism by mycobacterial peroxidases. Isoniazid is an irreversible inhibitor of the mammalian enzyme, MYELOPEROXIDASE [13, 14]. Isoniazid therefore decreases the formation of major products, hypochlorous, hypobromous and hypothiocyanous acids of the respiratory burst of NEUTROPHILS. These oxidants are antibacterial but may also cause tissue damage. Isoniazid has, however, not been tested for activity against purely inflammatory diseases in vivo.
8 Lincosamides
Clindamycin (Fig. 29.4) is a semisynthetic antibiotic derived from lincomycin, but clindamycin is now the more widely used drug of this group in modern medical practice. Both antibiotics interact with bacterial protein synthesis at the level of the 50S ribosomal subunit. The nucleoside transport system has been suggested to explain the cellular accumulation of clindamycin (12- to 20-fold). Clindamycin is eliminated by hepatic metabolism with a TERMINAL HALF-LIFE of 2–3 h. Orally, it is generally administered twice daily.
Structure of unionised clindamycin . It is available mainly as the hydrochloride for oral and topical use, while the phosphate ester is included in solution for intravenous use
Clindamycin was presented as a possible IMMUNOMODULATORY DRUG in infection in the early 1980s. However, controversial effects on phagocyte functions (stimulation, inhibition or no action) have been reported with various techniques and drug concentrations. Interest in the ANTI-INFLAMMATORY effects of clindamycin was stimulated by its potential prophylactic effect in LPS-induced septic shock (see Chap. 26), through inhibition of PRO-INFLAMMATORY CYTOKINE release in vitro and in vivo [15]. Interestingly, modulation of CYTOKINE release in vitro is not accompanied by a parallel change in mRNA expression [16]. In dogs infected with Babesia gibsoni, a protozoal parasite which is rare in man, clindamycin does not eliminate the parasite but may stimulate humoral and immune responses to decrease the numbers of the infecting protozoa [17].
The relationship between the therapeutic plasma concentrations of clindamycin and its modulating effect on immunological processes is required for a better understanding of its potential non-antibacterial effects in clinical medicine.
9 Macrolides
Macrolides are widely used antibacterial drugs, which impair bacterial protein synthesis by acting on the 50S bacterial ribosomal subunit. Erythromycin is the original antibiotic in this class.
9.1 Chemistry of Macrolides
Macrolide antibiotics have a 12- to 16-membered ring structure containing a lactone group (internal ester) with substitutions by 2 amino groups and/or neutral sugars (Fig. 29.5). Modern semi-synthetic derivatives of erythromycin , azithromycin , roxithromycin and clarithromycin have been obtained by adding new substituents or by introducing a nitrogen atom into the ring structure. These have antibacterial activity. Extensive derivatisation of the scaffold has also resulted in a number of non-ANTIBACTERIAL macrolides with IMMUNOMODULATORY/ANTI-INFLAMMATORY activities [18].
Structures of macrolide antibiotics in the unionised forms. Erythromycin is available as the unionised form, a salt with stearic acid and an ester with ethyl succinic acid for oral dosage. It is also available as the lactobionate salt for intravenous infusion
9.2 Metabolism and Pharmacokinetics of Macrolides
The macrolides are eliminated primarily by metabolism. The TERMINAL HALF-LIVES are very much dependent upon the macrolide, ranging from approximately 1.6 h (erythromycin), 3.5 h (clarithromycin), 12 h (roxithromycin) to 40 h (azithromycin). The long TERMINAL HALF-LIFE of azithromycin makes it suitable for long-term dosage where it is often administered every second day. The macrolides are taken up by NEUTROPHILS and MACROPHAGES and concentrate, like other cationic drugs, in the lysosomes, making it difficult to compare concentrations in plasma with those in experiments in vitro (see Sect. 29.1). However, this leucocyte accumulation may act to deliver macrolides to sites of INFLAMMATION and infection.
Erythromycin is unstable in the stomach and is administered orally in two forms: either the base form in ENTERIC-COATED tablets or as the ester form with ethyl succinic acid. The latter form is hydrolysed after absorption from the gastrointestinal tract.
