Can Betalactam Antibiotics Be Used to Treat Tuberculosis - Essay Example

CAN BETALACTAM ANTIBIOTICS BE USED TO TREAT TUBERCULOSIS TABLE OF CONTENTS 2. The beta lactam antibiotics a. b. Classification c. Mode of action 3. The challenge of tuberculosis treatment 4. Review of the Literature a. Mechanistic and genetic studies b. Susceptibility studies 5. Discussion a. Why the beta-lactams have not been used in tuberculosis treatment b. Taking a second look: a case for the use of beta-lactam drugs in tuberculosis management c. A rational approach to the use of beta-lactams in tuberculosis management 6. Conclusion Abstract Beta-lactam antibiotics are a widely utilised class of antibiotics in clinical treatment. However, they have not been associated with the treatment of tuberculosis. The reasons for this situation are examined, as well as the recent advances in research which point to the potential utility of these antibiotics in the tuberculosis treatment, especially in cases of multidrug-resistant tuberculosis. They are mainly to be thought of as agents which would find great potential as second line components of a multidrug treatment regimen, given in tandem with first line antitubercular drugs. They are expected to work best when administered in the early phase of treatment, and should typically be used in conjunction with beta-lactamase inhibitors. This review addresses the feasibility of utilizing members of the beta-lactam group of antibiotics in the management of tuberculosis. The first part provides an introduction into the beta-lactam antibiotics as a group, their distinguishing features, their classification, their spectrum of activity, and their mechanism of antibacterial action. Next follows a brief overview of tuberculosis as a disease which poses a peculiar challenge with drug therapy. The literature review section features an extensive overview of current research publications addressing various angles of the question of utilizing beta-lactam antibiotics in tuberculosis treatment, including results from in vitro as well as in vivo testing, clinical trials, and comments from reviewers. Finally, an appraisal of the available information is done, drawing out answers to the questions of why the beta-lactams have not been used in tuberculosis treatment, what are the issues involved, how they may be used to treat tuberculosis, what conclusions may be drawn from the literature information available, and the place of combination therapy in facilitating the utility of the beta-lactams in tuberculosis therapy. The Beta-Lactam Antibiotics Description Beta-lactam antibiotics refer to a broad class of antimicrobials which possess in their chemical structure a beta-lactam ring moeity. The beta-lactam moiety (also known as a penam or azetidin-2-one) is a heterocyclic four-membered ring containing a nitrogen atom and a carbonyl group, and is essential for their antibiotic activity (Nayler, 1971). Beta-lactam antibiotics include the penicillins, cephalosporins, carbapenems, monobactams and the beta-lactamase inhibitors, which together constitute the most widely prescribed group of antibiotics in existence. They are favoured in clinical practice over other antibiotics because of their safety profile (low toxicity), wide therapeutic index, relatively affordable cost, low potential for adverse drug interactions, and broad spectrum of action. Classification Beta-lactam antibiotics can be broadly classified into four broad subgroups: penicillins, cephalosporins carbapenems (or penems) monobactams beta-lactamase inhibitors Penicillins. These are the first beta-lactam antibiotics to be discovered and introduced into clinical use. They possess a thiazolidine ring fused with a beta-lactam ring.with different acylamino side chains at C6. The differences between these side chains account for the varying properties of each subclass of penicillins. Benzylpenicillin (penicillin G) is the prototype member, with a narrow spectrum and no oral activity. Phenoxymethylpenicillin (penicillin V) is orally active but also possesses a narrow spectrum of activity. Semisynthetic derivatives of penicillins have been made by modifying the acylamino side chains, resulting in broadening of spectrum, increased oral bioavailability and penicillinase resistance. Variants that are good at penicillinase resistance include