PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (97)
 

Clipboard (0)
None
Journals
more »
Year of Publication
more »
1.  Impact of Early Valve Surgery on Outcome of Staphylococcus aureus Prosthetic Valve Infective Endocarditis: Analysis in the International Collaboration of Endocarditis–Prospective Cohort Study 
Chirouze, Catherine | Alla, François | Fowler, Vance G. | Sexton, Daniel J. | Corey, G. Ralph | Chu, Vivian H. | Wang, Andrew | Erpelding, Marie-Line | Durante-Mangoni, Emanuele | Fernández-Hidalgo, Nuria | Giannitsioti, Efthymia | Hannan, Margaret M. | Lejko-Zupanc, Tatjana | Miró, José M. | Muñoz, Patricia | Murdoch, David R. | Tattevin, Pierre | Tribouilloy, Christophe | Hoen, Bruno | Clara, Liliana | Sanchez, Marisa | Nacinovich, Francisco | Oses, Pablo Fernandez | Ronderos, Ricardo | Sucari, Adriana | Thierer, Jorge | Casabé, José | Cortes, Claudia | Altclas, Javier | Kogan, Silvia | Spelman, Denis | Athan, Eugene | Harris, Owen | Kennedy, Karina | Tan, Ren | Gordon, David | Papanicolas, Lito | Eisen, Damon | Grigg, Leeanne | Street, Alan | Korman, Tony | Kotsanas, Despina | Dever, Robyn | Jones, Phillip | Konecny, Pam | Lawrence, Richard | Rees, David | Ryan, Suzanne | Feneley, Michael P. | Harkness, John | Jones, Phillip | Ryan, Suzanne | Jones, Phillip | Ryan, Suzanne | Jones, Phillip | Post, Jeffrey | Reinbott, Porl | Ryan, Suzanne | Gattringer, Rainer | Wiesbauer, Franz | Andrade, Adriana Ribas | de Brito, Ana Cláudia Passos | Guimarães, Armenio Costa | Grinberg, Max | Mansur, Alfredo José | Siciliano, Rinaldo Focaccia | Strabelli, Tania Mara Varejao | Vieira, Marcelo Luiz Campos | de Medeiros Tranchesi, Regina Aparecida | Paiva, Marcelo Goulart | Fortes, Claudio Querido | de Oliveira Ramos, Auristela | Ferraiuoli, Giovanna | Golebiovski, Wilma | Lamas, Cristiane | Santos, Marisa | Weksler, Clara | Karlowsky, James A. | Keynan, Yoav | Morris, Andrew M. | Rubinstein, Ethan | Jones, Sandra Braun | Garcia, Patricia | Cereceda, M | Fica, Alberto | Mella, Rodrigo Montagna | Barsic, Bruno | Bukovski, Suzana | Krajinovic, Vladimir | Pangercic, Ana | Rudez, Igor | Vincelj, Josip | Freiberger, Tomas | Pol, Jiri | Zaloudikova, Barbora | Ashour, Zainab | El Kholy, Amani | Mishaal, Marwa | Rizk, Hussien | Aissa, Neijla | Alauzet, Corentine | Alla, Francois | Campagnac, Catherine | Doco-Lecompte, Thanh | Selton-Suty, Christine | Casalta, Jean-Paul | Fournier, Pierre-Edouard | Habib, Gilbert | Raoult, Didier | Thuny, Franck | Delahaye, François | Delahaye, Armelle | Vandenesch, Francois | Donal, Erwan | Donnio, Pierre Yves | Michelet, Christian | Revest, Matthieu | Tattevin, Pierre | Violette, Jérémie | Chevalier, Florent | Jeu, Antoine | Sorel, Claire | Tribouilloy, Christophe | Bernard, Yvette | Chirouze, Catherine | Hoen, Bruno | Leroy, Joel | Plesiat, Patrick | Naber, Christoph | Neuerburg, Carl | Mazaheri, Bahram | Naber, Christoph | Neuerburg, Carl | Athanasia, Sofia | Giannitsioti, Efthymia | Mylona, Elena | Paniara, Olga | Papanicolaou, Konstantinos | Pyros, John | Skoutelis, Athanasios | Sharma, Gautam | Francis, Johnson | Nair, Lathi | Thomas, Vinod | Venugopal, Krishnan | Hannan, Margaret | Hurley, John | Gilon, Dan | Israel, Sarah | Korem, Maya | Strahilevitz, Jacob | Rubinstein, Ethan | Strahilevitz, Jacob | Casillo, Roberta | Cuccurullo, Susanna | Dialetto, Giovanni | Durante-Mangoni, Emanuele | Irene, Mattucci | Ragone, Enrico | Tripodi, Marie Françoise | Utili, Riccardo | Cecchi, Enrico | De Rosa, Francesco | Forno, Davide | Imazio, Massimo | Trinchero, Rita | Tebini, Alessandro | Grossi, Paolo | Lattanzio, Mariangela | Toniolo, Antonio | Goglio, Antonio | Raglio, Annibale | Ravasio, Veronica | Rizzi, Marco | Suter, Fredy | Carosi, Giampiero | Magri, Silvia | Signorini, Liana | Baban, Tania | Kanafani, Zeina | Kanj, Souha S. | Yasmine, Mohamad | Abidin, Imran | Tamin, Syahidah Syed | Martínez, Eduardo Rivera | Soto Nieto, Gabriel Israel | van der Meer, Jan T.M. | Chambers, Stephen | Holland, David | Morris, Arthur | Raymond, Nigel | Read, Kerry | Murdoch, David R. | Dragulescu, Stefan | Ionac, Adina | Mornos, Cristian | Butkevich, O.M. | Chipigina, Natalia | Kirill, Ozerecky | Vadim, Kulichenko | Vinogradova, Tatiana | Edathodu, Jameela | Halim, Magid | Lum, Luh-Nah | Tan, Ru-San | Lejko-Zupanc, Tatjana | Logar, Mateja | Mueller-Premru, Manica | Commerford, Patrick | Commerford, Anita | Deetlefs, Eduan | Hansa, Cass | Ntsekhe, Mpiko | Almela, Manuel | Armero, Yolanda | Azqueta, Manuel | Castañeda, Ximena | Cervera, Carlos | del Rio, Ana | Falces, Carlos | Garcia-de-la-Maria, Cristina | Fita, Guillermina | Gatell, Jose M. | Marco, Francesc | Mestres, Carlos A. | Miró, José M. | Moreno, Asuncion | Ninot, Salvador | Paré, Carlos | Pericas, Joan | Ramirez, Jose | Rovira, Irene | Sitges, Marta | Anguera, Ignasi | Font, Bernat | Guma, Joan Raimon | Bermejo, Javier | Bouza, Emilio | Fernández, Miguel Angel Garcia | Gonzalez-Ramallo, Victor | Marín, Mercedes | Muñoz, Patricia | Pedromingo, Miguel | Roda, Jorge | Rodríguez-Créixems, Marta | Solis, Jorge | Almirante, Benito | Fernandez-Hidalgo, Nuria | Tornos, Pilar | de Alarcón, Arístides | Parra, Ricardo | Alestig, Eric | Johansson, Magnus | Olaison, Lars | Snygg-Martin, Ulrika | Pachirat, Orathai | Pachirat, Pimchitra | Pussadhamma, Burabha | Senthong, Vichai | Casey, Anna | Elliott, Tom | Lambert, Peter | Watkin, Richard | Eyton, Christina | Klein, John L. | Bradley, Suzanne | Kauffman, Carol | Bedimo, Roger | Chu, Vivian H. | Corey, G. Ralph | Crowley, Anna Lisa | Douglas, Pamela | Drew, Laura | Fowler, Vance G. | Holland, Thomas | Lalani, Tahaniyat | Mudrick, Daniel | Samad, Zaniab | Sexton, Daniel | Stryjewski, Martin | Wang, Andrew | Woods, Christopher W. | Lerakis, Stamatios | Cantey, Robert | Steed, Lisa | Wray, Dannah | Dickerman, Stuart A. | Bonilla, Hector | DiPersio, Joseph | Salstrom, Sara-Jane | Baddley, John | Patel, Mukesh | Peterson, Gail | Stancoven, Amy | Afonso, Luis | Kulman, Theresa | Levine, Donald | Rybak, Michael | Cabell, Christopher H. | Baloch, Khaula | Chu, Vivian H. | Corey, G. Ralph | Dixon, Christy C. | Fowler, Vance G. | Harding, Tina | Jones-Richmond, Marian | Pappas, Paul | Park, Lawrence P. | Redick, Thomas | Stafford, Judy | Anstrom, Kevin | Athan, Eugene | Bayer, Arnold S. | Cabell, Christopher H. | Chu, Vivian H. | Corey, G. Ralph | Fowler, Vance G. | Hoen, Bruno | Karchmer, A. W. | Miró, José M. | Murdoch, David R. | Sexton, Daniel J. | Wang, Andrew | Bayer, Arnold S. | Cabell, Christopher H. | Chu, Vivian | Corey, G. Ralph | Durack, David T. | Eykyn, Susannah | Fowler, Vance G. | Hoen, Bruno | Miró, José M. | Moreillon, Phillipe | Olaison, Lars | Raoult, Didier | Rubinstein, Ethan | Sexton, Daniel J.
Using appropriate analytical methods to examine data from the International Collaboration on Endocarditis–Prospective Cohort Study, we found that early valve surgery was not associated with reduced 1-year mortality in Staphylococcus aureus prosthetic valve infective endocarditis.
Background. The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis–Prospective Cohort Study.