9.3 Basic Immune and Anti-inflammatory Pharmacology of Macrolides
The macrolides have several cellular effects both in vitro and in vivo (Table 29.5). These pleiotropic effects indicate that there are several cellular targets of their actions. Among the cellular mechanisms of action, inhibition of MAP kinase/ERK pathway and consequent suppression of transcription factor activation have been suggested. Furthermore, the pharmacological effects of the individual macrolides often vary between the various members of drug class. A non-antibacterial analogue of erythromycin (EM703) has potential ANTI-INFLAMMATORY actions which are indicated by its inhibition of the respiratory burst of NEUTROPHILS (Table 29.5).
9.4 Immune and Anti-inflammatory Clinical Effects of Macrolides
Macrolides display IMMUNOMODULATORY properties that may confer beneficial effects on patients with respiratory diseases associated with chronic INFLAMMATION. The macrolides attenuate inflammatory responses in the lung, regulate mucus production and decrease bronchial responsiveness. Panbronchiolitis and cystic fibrosis are the two main clinical indications for macrolide action, but their use in other respiratory diseases is being investigated. Most clinical research has been centred on azithromycin .
9.4.1 Diffuse Panbronchiolitis
Diffuse panbronchiolitis is a potentially fatal disease which is an inflammatory disease of bronchioles. It is found most commonly in patients of Asian descent. Erythromycin or azithromycin is recommended widely for the treatment of diffuse panbronchiolitis, with azithromycin favoured because of its long TERMINAL HALF-LIFE. Dosage is once daily to once every 2 or 3 days [19, 20].
9.4.2 Cystic Fibrosis (CF)
There is fair evidence for the long-term use of azithromycin in the treatment of cystic fibrosis in patients with and without infection with Pseudomonas aeruginosa [19,20,21,22]. However, the EFFICACY often decreases markedly after treatment for 1 year with no significant effect after treatment for 3 years. Nevertheless, azithromycin is recommended by the Cystic Fibrosis Foundation for patients who are more than 6 years old [23]. Non-cystic fibrosis bronchiectasis is also treated usefully by azithromycin [23].
9.4.3 Asthma
A recent conclusion is that macrolides do not have significant activity in the treatment of acute or chronic ASTHMA [24, 25], although, possible benefits of macrolides in patients with non-eosinophilic asthma was noted in two studies [26]. This finding requires further study.
9.4.4 Chronic Obstructive Pulmonary Disease (COPD)
COPD is a major chronic disease. Azithromycin decreases the frequency of acute exacerbations even in patients with optimal treatment with bronchodilators [23] (see also Chap. 23).
9.4.5 Bronchiolitis Obliterans Syndrome (BOS)
BOS is major problem after lung transplantation. Some, but not all patients, respond with an improvement in FEV1 during treatment with azithromycin (250 mg every second day) [27, 28].
9.5 Adverse Effects of Macrolides
The macrolides are generally well t olerated although gastrointestinal adverse effects, such as discomfort, nausea, etc., are well known and often lead to cessation of their use. The cardiovascular effects of the macrolides are of considerable interest. Prolongation of the QT INTERVAL is of concern, but patients’ underlying cardiac pathophysiology makes it difficult to make definite conclusions about cardiac adverse effects [23]. Nevertheless, they should be taken with care by patients with a history of arrhythmias or taking antiarrhythmic drugs. Because of their antibiotic activities, overgrowth with Clostridium difficile is possible, and patients with severe diarrhoea should be examined carefully.
10 Rifampicin and Related Drugs
Rifampicin (rifampin) is a member of the ansamycin group of macrocyclic antibiotics. Rifampicin is a major antibiotic for the treatment of tuberculosis, while rifaximin is used for INFLAMMATORY BOWEL DISEASES and travellers’ diarrhoea which is not due to species of Campylobacter, Salmonella or Shigella. Rifampicin and the related antibiotics bind to the DNA-dependent RNA polymerase and, thereby, inhibit RNA synthesis and bacterial proliferation.
10.1 Chemistry of Rifampicin and Analogues
Rifampicin and rifaximin are ZWITTERIONS at physiological pH values (Fig. 29.6). Several crystal forms of rifaximin exist. These have different absorption characteristics after oral administration (see below).
Structures of rifampicin (upper) and rifaximin (lower) in the ZWITTERION forms at physiological pH values. Several ZWITTERION forms of rifaximin may exist and one such form is shown
10.2 Metabolism and Pharmacokinetics of Rifampicin and Analogues
Rifampicin and rifaximin are incompletely absorbed after oral dosage, in part, due to their ionised ZWITTERION structures (Fig. 29.6). The absorption of rifaximin is reduced further due its slow dissolution. The alpha-crystalline form is less soluble than that of other crystalline forms, and, in order to achieve maximal availability in the colon, the alpha form is probably the optimal form for the treatment of ulcerative colitis [29]. The TERMINAL HALF-LIFE of rifampicin is approximately 4 h.