cloxacillin, methicillin, flucloxacillin and nafcillin. Ampicillin and amoxicillin have a moderately broad spectrum, and very good oral activity. Members with good gram-negative activity include piperacillin, ticarcillin, carbenicillin, and azlocillin. Some of these have been found to be active against strains of Pseudomonas aeruginosa (Rossi, 2006). There are also combinations of penicillins with beta-lactamase inhibitors, which will be discussed later under the beta-lactamase inhibitors. Cephalosporins. In this group, a dihydrothiazine ring replaces the thiazolidine ring found in the penicillins Depending on the time they were developed and the degree of sophistication in terms of spectrum of activity and their robustness in the presence of beta-lactamases, they are classified into generations (first, second, third, and fourth generation cephalosporins). Successive generations reflect gradual improvements in spectrum of activity, bioavailability, and beta-lactamase resistance. First-generation cephalosporins: These were the earliest cephalosporins to be introduced into clinical use. They have a moderate spectrum of action, which extends to some penicillinase-producing bacteria, streptococci, but not Pseudomonas or enterococci. Members of this class include cephalexin, cefalotin, ceftezole, cefacetrile, cefadroxil, cefalonium and cefradine (Rossi, 2006). Second-generation cephalosporins The introduction of this subclass featured molecular analogues with increased activity against Gram-negative organisms, in addition to their Gram-positive activity, as well as higher beta-lactamase resistance. Examples of second generation cephalosporins include cefprozil, cefamandole, cefuroxime, cefaclor and cefotiam. Some of them, like cefamandole and cefotiam, also possess activity against anaerobic organisms. Cephem antibiotics which fall under this category include the cephamycins cefoxitin, cefmetazole and cefotetan, as well as the carbacephem loracarbef (Rossi, 2006). Third-generation cephalosporins The third-generation cephalosporins go a notch higher than the older cephalosporins in respect of Gram-negative activity and antimicrobial spectrum. Some of them have a high degree of activity against Pseudomonas aeruginosa, and are of utility in treating nosocomial infections. Examples of members in the class are cefotaxime, ceftriaxone, cefixime, cefmenoxime, ceftizoxime, and cefpodoxime. Members which are active against Pseudomonas include ceftazidime, cefsulodin, and cefpiramide. Moxalactam, an oxacephem-type cephem is also grouped with third-generation cephalosporin antibiotics. Fourth-generation cephalosporins These cephalosporins have been developed with a view to achieving a very broad spectrum by combining strong Gram-positive activity and Gram-negative efficacy with reinforced beta-lactamase resistance. Examples include cefepime, cefipirome, cefquinome, cefoselis and cefclidin. Because of their non-polar chemical properties, they can cross the cerebrospinal diffusional barrier and are hence of utility in the treatment of cerebrospinal meningitis. The oxacephem flomoxef is also regarded as a fourth generation cephalosporin (Rossi, 2006). Unclassified cephalosporins A number of newer cephems are yet to be unequivocally grouped into a defined generation. Examples of such molecules are cefoxazole, ceftobiprole, cefsumide, cefcanel, cefaloram, cefrotil, ceftioxide and cefovecin (Rossi, 2006). Carbapenems. These beta-lactam antibiotics are highly resistant to beta-lactamase and have very broad spectrum (Dalhoff et al., 2006). However, they are poorly available orally and are more suitable for parenteral administration, hence limiting their use to resistant infections encountered in hospitalised patients. Members of drugs in the class include imipenem, faropenem, ertapenem and doripenem (Amyes, 2003; Burkhardt et al., 2007; Hadley et al., 2006; Hamilton-Miller, 2003; Keating & Perry, 2005). Monobactams. This beta-lactam class has structural peculiarity of the absence of a fused ring attached to the beta-lactam ring. The prototype member is aztreonam. The chemical structure makes it unlikely for cross-sensitivity to occur between it and other beta-lactam antibiotics (Martin & Kaye, 2004). Beta-lactamase inhibitors. These are not primarily antimicrobial in themselves, but they enhance the activity of beta-lactam