Methods. Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use.
Results. EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non–S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39–1.15]; P = .15).
Conclusions. In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE.
doi:10.1093/cid/ciu871
PMCID: PMC4366581  PMID: 25389255
endocarditis; prosthetic valve; surgery; 1-year mortality
2.  Validated Risk Score for Predicting 6‐Month Mortality in Infective Endocarditis 
Park, Lawrence P. | Chu, Vivian H. | Peterson, Gail | Skoutelis, Athanasios | Lejko‐Zupa, Tatjana | Bouza, Emilio | Tattevin, Pierre | Habib, Gilbert | Tan, Ren | Gonzalez, Javier | Altclas, Javier | Edathodu, Jameela | Fortes, Claudio Querido | Siciliano, Rinaldo Focaccia | Pachirat, Orathai | Kanj, Souha | Wang, Andrew | Clara, Liliana | Sanchez, Marisa | Casabé, José | Cortes, Claudia | Nacinovich, Francisco | Fernandez Oses, Pablo | Ronderos, Ricardo | Sucari, Adriana | Thierer, Jorge | Kogan, Silvia | Spelman, Denis | Athan, Eugene | Harris, Owen | Kennedy, Karina | Gordon, David | Papanicolas, Lito | Korman, Tony | Kotsanas, Despina | Dever, Robyn | Jones, Phillip | Konecny, Pam | Lawrence, Richard | Rees, David | Ryan, Suzanne | Feneley, Michael P. | Harkness, John | Jones, Phillip | Ryan, Suzanne | Jones, Phillip | Ryan, Suzanne | Jones, Phillip | Post, Jeffrey | Reinbott, Porl | Ryan, Suzanne | Gattringer, Rainer | Wiesbauer, Franz | Andrade, Adriana Ribas | de Brito, Ana Cláudia Passos | Guimarães, Armenio Costa | Grinberg, Max | Mansur, Alfredo José | Strabelli, Tania Mara Varejao | Vieira, Marcelo Luiz Campos | de Medeiros Tranchesi, Regina Aparecida | Paiva, Marcelo Goulart | de Oliveira Ramos, Auristela | Weksler, Clara | Ferraiuoli, Giovanna | Golebiovski, Wilma | Lamas, Cristiane | Karlowsky, James A. | Keynan, Yoav | Morris, Andrew M. | Rubinstein, Ethan | Jones, Sandra Braun | Garcia, Patricia | Fica, Alberto | Mella, Rodrigo Montagna | Fernandez, Ricardo | Franco, Liliana | Jaramillo, Astrid Natalia | Barsic, Bruno | Bukovski, Suzana | Krajinovic, Vladimir | Pangercic, Ana | Rudez, Igor | Vincelj, Josip | Freiberger, Tomas | Pol, Jiri | Zaloudikova, Barbora | Ashour, Zainab | El Kholy, Amani | Mishaal, Marwa | Osama, Dina | Rizk, Hussien | Aissa, Neijla | Alauzet, Corentine | Alla, Francois | Campagnac, Catherine | Doco‐Lecompte, Thanh | Selton‐Suty, Christine | Casalta, Jean‐Paul | Fournier, Pierre‐Edouard | Raoult, Didier | Thuny, Franck | Delahaye, Francois | Delahaye, Armelle | Vandenesch, Francois | Donal, Erwan | Donnio, Pierre Yves | Flecher, Erwan | Michelet, Christian | Revest, Matthieu | Chevalier, Florent | Jeu, Antoine | Rémadi, Jean Paul | Rusinaru, Dan | Tribouilloy, Christophe | Bernard, Yvette | Chirouze, Catherine | Hoen, Bruno | Leroy, Joel | Plesiat, Patrick | Naber, Christoph | Neuerburg, Carl | Mazaheri, Bahram | Naber, Christoph | Neuerburg, Carl | Athanasia, Sophia | Deliolanis, Ioannis | Giamarellou, Helen | Thomas, Tsaganos | Giannitsioti, Efthymia | Mylona, Elena | Paniara, Olga | Papanicolaou, Konstantinos | Pyros, John | Mylona, Elena | Paniara, Olga | Papanikolaou, Konstantinos | Pyros, John | Sharma, Gautam | Francis, Johnson | Nair, Lathi | Thomas, Vinod | Venugopal, Krishnan | Hannan, Margaret M. | Hurley, John P. | Cahan, Amos | Gilon, Dan | Israel, Sarah | Korem, Maya | Strahilevitz, Jacob | Rubinstein, Ethan | Strahilevitz, Jacob | Durante‐Mangoni, Emanuele | Mattucci, Irene | Pinto, Daniela | Agrusta, Federica | Senese, Alessandra | Ragone, Enrico | Utili, Riccardo | Cecchi, Enrico | De Rosa, Francesco | Forno, Davide | Imazio, Massimo | Trinchero, Rita | Grossi, Paolo | Lattanzio, Mariangela | Toniolo, Antonio | Goglio, Antonio | Raglio, Annibale | Ravasio, Veronica | Rizzi, Marco | Suter, Fredy | Carosi, Giampiero | Magri, Silvia | Signorini, Liana | Kanafani, Zeina | Kanj, Souha S. | Sharif‐Yakan, Ahmad | Abidin, Imran | Tamin, Syahidah Syed | Martínez, Eduardo Rivera | Soto Nieto, Gabriel Israel | van der Meer, Jan T.M. | Chambers, Stephen | Holland, David | Morris, Arthur | Raymond, Nigel | Read, Kerry | Murdoch, David R. | Dragulescu, Stefan | Ionac, Adina | Mornos, Cristian | Butkevich, O.M. | Chipigina, Natalia | Kirill, Ozerecky | Vadim, Kulichenko | Vinogradova, Tatiana | Halim, Magid | Liew, Yee‐Yun | Tan, Ru‐San | Logar, Mateja | Mueller‐Premru, Manica | Commerford, Patrick | Commerford, Anita | Deetlefs, Eduan | Hansa, Cass | Ntsekhe, Mpiko | Almela, Manuel | Armero, Yolanda | Azqueta, Manuel | Castañeda, Ximena | Cervera, Carlos | Falces, Carlos | Garcia‐de‐la‐Maria, Cristina | Fita, Guillermina | Gatell, Jose M. | Heras, Magda | Llopis, Jaime | Marco, Francesc | Mestres, Carlos A. | Miró, José M. | Moreno, Asuncion | Ninot, Salvador | Paré, Carlos | Pericas, Juan M. | Ramirez, Jose | Rovira, Irene | Sitges, Marta | Anguera, Ignasi | Font, Bernat | Guma, Joan Raimon | Bermejo, Javier | Garcia Fernández, Miguel Angel | Gonzalez‐Ramallo, Victor | Marín, Mercedes | Muñoz, Patricia | Pedromingo, Miguel | Roda, Jorge | Rodríguez‐Créixems, Marta | Solis, Jorge | Almirante, Benito | Fernandez‐Hidalgo, Nuria | Tornos, Pilar | de Alarcón, Arístides | Parra, Ricardo | Alestig, Eric | Johansson, Magnus | Olaison, Lars | Snygg‐Martin, Ulrika | Pachirat, Pimchitra | Pussadhamma, Burabha | Senthong, Vichai | Casey, Anna | Elliott, Tom | Lambert, Peter | Watkin, Richard | Eyton, Christina | Klein, John L. | Bradley, Suzanne | Kauffman, Carol | Bedimo, Roger | Corey, G. Ralph | Crowley, Anna Lisa | Douglas, Pamela | Drew, Laura | Fowler, Vance G. | Holland, Thomas | Lalani, Tahaniyat | Mudrick, Daniel | Samad, Zaniab | Sexton, Daniel | Stryjewski, Martin | Woods, Christopher W. | Lerakis, Stamatios | Cantey, Robert | Steed, Lisa | Wray, Dannah | Dickerman, Stuart A. | Bonilla, Hector | DiPersio, Joseph | Salstrom, Sara‐Jane | Baddley, John | Patel, Mukesh | Stancoven, Amy | Levine, Donald | Riddle, Jonathan | Rybak, Michael | Cabell, Christopher H. | Baloch, Khaula | Corey, G. Ralph | Dixon, Christy C. | Fowler, Vance G. | Harding, Tina | Jones‐Richmond, Marian | Sanderford, Bob | Sanderford, Bob | Stafford, Judy | Stafford, Judy | Anstrom, Kevin | Athan, Eugene | Bayer, Arnold S. | Cabell, Christopher H. | Corey, G. Ralph | Fowler, Vance G. | Hoen, Bruno | Karchmer, A. W. | Miró, José M. | Murdoch, David R. | Sexton, Daniel J. | Bayer, Arnold S. | Cabell, Christopher H. | Chu, Vivian | Corey, G. Ralph | Durack, David T. | Eykyn, Susannah | Fowler, Vance G. | Hoen, Bruno | Miró, José M. | Moreillon, Phillipe | Olaison, Lars | Raoult, Didier | Rubinstein, Ethan | Sexton, Daniel J.
Background
Host factors and complications have been associated with higher mortality in infective endocarditis (IE). We sought to develop and validate a model of clinical characteristics to predict 6‐month mortality in IE.
Methods and Results
Using a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ICE]–Prospective Cohort Study [PCS], 2000–2006, n=4049), a model to predict 6‐month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry (ICE‐PLUS, 2008–2012, n=1197). The 6‐month mortality was 971 of 4049 (24.0%) in the ICE‐PCS cohort and 342 of 1197 (28.6%) in the ICE‐PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE, causative organism, left‐sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6‐month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62–0.89). A simplified risk model was developed by weight adjustment of these variables.