10.3 Basic Immune and Anti-inflammatory Pharmacology of Rifampicin and Analogues
Rifampicin has potential anti-inflammatory and immunological effects because of its activity in several cellular systems in vitro (Table 29.6). Some effects, such as inhibition of chemotaxis and PHAGOCYTOSIS, are produced in vitro at therapeutic unbound concentrations in plasma. However, several other effects are produced well above therapeutic concentrations in plasma (Table 29.6), and, consequently, some of their clinical relevance is often discounted but cannot be rejected totally at this stage.
The ability of rifampicin to increase the serum levels of IL-10 (Table 29.6) indicates a potential mechanism increased immunosuppressant or ANTI-INFLAMMATORY effects as this CYTOKINE is considered to have ANTI-INFLAMMATORY actions by several mechanisms including the suppression of LPS-induced secretion of PRO-INFLAMMATORY CYTOKINES.
Apart from its direct antibacterial activity, several mechanisms have been suggested for the ANTI-INFLAMMATORY or immunosuppressive actions of rifaximin on the gastrointestinal tract (Table 29.6) [30, 31]. An important mode of action of rifampicin and rifaximin is the activation of pregnane X receptor, which is a nuclear receptor and transcription factor that regulates INFLAMMATION (Table 29.6) [31].
10.4 Immune and Anti-inflammatory Clinical Effects of Rifampicin and Analogues
10.4.1 Rheumatoid Arthritis
The first trials of rifampicin in early disease showed a possible improvement in RHEUMATOID ARTHRITIS, but later studies showed no improvement [32,33,34]. Intraarticular injection of rifampicin has been tested but did not improve response to intraarticular CORTICOSTEROID alone [35]. Further studies have not been considered worthwhile because of adverse effects, doubtful clinical effects and weak effects in vitro. The improved modern treatments of RHEUMATOID ARTHRITIS with METHOTREXATE and BIOLOGICALS also have decreased interest in the possible anti-antirheumatic actions of rifampicin (see Chap. 34).
10.4.2 Crohn’s Disease and Ulcerative Colitis
Rifaximin is beneficial in the treatment of CROHN’S DISEASE and ulcerative colitis although possibly not as effective as other drugs [30, 31, 36] (see Chap. 35). Rifaximin may, however, be useful in combination with other drugs.
10.5 Adverse Effects of Rifampicin and Analogues
Liver dysfunction may be produced by rifampicin and should be checked routinely. The severe syndrome drug reaction with eosinophilia and systemic symptom (DRESS) has also been reported.
10.6 Drug Interactions of Rifampicin and Analogues
Rifampicin and rifaximin induce the metabolism of drugs by cytochrome P450 3A4 and several cytochrome P450 Cs and transport by P-glycoprotein [37]. The result is that the plasma concentrations of many other drugs are greatly reduced by concurrent dosage with rifampicin and rifaximin. It is strongly advised to check for interactions with any drugs that are taken with rifampicin or rifaximin. Induction of the metabolism of dapsone has been reported (see Sect. 29.11 below).
11 Sulphones/Sulphonamides
The major sulphone drug is dapsone (4,4′ diaminophenyl sulphone) (Fig. 29.7) which was initially developed as an antitubercular drug. It was tested in leprosy in the early 1950s and is still a part of drug combinations used in this disease. Apart from its use in leprosy, dapsone is administered orally for several cutaneous diseases, particularly dermatitis herpetiformis [38]. Dapsone is also applied locally for the treatment of acne vulgaris because of its antibacterial and ANTI-INFLAMMATORY actions.
Structures and metabolism of dapsone and sulfapyridine. Sulfapyridine is a metabolite of sulfasalazine. Both dapsone and sulfapyridine are metabolised to reactive hydroxylamine derivatives and also by acetylation, as shown
The immunosuppressive and ANTI-INFLAMMATORY activities of two groups, sulphones and sulphonamides, are discussed together in this section because of their similar basic and clinical pharmacological properties. SULFAPYRIDNE is no longer used as an antibacterial agent, but it is still of research and clinical interest as it is the major metabolite of SULFASALAZINE , a widely used drug for RHEUMATOID ARTHRITIS and ulcerative colitis (Fig. 29.7) (see Chap. 34).