antibiotics when given in combination by inactivating beta-lactamase, thus potentiating the efficacy of the primary antibiotic. Examples include: clavulanic acid (co-administered with amoxicillin), sulbactam (co-administered with ampicillin) and tazobactam (co-administered with piperacillin) (Buynak, 2004). Mode of Action Beta-lactam antibiotics act by disrupting the integrity of bacterial cell walls. This is achieved by inhibiting the synthesis of the peptidoglycan layer of the cell walls. The peptidoglycan layer is a network polymeric material containing amino acids and two amino sugars alternating in sequance: N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). The crosslinking of these amino sugars and the amino acids result in an elaborate structure which is responsible for the great strength of bacterial cell walls, especially in Gram-positive bacteria. In the formation of the peptidoglycan layer, the last step is a polymeric crosslinking of peptides which is achieved by carboxypeptidases and transpeptidases known as penicillin binding proteins (PBPs). Penicillin binding proteins are activated by D-alanyl-D-alanine which is the terminal amino acid residue on the precursor peptide subunits of the peptidoglycan layer. Because D-alanyl-D-alanine is structurally analogous to the beta-lactam nucleus of the beta-lactam antibiotics, the antibiotic molecule binds in an acylation reaction to the Ser403 residue of the penicillin binding protein active site. This inhibits the penicillin binding proteins in an irreversible manner from catalyzing the terminal crosslinking of the peptidoglycan layer, and hence cell wall synthesis is aborted. It has also been suggested that penicillin binding protein inhibition may cause autolytic enzymes in the cell wall to be activated (Babic et al., 2006). By virtue of this mechanism, beta-lactam antibiotics are more active against Gram-positive than Gram-negative organisms (the latter not having a lot of peptidoglycan in the cell wall), and they are only active against actively dividing bacteria, as opposed to bacteria in the resting phase, as compromised cell wall integrity will cause the dividing bacteria to burst in hypotonic surroundings. The Challenge of Tuberculosis Treatment Tuberculosis is a deadly infectious disease which affects millions worldwide, both adult and children (Smith, 2001). It is caused by two mycobacteria: Mycobacterium tuberculosis and (to a lesser extent) Mycobacterium bovis (T. R. Frieden et al., 2003). Most commonly, it manifests as a pulmonary infection although in some cases it affects other organ systems in the body including the nervous system, the circulatory system, the skeletal system and the genitourinary system (Bukhary & Alrajhi, 2004; Peloquin & Berning, 1994). It is a leading cause of death, especially in developing countries (Schluger, 1996). It has been estimated that in 2005 alone, there were 1.6 million deaths from tuberculosis (World Health Organization, 2006), mostly from the African continent, in terms of total number of deaths as well as the mortality per capita. It is a rapidly spreading disease, with about 9 million new cases being diagnosed each year (Frieden, Sterling, Munsiff, Watt, & Dye, 2003). As of 2005, the highest number of new cases (34% of the global total) are reported to be occurring in South-East Asia (World Health Organization, 2006). According to the World Health Organization, there is a new infection of the tubercle bacilli ever second, and currently, one-third of the world's population is infected with the tubercle bacilli, although only about 5-10% of infected people go on to developing full-blown disease, particularly those who have compromised immune status (World Health Organization, 2006) It has been acknowledged to be one of the most difficult diseases to treat because of the rapid development of resistance by the tubercle bacteria to antibiotics, even when used in multidrug treatment regimens i.e. multidrug-resistant tuberculosis (MDR-TB) (M. Casal et al., 2005; Thomas R. Frieden et al., 2003). Among the antibiotics used to treat tuberculosis are rifampin and its analogues (rifabutin, rifapentin), isoniazid, pyrazinamide, streptomycin, ethambutol and the fluoroquinolones (Di Perri & Bonora, 2004). Review of the Literature Several researchers have published findings regarding in