Biology

p-lactams are commonly used in combination with p-lactamase inhibitors such as clavulanic acid (CA), sulbactam, and tazobactam which themselves are p-lactams. A variety of p-lactams have been tested for in vitro efficacy against MTb (see Table 8 for examples). However, despite activity of some p-lactams against MTb in vitro, especially in the presence of p-lactamase inhibitors, none have to date shown good efficacy in vivo. Amoxicillin (Table 8; 21a)/CA was found to be ineffective in mice [302], and imipenem (Table 8; 21f) showed only a 16-fold reduction in bacterial burden in lungs of infected mice over 4 weeks of treatment [50]. Furthermore, only a modest decrease in viable numbers was seen in sputum of patients receiving amoxicillin(Table 8; 21a)/CA or ampicillin(Table 8; 21b)/ sulbactam monotherapy [303]. The poor in vivo efficacy may be due to the intracellular environment of MTb, making it difficult for drugs to penetrate the phagosomal compartment. Additionally, the bacterial physiology in vivo may

Table 8 Biological activity of select b-lactams against MTb H37Rv in the presence or absence of clavulanic acid [299-301]

Compound

Structure

Amoxicillin (21a)

Ampicillin (21b)

Ceftriaxone (21c)

o nh2

>25G

>23G

7-2S

Cephalothin (21d)

Meropenem (21e)

Imipenem (21f)

Aztreonam (21g)

h,c h3c

>147

>147

be different making it less responsive to p-lactam therapy, although the recent demonstration of activity of meropenem/CA against non-replicating persistent MTb has raised the possibility of use of this carbapenem against TB [299, 304].

CP-5484 (a carbapenem with activity against MRSA) [305] is currently in preclinical development for use against tuberculosis. Additionally, the merope-nem/CA combination has shown potent activity against strains of MTb [299] and is currently being investigated for possible clinical use.

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