Conclusions
Six‐month mortality after IE is ≈25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE.
doi:10.1161/JAHA.115.003016
PMCID: PMC4859286  PMID: 27091179
infection; mortality; prognosis; surgery; valves; Infectious Endocarditis; Valvular Heart Disease; Mortality/Survival; Clinical Studies
3.  Oritavancin for acute bacterial skin and skin structure infection 
Expert opinion on pharmacotherapy  2015;16(7):1091-1098.
Introduction
Inpatient treatment of acute bacterial skin and skin structure infections (ABSSSI) exerts a significant economic burden on the healthcare system. Oritavancin is a concentration-dependent, rapidly bactericidal agent approved for the treatment of ABSSSI. Its prolonged half-life with one-time intravenous (IV) dosing offers a potential solution to this burden. In addition, oritavancin represents an alternative therapy for Streptococci and multidrug resistant gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Animal models have also shown promising results with oritavancin for other disease states including those that require long courses of IV therapy.
Areas covered
This review covers oritavancin’s basic chemistry, spectrum of activity, pharmacodynamics/ pharmacokinetics, efficacy in clinical trials, and provides expert opinion on future directions. To compose this review, a search of PubMed was performed, and articles written in the English language were selected based on full text availability.
Expert Opinion
If oritavancin is proven to be a cost-effective strategy for outpatient treatment and prevents complications of prolonged IV therapy, it will be sought as an alternative antibiotic therapy for ABSSSI. In addition, further clinical data demonstrating efficacy in gram-positive infections requiring prolonged therapy such as endocarditis and osteomyelitis could support oritavancin’s success in the current market.
doi:10.1517/14656566.2015.1026256
PMCID: PMC4580226  PMID: 25803197
acute bacterial skin and skin structure infection; lipoglycopeptide; oritavancin; Staphylococcus aureus
4.  Increasing Incidence of Extended-Spectrum β-Lactamase-Producing Escherichia coli in Community Hospitals throughout the Southeastern United States 
OBJECTIVE
To describe the epidemiology of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) and Klebsiella pneumoniae (ESBL-KP) infections
DESIGN
Retrospective cohort
SETTING
Inpatient care at community hospitals
PATIENTS
All patients with ESBL-EC or ESBL-KP infections
METHODS
ESBL-EC and ESBL-KP infections from 26 community hospitals were prospectively entered into a centralized database from January 2009 to December 2014.
RESULTS
A total of 925 infections caused by ESBL-EC (10.5 infections per 100,000 patient days) and 463 infections caused by ESBL-KP (5.3 infections per 100,000 patient days) were identified during 8,791,243 patient days of surveillance. The incidence of ESBL-EC infections increased from 5.28 to 10.5 patients per 100,000 patient days during the study period (P =.006). The number of community hospitals with ESBL-EC infections increased from 17 (65%) in 2009 to 20 (77%) in 2014. The median ESBL-EC infection rates among individual hospitals with ≥1 ESBL-EC infection increased from 11.1 infections/100,000 patient days (range, 2.2–33.9 days) in 2009 to 22.1 infections per 100,000 patient days (range, 0.66–134 days) in 2014 (P =.05). The incidence of ESBL-KP infections remained constant over the study period (P = .14). Community-associated and healthcare-associated ESBL-EC infections trended upward (P =.006 and P = .02, respectively), while hospital-onset infections remained stable (P = .07). ESBL-EC infections were more common in females (54% vs 44%, P < .001) and Caucasians (50% vs 40%, P < .0001), and were more likely to be isolated from the urinary tract (61% vs 52%, P < .0001) than ESBL-KP infections.
CONCLUSIONS
The incidence of ESBL-EC infection has increased in community hospitals throughout the southeastern United States, while the incidence of ESBL-KP infection has remained stable. Community- and healthcare-associated ESBL-EC infections are driving the upward trend.
doi:10.1017/ice.2015.239
PMCID: PMC4748740  PMID: 26458226
5.  Pulse Field Gel Electrophoresis 
Pulse Field Gel Electrophoresis (PFGE) is a powerful genotyping technique used for the separation of large DNA molecules (entire genomic DNA) after digesting it with unique restriction enzymes and applying to a gel matrix under the electric field that periodically changes direction. PFGE is a variation of agarose gel electrophoresis that permits analysis of bacterial DNA fragments over an order of magnitude larger than that with conventional restriction enzyme analysis. It provides a good representation of the entire bacterial chromosome in a single gel with a highly reproducible restriction profile, providing clearly distinct and well-resolved DNA fragments.
doi:10.1007/7651_2014_191
PMCID: PMC4582012  PMID: 25682374
Pulse field gel electrophoresis; Restriction enzyme; Genomic DNA; Genotyping technique
6.  Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management 
Clinical Microbiology Reviews  2015;28(3):603-661.
