rifampin and lipoteichoic-acid

The inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)]. An acute release of these components occurs when pneumococcal infection is treated with β-lactam antibiotics.. We hypothesized that non-lytic rifampicin compared with lytic β-lactam antibiotic treatment would attenuate the inflammatory response in patients with pneumococcal pneumonia.. In the PRISTINE (Pneumonia treated with RIfampicin aTtenuates INflammation) trial, a randomized, therapeutic controlled, exploratory study in patients with community-acquired pneumococcal pneumonia, we looked at LTA release and inflammatory and clinical response during treatment with both rifampicin and β-lactam compared with treatment with β-lactam antibiotics only. The trial is registered in the Dutch trial registry, number NTR3751 (European Clinical Trials Database number 2012-003067-22).. Forty-one patients with community-acquired pneumonia were included; 17 of them had pneumococcal pneumonia. LTA release, LTA-mediated inflammatory responses, clinical outcomes, inflammatory biomarkers and transcription profiles were not different between treatment groups.. The PRISTINE study demonstrated the feasibility of adding rifampicin to β-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia, but, despite solid in vitro and experimental animal research evidence, failed to demonstrate a difference in plasma LTA concentrations and subsequent inflammatory and clinical responses. Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, LTA plasma concentration could be too low to mount a response via Toll-like receptor 2 in vitro, but may nonetheless have an effect in vivo.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactams; Community-Acquired Infections; Female; Humans; Inflammation; Lipopolysaccharides; Male; Middle Aged; Netherlands; Plasma; Pneumonia, Pneumococcal; Rifampin; Teichoic Acids; Treatment Outcome; Young Adult

Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), can be aggravated by a mild Streptococcus pneumoniae infection. This study was performed to assess whether treatment with antibiotics inhibiting bacterial protein synthesis reduces the detrimental effect of infection on the course of EAE.. In vitro, release of proinflammatory pneumococcal products was studied by enzyme immunoassay and western blot. Seven days after induction of EAE (prior to the onset of symptoms) mice were infected intraperitoneally with S. pneumoniae and treated either with the inhibitors of bacterial protein synthesis minocycline or rifampicin, or with the beta-lactam ceftriaxone.. During bacterial killing in vitro, minocycline and rifampicin released lower quantities of proinflammatory bacterial products from S. pneumoniae than ceftriaxone. Mice treated with minocycline developed symptoms of EAE 1 day later than mice treated with ceftriaxone. Neither minocycline nor rifampicin therapy, however, reduced the severity of EAE in comparison with ceftriaxone treatment.. Although statistically significant (P = 0.04), a delay of 1 day in the onset of symptoms of EAE after minocycline treatment is of minor clinical relevance. These data do not support the hypothesis of superiority of a bacterial protein synthesis inhibitor over a beta-lactam antibiotic for the treatment of concomitant infections during the latent phase of EAE or MS.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Encephalomyelitis, Autoimmune, Experimental; Female; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Minocycline; Pneumococcal Infections; Rifampin; Teichoic Acids

There are marked differences in the amount of immunoreactive components such as lipoteichoic acid (LTA) released from Gram-positive bacteria following exposure to different antibiotics. Little is known about the kinetics and amount of release of such components in relation to bacterial killing.. Bacterial killing and LTA release from Streptococcus pneumoniae type 3 during exposure to ceftriaxone, meropenem, rifampicin, rifabutin, quinupristin/dalfopristin, and trovafloxacin in tryptic soy broth were quantified microbiologically and by ELISA, respectively. We applied a mathematical model to characterize quantitatively the amount of lipoteichoic acid released and the statistical moments of this release.. The model approach revealed that (i) the lag time to release of LTA was very similar for individually killed bacterial cells (approximately 120 min), whatever the killing mechanism effected by the antibiotic, and (ii) the amount of LTA released per killed bacterial cell, a value that we regard as an indicator of the relation between antibacterial efficacy and possible adverse immunostimulatory effects due to release of cell wall components, differs markedly between antibiotics, even at antibiotic concentrations inducing equal killing. Rifamycins were most effective in killing S. pneumoniae while causing the least LTA release per killed bacterial cell; the amount released was about one-half that by quinupristin-dalfopristin and trovafloxacin, and one-quarter that by ceftriaxone and meropenem.. In the evaluation of antibacterial drugs, the present model provides useful information on the whole process of bacterial killing and release of immunoreactive components from the bacterial cell wall.

Topics: Anti-Bacterial Agents; Ceftriaxone; Lipopolysaccharides; Meropenem; Rifabutin; Rifampin; Streptococcus pneumoniae; Teichoic Acids; Thienamycins; Virginiamycin

Rifampin (RIF) releases smaller quantities of lipoteichoic acids (LTAs) from Streptococcus pneumoniae than ceftriaxone (CRO). Due to the rapid development of resistance, RIF cannot be used as a single agent for therapy of bacterial meningitis. For this reason, we compared the effect of treatment with RIF followed by treatment with CRO (RIF-CRO) or the effect of treatment with clindamycin (CLI) followed by treatment with CRO (CLI-CRO) to that of CRO alone on the concentrations of LTAs and teichoic acids in vitro. The effects of RIF-CRO on LTA concentrations in cerebrospinal fluid (CSF) and on neuronal injury were investigated in a rabbit model of S. pneumoniae meningitis. In vitro, bacterial titers were effectively reduced by CRO, RIF-CRO, and CLI-CRO when each drug was used at 10 micro g/ml. The levels of release of LTAs after the initiation of therapy were lower in RIF-CRO- and CLI-CRO-treated cultures than in cultures treated with CRO alone (P < 0.05 from 3 to 12 h after initiation of treatment). Similarly, in rabbits, the increase in the amount of LTAs in CSF was lower in RIF-CRO-treated animals than in CRO-treated animals (P = 0.02). The density of dentate apoptotic granular cells was lower after RIF-CRO therapy than after CRO therapy (medians, 58.4 and 145.6/mm(2), respectively; 25th quartiles, 36.3 and 81.7/mm(2), respectively; 75th quartiles, 100.7 and 152.3/mm(2), respectively; P = 0.03). Therefore, initiation of therapy with a protein synthesis-inhibiting antibacterial and continuation of therapy with a combination that includes a beta-lactam may be a strategy to decrease neuronal injury in bacterial meningitis.

Topics: Animals; Ceftriaxone; Drug Therapy, Combination; Lipopolysaccharides; Meningitis, Pneumococcal; Neurons; Rabbits; Rifampin; Teichoic Acids