vitro and in vivo experiments which provide useful information on the issues surrounding the potential utility of beta-lactam drugs in antitubercular therapy. These studies address a wide range of questions, ranging from the mode of resistance of Mycobacteria to beta-lactams, the molecular classification of beta-lactamases, to the susceptibility of the tubercle bacilli to selected beta-lactam agents and beta-lactamase inhibitors, both as monotherapy and combination therapy. Mechanistic and Genetic Studies The beta-lactamases of M. tuberculosis have been found to consist of class A beta-lactamases with predominant penicillinase activity and moderate cephalosporinase activity (Voladri et al., 1998). In a 2002 genetic study, the product of ponA, a gene in cosmid MTCY21D4 of the Mycobacterium tuberculosis genome was isolated as a soluble derivative and named the penicillin-binding protein 1* (PBP1*) (Bhakta & Basu, 2002). A recombinant version was found to bind penicillin G as well as other beta-lactams (especially the third generation cephalosporin cefotaxime) whith a very high degree of affinity. A more recent study confirmed that the penicillin binding protein A of Mycobacterium tuberculosis binds benzylpenicillin effectively (Dasgupta, Datta, Kundu, & Basu, 2006). It has been suggested that the beta-lactamase inhibitor is essential for the inactivation of mycobacterium beta-lactamase so that the bacterial cell wall can be penetrated (Kwon, Tomioka, & Saito, 1995). This was further investigated and confirmed in other studies (Segura, Salvado, Collado, Chaves, & Coira, 1998). A study of the beta-lactamase in mycobacteria (Kwon et al., 1995) has demonstrated the peculiarity of beta-lactamases in these organisms that pose a peculiar challenge to the utility of beta-lactam antibiotics in tuberculosis treatment. Mycobacterium tuberculosis beta-lactamases possessed strong penicillinase and cephalosporinase activity both in the slow-growth and rapid-growth phases, no dependency on metal ions, along with peculiar isoelectric focusing patterns. In a mechanism-based study (H. F. Chambers et al., 1995), the roles of penicillin binding proteins and membrane penetration were investigated in the development of mycobacterial resistance to beta-lactam antibiotics. It was demonstrated that the penicillin binding proteins are the major target of mycobacterial beta-lactamases, and when the beta-lactamases were circumvented by the use of beta-lactamase inhibitors or beta-lactamase-stable drugs, beta-lactam antibiotics were found to be effectively antimycobacterial at therapeutic concentrations. In a recent innovative crystallographic and genetic study (Wang, Cassidy, & Sacchettini, 2006), the BlaC gene responsible for coding the beta-lactamase of M. tuberculosis was structurally characterised. Deletion of the gene resulted in susceptibility of the organism to beta-lactam antibiotics, and so did inhibition of the enzymatic product. The crystal structure of the enzyme bore resemblances to class A beta-lactamase, but had some differences which seem to account for the broad specificity of the enzyme and resistance to clavulanate (which is a usually effective mechanism-based inhibitor of class A beta-lactamase). A recent genetic study (Saint-Joanis et al., 2006) demonstrated that the inactivation of Rv2525c, a substrate of the Twin Arginine Translocation (Tat) system of M. tuberculosis increases its susceptibility to some beta-lactam antibiotics as well as its virulence. The clinical implications of this finding are yet to be fully elucidated however. Also, MspA porin has been found to be crucial to increasing beta-lactam antibiotic susceptibility in M. tuberculosis (Mailaender et al., 2004). In a study involving genetic analysis (Flores, Parsons, & Pavelka, 2005), the contributions of variations in certain peptidoglycan biosynthetic enzymes to the development of resistance to beta-lactam antibiotics was investigated. The results showed that in addition to beta-lactamase activity, genetic mutations of the enzymes also contribute to the mechanism of resistance. Susceptibility Studies For over four decades, several workers have delved into studying the sensitivity of the tubercle bacillus to beta-lactams, including combinations of beta-lactam drugs with beta-lactamase inhibitors (Bhattacharya, Charkrabarty, & Dastidar, 