SUMMARY
Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to β-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.
doi:10.1128/CMR.00134-14
PMCID: PMC4451395  PMID: 26016486
7.  Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants 
JAMA pediatrics  2015;169(12):1105-1111.
Importance
Staphylococcus aureus is a frequent cause of infection in hospitalized infants. These infections are associated with increased mortality and morbidity, and longer hospital stays, but data on the burden of S. aureus disease in hospitalized infants are limited.
Objective
To compare demographics and mortality of infants with invasive methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA), determine the annual proportion of S. aureus infections that were MRSA, and compare the risk of death following an invasive MRSA infection to the risk following an invasive MSSA infection.
Design
Multicenter retrospective study of a large, nationally representative cohort.
Setting
348 neonatal intensive care units managed by the Pediatrix Medical Group.
Participants
3888 infants with an invasive S. aureus infection who were discharged between 1997 and 2012.
Exposure
Invasive S. aureus infection.
Main Outcomes and Measures
Incidence of invasive S. aureus infections. Infant characteristics and mortality following MRSA or MSSA infection.
Results
The 3888 infants had 3978 invasive S. aureus infections (2868 MSSA, 1110 MRSA). The incidence of invasive S. aureus infection was 44.8 infections/10,000 infants. The yearly proportion of invasive infections caused by MRSA increased from 1997 to 2006 and has remained relatively stable since then. Infants with invasive MRSA or MSSA infections had similar gestational ages and birth weights. Invasive MRSA infections occurred more often at a younger postnatal age. For infants with available mortality data, more infants with invasive MSSA infections died at hospital discharge (N=237) than those with invasive MRSA infections (N=110). The proportion of infants who died following invasive MSSA or MRSA infection were similar: 237/2474 (9.6%) and 110/926 (11.9%), P=.05, respectively. Adjusted risk of death at hospital discharge was similar after invasive MSSA and MRSA infections overall (risk ratio, 1.19; 95% CI, 0.96-1.49). Risks of death at 7 and 30 days after invasive infection were similar between infants with invasive MSSA and MRSA infection.
Conclusion
Infant mortality following invasive MRSA and MSSA infections is similar. MSSA causes more infections and more deaths in infants than MRSA. Measures to prevent S. aureus infection should include MSSA in addition to MRSA.
doi:10.1001/jamapediatrics.2015.2380
PMCID: PMC4694042  PMID: 26502073
8.  Survival Benefit of Empirical Therapy for Staphylococcus aureus Bloodstream Infections in Infants 
Background
The impact of early adequate empirical antibiotic therapy on outcomes of infants in the neonatal intensive care unit (NICU) who develop Staphylococcus aureus bloodstream infection (BSI) is unknown.
Methods
Infants with S. aureus BSI discharged in 1997–2012 from 348 NICUs managed by the Pediatrix Medical Group were identified. Early adequate empirical antibiotic therapy was defined as exposure to ≥1 antibiotic with anti-staphylococcal activity on the day the first positive blood culture was obtained. All other cases were defined as inadequate empirical antibiotic therapy. We evaluated the association between inadequate empirical antibiotic therapy on outcomes controlling for gestational age, small-for-gestational-age status, gender, discharge year, mechanical ventilation, inotropic support, and use of supplemental oxygen. The primary outcome was 30-day mortality. Secondary outcomes were 7-day mortality, death before hospital discharge, and length of bacteremia.
Results
Of the 3339 infants with S. aureus BSI, 2492 (75%) had methicillin-susceptible S. aureus (MSSA) BSI and 847 (25%) had methicillin-resistant S. aureus (MRSA) BSI. Inadequate empirical antibiotic therapy was administered in 725 (22%) cases. Inadequate empirical antibiotic therapy was associated with increased 30-day mortality (odds ratio, 2.03 [95% confidence interval, 1.08, 3.82]) among infants with MRSA BSI. Inadequate empirical antibiotic therapy was not associated with increases in mortality among infants with MSSA BSI.
Conclusions
After controlling for confounders, inadequate empirical antibiotic therapy was associated with a modestly increased mortality at 30 days for infants with MRSA BSI.
doi:10.1097/INF.0000000000000850
PMCID: PMC4604046  PMID: 26222060
infants; early empirical antibiotic therapy; Staphylococcus aureus bloodstream infection; NICU
9.  Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) 
Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and construction/analysis of a desirability of outcome ranking (DOOR). DOOR/RADAR addresses neglected challenges in assessing outcomes in clinical trials that compare antibiotic use strategies.
Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use.
doi:10.1093/cid/civ495
PMCID: PMC4542892  PMID: 26113652
DOOR; RADAR; antibiotic use strategies
10.  Neonatal Escherichia coli Bloodstream Infections: Clinical Outcomes and Impact of Initial Antibiotic Therapy 
Background
Escherichia coli is a common cause of bloodstream infections (BSI) in infants and is associated with high mortality and morbidity among survivors. The clinical significance of antibiotic resistance and timing of appropriate antimicrobial therapy in this population is poorly understood.
