Further study will be necessary to fully elucidate the epide

Further study will be necessary to fully elucidate the epidemiology of in vitro and in vivo susceptibility to β-lactam/β-lactamase inhibitor combinations globally and in other lineages of M. tuberculosis. The association between MDR and XDR clinical isolates and in vitro susceptibility to amoxicillin/clavulanate may provide effective treatment options for patients with XDR-TB, at least in regions of high LAM4 prevalence such as South Africa. However a recent study from Japan (Horita et al., 2014) suggests that drug-resistant strains with other genetic backgrounds also exhibit a similar phenotype. While the South African National TB program includes amoxicillin/clavulanate as part of a suggested drug regimen for XDR (), only 61% of patients in a recently published long-term cohort of XDR in South Africa were prescribed this PF-573228 drug combination for at least some part of their treatment course (Pietersen et al., 2014). Given the poor treatment outcomes for XDR that have been reported, the fact that β-lactam drug susceptibility testing is not routinely performed, and relative safety of the drug, empiric addition of amoxicillin/clavulanate to patients with XDR-TB in South Africa may be advisable, although the optimal dosing regimen still needs to be established. The following are the supplementary data related to this article.
Author Contributions
Funding Information KAC was supported by T32HL007633 of the National Heart, Lung and Blood Institute. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Open access publication of this article has been made possible through support from the Victor Daitz Information Gateway, an initiative of the Victor Daitz Foundation and the University of KwaZulu-Natal.
Conflicts of Interest
Acknowledgements We thank Eyal Privman for helpful discussions. We thank Anna Trigos for assistance with the gene-content analysis. We would like to thank Nonkqubela Bantubani of the Medical Research Council (MRC) in Durban, in addition to Drs. Max O′Donnell and Nesri Padayatchi for contributing clinical isolates of M. tuberculosis, which were used in this study. Lastly, we would like to thank Prof. Koleka P. Mlisana and Dr. Nomonde R. Mvelase of the KwaZulu-Natal National Health Laboratory Service and Dr. Gyanu Lamichhane for providing nitrocefin.
Introduction Sepsis is a systemic inflammatory response syndrome (SIRS) associated with infection. The pathogenesis of sepsis includes the disturbance of blood-vascular homeostasis, which may cause multiple organ failure, circulatory shock, and disseminated intravascular coagulation (DIC), leading to high mortality (Aziz et al., 2013; Dellinger et al., 2012; Hotchkiss et al., 2013; Semeraro et al., 2012). The proinflammatory cytokine response in the acute phase may be triggered by the constituents of invading pathogens and tissue damage-associated molecular patterns (Piccinini and Midwood, 2010; Ward, 2012), accompanied by the activation of vascular endothelial cells (VECs), a pivotal step for inducing the migration of leukocytes into inflammatory sites with pathogen invasion (Salomão et al., 2008; Williams et al., 2011). A recent study suggested that neutrophil adhesion on VECs may trigger platelet aggregation and immunothrombus formation in septic acute respiratory distress syndrome (ARDS) (Grommes and Soehnlein, 2011; Matthay and Zemans, 2011; Moreland et al., 2004; Engelmann and Massberg, 2013; Brinkmann et al., 2004; Yipp and Kubes, 2013). Thus, circulating neutrophils may play important roles in the pathogenesis of septic conditions in addition to infiltrating neutrophils. However, the uncontrolled activation of neutrophils has not been examined in detail due to methodological limitations (Alves-Filho et al., 2008). Neutrophils are easily activated by in vitro handling or even by withdrawing from blood vessels. Therefore, it might be rather difficult to know and speculate about the precise features of the circulating neutrophils by an in vitro analysis. Also, if any are present, a controlling factor of neutrophils in plasma, one that might regulate a fundamental state of circulating neutrophils in both healthy and disease conditions, remains to be determined.