11.1 Metabolism and Pharmacokinetics of Dapsone and Sulfapyridine
The TERMINAL HALF-LIFE OF ELIMINATION of dapsone is about 30 h but is very variable. As a result, dapsone is usually administered once daily, sometimes twice daily. Dapsone is an amino compound which is both acetylated and also oxidised by cytochrome P450 enzymes. Resulting from its two major modes of elimination, the half-life is longer in genetic slow acetylators, while its oxidative metabolism is induced by rifampicin with which it may be administered. SULFAPYRIDNE has a half-life of approximately 14 h in slow acetylators but about 6 h in fast acetylators.
11.2 Basic Immune and Anti-inflammatory Pharmacology of Dapsone and Sulphonamides
The antibacterial activities of dapsone and the sulphonamides are due to inhibition of dihydropteroate synthase.
The ANTI-INFLAMMATORY activity of dapsone is indicated by several in vitro and in vivo findings (Table 29.7). The activity of dapsone in rats with implants of carrageenan and cotton pellets is notable because inhibition of INFLAMMATION caused by these treatments is characteristic of the (aspirin-like) non- steroidal ANTI-INFLAMMATORY drugs (see Chap. 33).
There is considerable interest in the ANTI-INFLAMMATORY pharmacology of sulphonamides because the well-known drug, SULFASALAZINE, is metabolised to aminosalicylate and SULFAPYRIDNE (see Chap. 34). Both metabolites are active in the treatment of RHEUMATOID ARTHRITIS, but only the parent, SULFASALAZINE, is used clinically [39]. Like dapsone, SULFAPYRIDNE is active in the treatment of neutrophilic diseases [38]. In particular, SULFAPYRIDNE and dapsone are active in many patients with ocular cicatricial pemphigoid [40].
The antirheumatic activity of SULFAPYRIDNE and some other sulphonamides is backed up by limited experimental pharmacology (Table 29.8). Like dapsone, sulfamethizole decreases the INFLAMMATION caused by carrageenan and cotton pellets (Table 29.8). SULFAPYRIDNE reacts readily with (scavenges) hydroxyl radicals which can be derived from superoxide which is formed in turn from superoxide from the oxidative burst of NEUTROPHILS and MONOCYTES (Table 29.8). Hydroxyl radicals react readily with biological molecules, and it is doubtful that scavenging could lead to a selective action of SULFAPYRIDNE.
11.3 Adverse Effects of Dapsone and Sulfapyridine
The major adverse effects of dapsone and SULFAPYRIDNE are haemolysis and methemoglobinuria. AGRANULOYTOSIS and skin rashes also occur but are uncommon. The adverse effects of both drugs are probably derived from reactive metabolites, particularly the hydroxylamine derivatives which may be cytotoxic [41] (Fig. 29.7). These are formed by oxidation of the amino groups of both dapsone and SULFAPYRIDNE, by MYELOPEROXIDASE and cytochrome P450 enzymes. Alternatively, the reactive metabolites could induce the production of antibodies that could cause the destruction of NEUTROPHIL precursors. In skin, the target cells may be keratinocytes which subsequently activate DENDRITIC CELLS and initiate an immune response within the skin [42].
12 Tetracyclines and Related Drugs
The tetracyclines are a group of widely used broad-spectrum antibiotics including minocycline, doxycycline and an individual antibiotic which is termed tetracycline. The tetracyclines interfere with bacterial protein synthesis, by acting on the 30S ribosomal subunit. The tetracyclines have multiple ANTI-INFLAMMATORY and IMMUNOMODULATORY effects which may make them useful in several chronic non-antibacterial diseases.
The tetracycline molecule has been chemically modified in multiple ways, generating second series of semisynthetic tetracyclines (e.g. doxycycline and minocycline) which have both antibiotic and ANTI-INFLAMMATORY properties. A new family of compounds called chemically modified tetracyclines (CMTs) lack antimicrobial activity but have retained some ANTI-INFLAMMATORY actions.
12.1 Chemistry of Tetracyclines
The tetracyclines are organic bases with pKa values of about 8 and are, therefore, largely present as the cationic (ionised forms) in blood. They are usually administered as their hydrochloride salts (Fig. 29.8). Many chemical analogues of the tetracyclines have been synthesised. The best known is CMT-3 which is a neutral unionised compound (Fig. 29.8).