Methods
We identified all infants with E. coli BSIs discharged from 77 neonatal intensive care units managed by the Pediatrix Medical Group in 2012. We used multivariable logistic regression to evaluate the association between 30-day mortality and ampicillin-resistant E. coli BSI, as well as the number of active empiric antimicrobial agents administered, controlling for gestational age, small-for-gestational age status, early- versus late-onset BSI, oxygen requirement, ventilator support, and inotropic support on the day of the first positive blood culture.
Results
We identified 258 episodes of E. coli BSI, including 123 (48%) ampicillin-resistant isolates. Unadjusted 30-day mortality did not significantly differ between infants with ampicillin-resistant vs. -susceptible E. coli BSI (11/123 [9%] vs. 7/135 [5%]; p=0.33; adjusted odds ratio=1.37 [95% confidence interval 0.39, 4.77]). Among ampicillin-resistant E. coli BSIs, 30-day mortality was not significantly lower for infants treated with at least one empiric antimicrobial active against ampicillin-resistant E. coli vs. infants receiving no active empiric agent (adjusted odds ratio=1.50 [0.07, 33.6]).
Conclusions
In this population of infants with E. coli BSI, ampicillin resistance was not associated with significantly increased mortality. Among the subset of infants with ampicillin-resistant E. coli, appropriate empirical antibiotic therapy was not associated with lower mortality.
doi:10.1097/INF.0000000000000769
PMCID: PMC4581845  PMID: 26065862
Escherichia coli; antimicrobial resistance; early-onset sepsis; late-onset sepsis; bacteremia
11.  Residence in Skilled Nursing Facilities is Associated with Tigecycline Non-Susceptibility in Carbapenem-Resistant Klebsiella pneumoniae 
Objective
To determine the rates of and risk factors for tigecycline non-susceptibility among carbapenem-resistant Klebsiella pneumoniae (CRKP) isolated from hospitalized patients.
Design
Multicenter prospective observational study
Setting
Acute care hospitals participating in the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle)
Patients
287 patients who had CRKP isolated from clinical cultures during hospitalization
Methods
Within the study period of 12/24/2011 – 10/1/2013, the first hospitalization of each patient with CRKP was included during which tigecycline susceptibility for the CRKP isolate was determined. Clinical data was entered into a centralized database, including data on pre-hospital origin. Breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used to interpret tigecycline susceptibility testing.
Results
Of 287 patients included, 155 (54%) had tigecycline-susceptible CRKP, whereas 81 (28%) of index isolates were tigecycline-intermediate, and 51 (18%) were tigecycline-resistant. In multivariable modeling, admission from a skilled nursing facility (OR 2.51, 95% CI 1.51–4.21, p=0.0004), positive culture within 2 days of admission (OR 1.82, 95% CI 1.06–3.15, p=0.03), and receipt of tigecycline within 14 days (OR 4.38, 95% CI 1.37–17.01, p=0.02) were found to be independent risk factors for tigecycline non-susceptibility.
Conclusions
In hospitalized patients with CRKP, tigecycline non-susceptibility was more frequently seen in admissions from skilled nursing facilities and occurred earlier during hospitalization. Skilled nursing facilities are an important target for interventions to decrease antibacterial resistance to antibiotics of last resort for treatment of CRKP.
doi:10.1017/ice.2015.118
PMCID: PMC4642723  PMID: 25990806
12.  Efficient Delivery of Investigational Antibacterial Agents via Sustainable Clinical Trial Networks 
The economics of antibiotics can be improved by infectious diseases–specific clinical trial networks. While developers would still need to implement an independent phase 1 program as well as studies focused on highly resistant pathogens, standardized procedures in a network focused on usual drug resistance phenotype isolates would permit sharing of controls and would predictably generate high-quality pivotal data for product registration while creating cost and time savings in the range of 30%–40%. This would reduce economic barriers to antibiotic development and contribute to public health.
doi:10.1093/cid/ciw244
PMCID: PMC4967592  PMID: 27481955
antibiotic development; antimicrobial resistance; trial networks
13.  Diagnosis of Capnocytophaga canimorsus Sepsis by Whole-Genome Next-Generation Sequencing 
Open Forum Infectious Diseases  2016;3(3):ofw144.
We report the case of a 60-year-old man with septic shock due to Capnocytophaga canimorsus that was diagnosed in 24 hours by a novel whole-genome next-generation sequencing assay. This technology shows great promise in identifying fastidious pathogens, and, if validated, it has profound implications for infectious disease diagnosis.
doi:10.1093/ofid/ofw144
PMCID: PMC5047422  PMID: 27704003
high-throughput nucleotide sequencing; microbiological techniques; sepsis/diagnosis
14.  Echocardiographic Findings Predict In-Hospital and One-Year Mortality in Left-Sided Native Valve Staphylococcus aureus Endocarditis: An Analysis from The International Collaboration on Endocarditis-Prospective Echo Cohort Study 
Circulation. Cardiovascular imaging  2015;8(7):10.1161/CIRCIMAGING.114.003397 e003397.
