RESUMO
The historical view of ß-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis (Mtb) in the presence of a ß-lactamase inhibitor. However, most antimycobacterial ß-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 ß-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3' that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a ß-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A ß-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent ß-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states.
Assuntos
Antituberculosos/farmacologia , Cefalosporinas/farmacologia , Replicação do DNA , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/farmacologia , Tionas/farmacologia , Administração Oral , Animais , Antituberculosos/administração & dosagem , Callithrix , Cefalosporinas/administração & dosagem , Descoberta de Drogas , Feminino , Células Hep G2 , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mycobacterium tuberculosis/fisiologia , Piridinas/administração & dosagem , Tionas/administração & dosagemRESUMO
After a cluster of fatal toxoplasmosis among stem cell transplant recipients at 2 hospitals, surveillance with polymerase chain reaction (PCR) (blood) was instituted. Rate of reactivation among seropositive recipients was 2.2 and 16%. Parasitemia was successfully managed with preemptive treatment. For seropositive recipients unable to take prophylaxis, toxoplasma PCR surveillance should be routinely performed.