Structures of tetracycline, minocycline and tigecycline in their ionised forms. CMT-3 is a non-antibacterial analogue which is not ionisable
12.2 Metabolism and Pharmacokinetics of Tetracyclines
The tetracyclines are well absorbed and have similar ranges of TERMINAL HALF-LIVES but different modes of elimination (Table 29.9). The dosage of tetracycline and doxycycline should be reduced in renal impairment because of their significant renal excretion. CMT-3 has a long TERMINAL HALF-LIFE (about 57 h) which allows dosage every day or every second day [43].
The tetracyclines are taken up by NEUTROPHILS by saturable, sodium-dependent transport [44]. The observed cellular/extracellular concentration ratios are greater than 60 for minocycline and >7 for doxycycline.
12.3 Basic Immune and Anti-inflammatory Pharmacology of Tetracyclines
There are two aspects of the activity of tetracyclines in pharmacological systems in vitro: inhibition of the respiratory burst and suppression of the release of INFLAMMATORY MEDIATORS by NEUTROPHILS. Many reports show the inhibitory action of tetracyclines on various phagocyte functions in vitro (Table 29.10). The production of REACTIVE OXYGEN SPECIES is apparently reduced, but the underlying mechanisms may include chelation of Ca2+ or Mg2+ or Zn2+ and scavenging of reactive products of the respiratory burst of NEUTROPHILS. These chelating actions make it very difficult to correlate therapeutic plasma concentrations with the concentrations in the in vitro experiments. Furthermore, tetracyclines are oxidisable by hypochlorous acid, potentially making the inhibition dependent upon the molecular ratio of concentrations of tetracycline to the yield of hypochlorous acid.
The tetracyclines inhibit metalloproteinases, particularly the matrix metalloproteinases which breakdown several INFLAMMATORY CYTOKINES and many proteins in the intracellular matrix. Matrix metalloproteinases also convert several factors, such as vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β), into their active forms. Overall, inhibition of matrix metalloproteinases may be responsible for much of the ANTI-INFLAMMATORY activity of tetracyclines.
The anti-oxidative actions of the tetracyclines indicate their potential use in the treatment of inflammatory states. Tetracyclines also inhibit several inflammatory diseases in mice and other experimental animals [10]. Treatment of these experimental conditions is consistent with their value in several chronic diseases in people.
12.4 Immune and Anti-inflammatory Clinical Effects of Tetracyclines
The tetracyclines have been tested in several inflammatory disease states, while CMT-3 may have activity in Kaposi’s sarcoma but not in other sarcomas.
12.4.1 Rheumatoid Arthritis
Minocycline and doxycycline relieve the symptoms of RHEUMATOID ARTHRITIS with a better response seen in early-onset seropositive disease. A meta-analysis of ten studies indicates the activity of tetracyclines [45]. Two studies lasted 48 weeks but showed no significant reduction in erosions or joint space narrowing. Treatment of this disease by these tetracyclines is uncommon. Furthermore, alternative antirheumatic drugs are available (see Chap. 34), and it is unlikely that the tetracyclines will achieve widespread use in RHEUMATOID ARTHRITIS.
12.4.2 Osteoarthritis
Osteoarthritis may have an inflammatory component. Doxycycline slows the progression of osteoarthritis to a small degree, but there is no reduction in pain or disability [46, 47]. However, some patients may respond to a greater degree than others.
12.4.3 Dermatological Diseases
The tetracyclines are useful in treating inflammatory lesions of rosacea and acne such as erythema, papules, pustules and blepharitis but not sebaceous changes that do not appear to be inflammatory [48, 49]. Doses of doxycycline that are low (typically 20 mg twice daily) and considered insufficient for antibacterial activity appear active in the treatment of rosacea and acne. Several other uncommon dermatological diseases have also responded to tetracyclines. These include blistering disorders, chronic wounds (inability of wounds to heal) and GRANULOCYTE disorders (including sarcoidosis) [48, 49].
12.4.4 Periodontal Disease
Low-dose doxycycline is approved for treatment of periodontitis (pyorrhoea), a disease in which there is excessive INFLAMMATION due to bacteria adhering to the teeth [48].
12.4.5 Asthma
Minocycline lessens symptoms of ASTHMA and allows reduction in the dose of CORTICOSTEROIDS [50] (see also Chap. 23). Serum concentrations of IMMUNOGLOBULIN E decrease during treatment with minocycline without effects on immunoglobulins A, G and M.