1988; M. J. Casal, Rodriguez, Luna, & Benavente, 1987; Lorian & Sabath, 1972; Vaichulis, Vicher, & Novak, 1964; Wong, Palmer, & Cynamon, 1988). These studies continue in recent years with undiminished vigour, but also with newer and more sophisticated tools available for laboratory research. Chen and co-workers investigated the minimum inhibitory concentrations of five cephalosporins used in combination with the beta-lactamase inhibitor sulbactam (Chen, Yang, Lin, Lee, & Perng, 1995). The cephalosporins used were ceforanide, cefamandole, cefapirin, cefotaxime and ceftriaxone. It was found that the addition of sulbactam reduced the minimum inhibitory concentrations by a factor of 2 to 5 among the cephalosporins investigated. From this they concluded that the combination of cephalosporins and a beta-lactamase inhibitor enhances the efficacy of the cephalosporin against Mycobacterium tuberculosis. In in vitro testing, amoxicillin was found inadequately bactericidal against Mycobacterium tuberculosis when used alone, but its combination with the beta-lactamase inhibitor clavulanic acid afforded good bactericidal activity (Bhattacharya et al., 1988; Cynamon & Palmer, 1983; Herbert, Paramasivan, Venkatesan, Kubendiran, Prabhakar, Mitchison et al., 1996). This suggests the strong involvement of mycobacterial beta-lactamases in the development of resistance to beta-lactam drugs, as corroborated by other workers (Quinting et al., 1997). The early bactericidal activity (EBA) of co-amoxiclav (i.e. amoxicillin + clavulanic acid) was found to be comparable to that of the fluoroquinolone ofloxacin, which suggests that it could be of potential utility in clinical treatment (H. F. Chambers, Kocagoz, Sipit, Turner, & Hopewell, 1998). In a study involving 13 multidrug-resistant strains of M. tuberculosis along with 20 other strains of mycobacteria, the possibility of synergism between cefepime, a cephalosporin, and ethambutol was investigated using the BACTEC radiometric system (Getahun Abate & Hoffner, 1997). In almost one third of the M. tuberculosis strains, the combination proved effective, and drug resistance was reversed in about 71% of the mycobacterial strains. This suggests the possible utility of combinations of beta-lactam drugs and ethambutol. In similar work (G. Abate & Miorner, 1998), the synergism of amoxicillin/clavulanic acid combinations with ethambutol was found effective at therapeutically achievable concentrations in thirty clinical isolates of M. tuberculosis (including 20 MDR strains). A study involving 50 MDR and 50 susceptible mycobacterial strains (Dincer, Ergin, & Kocagoz, 2004)reported that a cefazolin-clavulanic acid combination was effective in vitro against 74% of the strains tested, further demonstrating the plausibility of using such a combination in clinical treatment. In clinical practice, some anecdotal evidence has been adduced for the clinical efficacy of beta-lactam drugs added to second-line antitubercular therapy in MDR tuberculosis patients (Nadler, Berger, Nord, Cofsky, & Saxena, 1991), but these are yet to be corroborated by definite clinical trials. Imipenem has been investigated in a mouse model of tuberculosis, and in human patients suffering from MDR-TB, and was found to be modestly effective, improving outcomes in humans at risk of failure treatment with more conventional therapy (Henry F. Chambers, Turner, Schecter, Kawamura, & Hopewell, 2005). The in vitro susceptibility of clinical isolates of Mycobacterium tuberculosis H37Rv in the exponential phase to the semisynthetic cephalosporin cefadroxil in Middlebrook 7H9 medium has been studied (Selvakumar, Kumar, & Paramasivan, 1997). The results were do not suggest a great potential for the clinical use of cefadroxil in view of the fact that in about in 40% of the isolates, the minimum inhibitory concentrations required for bactericidal action were almost one and a half times the peak plasma concentrations attained in humans. Herbert and co-workers studied the in vitro bactericidal activity of the fluoroquinolone and the combination of sulbactam and ampicillin, alone, and in combination with rifampin and isoniazid, on tubercle bacilli cultures both in the stationary phase as well as in the exponential phase (Herbert, Paramasivan, Venkatesan, Kubendiran, Prabhakar, & Mitchison, 1996). All drugs demonstrated bactericidal activity against exponential-phase cultures at high concentrations. When combined with rifampicin or isoniazid, both drugs increased the activity of the first line antitubercular agents, and in fact, proved as bactericidal as the combination of rifampin and isoniazid. But this activity was not pronounced against stationary-phase cultures, and as well, there was no potentiation of the activity of rifampin or isoniazid in stationary-phase cultures. Their findings lend credence to the conclusion that beta-lactam drugs will most likely be of utility during the early stage of treatment, and to prevent the development of resistance to other therapeutic agents, but they may not find much use as sterilizing drugs for eradicating persistent bacilli. Using an interestingly innovative synthetic approach, Zhao and co-workers described the syntheses and antitubercular activities of quinolone-cephalosporin conjugates (Zhao, Miller, Franzblau, Wan, & Mollmann, 2006). They compared two chemical approaches: using a carbamate linkage and using a direct amine linkage. Their findings showed that while both conjugates showed significant activity over the tubercle bacillus, the carbamate linked quinolone-cephem demonstrated superior antimycobacterial activity over the direct amine-linked conjugate. Discussion Why the Beta-lactams Have Not Been Used in Tuberculosis Treatment A question of immediate interest is why the immensely popular and successful beta-lactam antibiotics have not found their way into standard tuberculosis management regimens. It would be an ideal situation if the world's most successful and time-tested class of antibiotics found a place in the treatment of one of the world's most problematic infectious diseases, but this has not been. There are historical, mechanistic and experimental explanations for why beta-lactam antibiotics have not been used in tuberculosis management. Firstly, it has been observed that in the history of clinical chemotherapy, there have been several cases of patients falsely diagnosed with bacterial pneumonia who were placed on beta-lactam antibiotics, but were later discovered to have tuberculosis, and they never improved while on the beta-lactam drugs. If those beta-lactam antibiotics were efficacious, it would have been apparent in the improvement of the patients (Kernodle, 1998). Also, given the widespread use of beta-lactam antibiotics over several decades, it is obvious that if they were of utility against clinical tuberculosis, this fact would have been discovered some time or the other. Together, these two historical arguments form a basis for why beta-lactam drugs have not been seriously considered for use in tuberculosis management for a long time. However, of greater importance is the mechanistic explanation concerning the mode of resistance of bacteria to beta-lactam antibiotics and the particular strength of Mycobacterium tuberculosis in this regard. There are three main mechanisms of bacterial resistance to beta-lactam antibiotics, which stem from the mode of action of the drugs (Jones, 1998; Thomson & Bonomo, 2005). The first is the hydrolysis of the all-important beta-lactam ring of the antibiotic by enzymes known as beta-lactamases which are produced by resistant organisms (Paterson & Bonomo, 2005; Shah et al., 2004; Sturenburg & Mack, 2003; Turner, 2005; Timothy R. Walsh, Toleman, Poirel, & Nordmann, 2005). This breakdown of the lactam ring renders the antibiotic unable to bind to the penicillin binding proteins and halt peptidoglycan crosslinking (Babic et al., 2006). The second is a diffusional barrier to the movement of the beta-lactam antibiotic across the cell wall. If the drug cannot reach the site of action, obviously it would not be highly effective against the bacterium (Suarez, Lolans, Villegas, & Quinn, 2005). The third is alteration of the penicillin binding proteins themselves, rendering them resistant to attack by the beta-lactam antibiotics (Goffin & Ghuysen, 2002). This is achieved by mutations which produce penicillin binding proteins with low binding affinity (Suarez et al., 2005; T. R. Walsh, 2005; Timothy R. Walsh et al., 2005). Finally, experimental barriers to bacteriological testing have for a long time hindered extensive investigation of beta-lactamases in laboratory settings. The barriers have been identified as the