12.5 Adverse Effects of Tetracyclines
The use of tetracyclines has been limited because of concerns about the development of resistant organisms resulting from their antibiotic activity. This is not a problem with the nonantibiotic CMTs which appear to have lesser adverse effects although a small proportion of patients have developed a lupus-like syndrome.
A variety of adverse effects have been associated with treatment by tetracyclines:
-
Continued therapy for more than 2 years is associated with hyperpigmentation of skin and nails in 10–20% of patients and may take a year to resolve.
-
Up to age of about 8 years, the tetracyclines may cause discolouration of teeth and hypoplasia of dental enamel, and their use should be avoided.
-
Tetracyclines cause discolouration of babies’ teeth following administration in the second half of pregnancy, and their use should be avoided at this time.
-
Tetracyclines may depress prothrombin activity, and the dosage of warfarin should be decreased accordingly.
-
Capsules of tetracyclines have caused ulceration of the oesophagus due to their retention in the oesophagus. They should be taken with milk or food to prevent this.
-
The tetracyclines may cause supersensitivity to ultraviolet light (excessive sunburn). This adverse effect is also seen with some CMTs.
-
Minocycline is associated with autoimmune reactions, a lupus-like syndrome and hepatitis, which are not shown by other tetracyclines. This tetracycline is metabolised by hepatic cytochrome P450 systems and the NEUTROPHIL enzyme, MYELOPEROXIDASE, to reactive products which may cause adverse effects specific to minocycline [51]. Appropriate monitoring is therefore indicated in patients early in polyarthritis when diagnostic uncertainty may still exist.
12.6 Drug Interactions of Tetracyclines
-
The absorption of tetracyclines is reduced by complexation with iron salts and by both calcium and bismuth antacids. The combinations should be avoided. Alternatively, a 3 h delay between the administration of the tetracycline and the interacting compounds should decrease the extent of the interactions.
-
The EFFICACY of oral anticoagulants (warfarin) may be increased, and oral contraceptives may become ineffective, both interactions occurring because of changes in the gut flora due to the antibiotic activities of the tetracyclines.
13 Tigecycline
Tigecycline is the first clinically available drug in a new class of antibiotics termed the glycylcyclines. Structurally, it is tetracycline with a central four-ring carbocyclic skeleton and is closely related to minocycline (Fig. 29.8).
Tigecycline has actions both in vitro and in vivo which indicate modulation of immunological and inflammatory processes. Both inhibition and activation have been reported (Table 29.11). As yet, tigecycline has not been tested for immunological or inflammatory diseases in people.
14 Conclusions and Future Research
It is now widely acknowledged that in addition to their antibacterial activity, several ANTIBACTERIAL AGENTS display IMMUNOMODULATORY and ANTI-INFLAMMATORY properties with potential therapeutic importance. Modulation of immune functions is presently a major focus of attention, particularly in inflammatory diseases and cancer. In particular, sulphones (dapsone), tetracyclines, macrolides and rifampicin and their analogues show inhibitory activity towards several initiators of the inflammatory cascade, as well as to mediators of tissue damage. However, lengthy administration and absence of selectivity of these antimicrobial immunomodulators can lead to the induction of microbial resistance. As a result, intensive research is ongoing, to identify IMMUNOMODULATORY antibiotic derivatives which are devoid of antibacterial activity, most notably with tetracycline and macrolide derivatives.
Finally, recent discoveries related to the role that MICROBIOTA plays, both in health and disease, may shed new light on possible ways in which ANTIBACTERIAL AGENTS can influence numerous pathological conditions.
Selected Readings
Garrido-Mesa N, Zarzuelo A, Galvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169(2):337–52.
Parnham MJ, Haber Erakovic V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014;143(2):225–45.
Rothstein DM. Rifamycins, alone and in combination. Cold Spring Harbor Perspect Med. 2016;6(7):a027011.
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This is an update of the chapter from the third edition, written by Marie-Therese Labro, who died in 2016.
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Bosnar, M., Haber, V.E., Graham, G.G. (2019). Influence of Antibacterial Drugs on Immune and Inflammatory Systems. In: Parnham, M., Nijkamp, F., Rossi, A. (eds) Nijkamp and Parnham's Principles of Immunopharmacology. Springer, Cham. https://doi.org/10.1007/978-3-030-10811-3_29
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DOI: https://doi.org/10.1007/978-3-030-10811-3_29
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