intrinsically slow growth of mycobacteria which makes in vitro testing tedious, lack of standardized methodology until recent times, and the tendency of beta-lactam antibiotics to break down in conditions of prolonged incubation (Finch, 1986). Given all these difficulties, it is no wonder that beta-lactam antibiotics have been put on the back burner in tuberculosis management, but the situation may be about to change. Taking a Second Look: A Case For The Use of Beta-Lactam Drugs in Tuberculosis Management The development of resistance necessitating multiple drug treatment has always been a problem with tuberculosis management. However, the recent emergence of multiple drug resistance (MDR-TB or multidrug-resistant tuberculosis) has engendered a dire need for additional drugs in the medical arsenal against tuberculosis. This has regenerated considerable interest in taking a second look at beta-lactam antibiotics in the past one decade or so. MDR-TB is defined as tuberculosis that is resistant to isoniazid and rifampin, which are the mainstay first-line drugs in tuberculosis treatment. Hence the treatment approach requires the combination of residual first-line drugs (ethambutol, pyrazinamide and streptomycin) with appropriately selected second-line drugs. Principal drugs in the second-line category include the following (Di Perri & Bonora, 2004): aminoglycosides (streptomycin, amikacin, kanamycin); polypeptides (capreomycin); p-aminosalicylic acid (PAS); thioamides (ethionamide and prothionamide); cycloserine; rifamycins other than rifampicin (rifabutin, rifapentine); fluoroquinolones (gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin, moxifloxacin) Other second-line drugs currently under investigation include (Di Perri & Bonora, 2004): oxazolidinones (linezolid), macrolides (clarithromycin); riminophanazines (clofazimine); beta-lactams; phenothiazines (chlorpromazine, thioridazine); nitroimidazopyrans (metronidazole); tuberactinomycin; acetamides pyrrole derivatives. From the literature review, there is a lot of laboratory (both in vitro and in vivo) evidence, and now some clinical evidence that has been made available to support the idea of the potential rational use of beta-lactam antibiotics in tuberculosis treatment. In addition, there is a theoretical consideration why it makes sense to consider beta-lactams as potentially useful drugs in tuberculosis treatment. This is found in the success of cycloserine as a second-line antitubercular drug. A close look at the chemical structure of cycloserine shows that it is an analogue of D-alanine. It acts by inhibition of peptidoglycan synthesis via the D-alanyl-d-alanine synthetase pathway (Kernodle, 1998). This bears a striking resemblance to beta-lactams, which are also D-alanyl-d-alanine analogues. A Rational Approach to the Use of Beta-Lactams in Tuberculosis Management Given what is known about the mode of action of beta-lactams, the mechanisms of resistance in mycobacteria, and the clinical standards for tuberculosis management, an attempt will be made in this section to articulate a suggested rational approach to the use of beta-lactam antibiotics in the treatment of tuberculosis. First, a rational approach must be predicated on an understanding of how and why beta-lactams are limited in efficacy against Mycobacterium tuberculosis. As earlier stated, there are three known mechanisms of resistance to the beta-lactams: beta-lactamase production, mutations of penicillin binding proteins producing variants with low binding affinity, and the development of cell wall permeability barriers. Of these three, by far the most important is beta-lactamase activity, and it is this aspect that should be focused on in developing a strategy to bring the best out of beta-lactam use in tuberculosis management. Beta-lactamase-mediated resistance is an old problem with antibiotic treatment with the beta-lactams (Amyes, 2003). Two classical approaches have been used to overcome this problem: the development of beta-lactamase resistant analogues of beta-lactams by chemical modifications which greatly reduce the susceptibility of the beta-lactam ring to enzymatic hydrolysis, and the co-administration of beta-lactam antibiotics with beta-lactamase inhibitors in which the beta-lactamase inhibitor presents itself as a sort of decoy target to beta-lactamases and leave the actual antibiotic free to disrupt the peptidoglycan crosslinking of the bacterial cell walls. Examples of the former approach are found in semisynthetic penicillin analogues (cloxacillin, dicloxacillin, flucloxacillin) or cephalosporinase-resistant cephalosporins (ceftizoxime, cephapirin, ceforanide), while the latter approach is exemplified by the combinations of ampicillin with sulbactam, amoxicillin with clavulanic acid, and piperacillin with tazobactam. A plethora of research evidence shows that these strategies have been successful in laboratory testing of beta-lactam activity against Mycobacterium and it will form the bedrock for rational clinical use of the beta-lactams in tuberculosis treatment. It has been suggested that a comprehensive characterization of the beta-lactamases in Mycobacterium tuberculosis is necessary, in order to identify the most suitable beta-lactam drugs for treatment. Not only that, it is important to carry out studies of the mechanisms of how beta-lactamases interact with beta-lactam drugs in order to correctly identify the most suitable beta-lactam and beta-lactamase inhibitor drugs for use in tuberculosis management (Kernodle, 1998). In terms of practical use in the clinical setting, there still remains a lot to be elucidated in terms of the exact place of beta-lactam therapy, but available evidence suggests a few guidelines. In the in vitro study showing the activity of ampicillin co-administered with sulbactam, it was found that the beta-lactam drugs work better against Mycobacterium tuberculosis cultures in the exponential phase than those in the stationary phase. Also the clinical study of the activity of amoxicillin/clavulanic acid against sputum cultures showed that the greatest activity of the beta-lactam combination was during the exponential phase. From this evidence, it may be concluded that the best place for rational use of beta-lactams will be in the early phase of treatment, and not as sterilizing agents. Given the combination therapy basis of tuberculosis treatment, it may also be expected that including beta-lactams in the treatment regimen will be of utility in delaying the development of resistance to other antibiotics used in tuberculosis management. Moreover, in the treatment of multidrug-resistant tuberculosis, it is expected that beta-lactams will have a crucial role to play, in combination with other drugs. Finally, it may also be argued that the prospects of introducing an old class of antibiotics such as the beta-lactams into tuberculosis management may well be a good thing from the viewpoint of drug development economics (Elzinga, Raviglione, & Maher, 2004). Since tuberculosis rates are falling in the West and are more prevalent in developing countries with limited financial resources (Elzinga et al., 2004; Khatri & Frieden, 2000; World Health Organization, 2006), there is not much of an incentive to drug companies to develop new therapeutic entities for the disease (Sharma, 2004). It will prove highly fortuitous if a currently widely used and available drug can be brought into the clinical arsenal against the tubercle bacillus. Conclusion The review has featured an introduction to the beta-lactam group of antibiotics, including their description, classification, and mode of action. The historical, mechanistic, and practical reasons why these drugs have not had a place of prominence in antituberculosis treatment have been elucidated. From the recent flurry of research activities concerning the possibility of utilising these agents in the management of tuberculosis, it is obvious that a rethink of current therapy guidelines may be justified, to allow for the use of beta-lactam drugs within certain boundaries. This is all the more important in the face of the emergence of the menace of multidrug-resistant tuberculosis, which necessitates the utilisation of additional therapeutic agents in the fight against tuberculosis. However, extensive clinical trials still remain to be done in order to provide solid foundations for evidence-based treatment guidelines incorporating beta-lactam drugs in the management of tuberculosis. Nonetheless, there is significant empirical reason to believe that the concept of using beta-lactam drugs in the management of tuberculosis is a feasible one in the nearest future. References Read More