Background
Staphylococcus (S.) aureus left-sided native valve infective endocarditis (LNVIE) has higher complication and mortality rates compared with endocarditis from other pathogens. Whether echocardiographic variables can predict prognosis in S. aureus LNVIE is unknown.
Methods and Results
Consecutive patients with LNVIE, enrolled between January 2000 and September 2006, in the International Collaboration on Endocarditis were identified. Subjects without S. aureus IE were matched to those with S. aureus IE by the propensity of having S. aureus. Survival differences were determined using log-rank significance tests. Independent echocardiographic predictors of mortality were identified using Cox-proportional hazards models that included inverse probability of treatment weighting and surgery as a time-dependent covariate. Of 727 subjects with LNVIE and 1-year follow-up, 202 had S. aureus IE. One-year survival rates were significantly lower for patients with S. aureus IE overall (57% S. aureus IE vs. 80% non-S. aureus IE, p<0.001) and in the propensity-matched cohort (59% S. aureus IE vs. 68% non-S. aureus IE, p<0.05). Intracardiac abscess (HR 2.93; 95%CI 1.52–5.40, p<0.001) and left ventricular ejection fraction (LVEF)<40% (OR 3.01; 95%CI 1.35–6.04, p=0.004) were the only independent echocardiographic predictors of in-hospital mortality in S. aureus LNVIE. Valve perforation (HR 2.16; 95% CI 1.21–3.68, p=0.006) and intracardiac abscess (HR 2.25; 95%CI 1.26–3.78, p=0.004) were the only independent predictors of one-year mortality.
Conclusions
S. aureus is an independent predictor of one-year mortality in subjects with LNVIE. In S. aureus LNVIE, intracardiac abscess and LVEF<40% independently predicted in-hospital mortality and intracardiac abscess and perforation independently predicted one-year mortality.
doi:10.1161/CIRCIMAGING.114.003397
PMCID: PMC4503384  PMID: 26162783
endocarditis; echocardiography; valve; risk factor; survival analysis; infective endocarditis
15.  Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia 
Journal of Clinical Microbiology  2014;53(1):227-236.
Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 μg/ml, versus failure, 1.09 μg/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates (P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study.
doi:10.1128/JCM.02023-14
PMCID: PMC4290928  PMID: 25392350
16.  Antibacterial Resistance Leadership Group: Open for Business 
The Antibacterial Resistance Leadership Group (ARLG) is tasked with prioritizing, designing, implementing, and conducting clinical studies to address antibacterial resistance. This article outlines clinical research resources and opportunities made available by ARLG and encourages submission of proposals that address antibacterial resistance.
Funded by the National Institute of Allergy and Infectious Diseases, the Antibacterial Resistance Leadership Group (ARLG) is tasked with developing a clinical research agenda and conducting clinical studies to address the growing public health threat of antibacterial resistance. The ARLG has identified 4 high-priority areas of research: infections caused by gram-negative bacteria, infections caused by gram-positive bacteria, antimicrobial stewardship and infection prevention, and diagnostics. The ARLG will be accepting proposals from the scientific community for clinical research that addresses 1 or more of these high-priority areas. These studies should have the potential to transform medical practice and be unlikely to occur without ARLG support. The purpose of this article is to make interested parties aware of clinical research opportunities made available by ARLG and to encourage submission of clinical research proposals that address the problem of antibacterial resistance.
doi:10.1093/cid/ciu132
PMCID: PMC4017892  PMID: 24610430
antibacterial resistance; ARLG; Leadership Group; clinical trials; clinical research
17.  Endovascular Infections Caused by Methicillin-Resistant Staphylococcus aureus Are Linked to Clonal Complex-Specific Alterations in Binding and Invasion Domains of Fibronectin-Binding Protein A as Well as the Occurrence of fnbB 
Infection and Immunity  2015;83(12):4772-4780.
Endovascular infections caused by Staphylococcus aureus involve interactions with fibronectin present as extracellular matrix or surface ligand on host cells. We examined the expression, structure, and binding activity of the two major S. aureus fibronectin-binding proteins (FnBPA, FnBPB) in 10 distinct, methicillin-resistant clinical isolates from patients with either persistent or resolving bacteremia. The persistent bacteremia isolates (n = 5) formed significantly stronger bonds with immobilized fibronectin as determined by dynamic binding measurements performed with atomic force microscopy. Several notable differences were also observed when the results were grouped by clonal complex 5 (CC5) strains (n = 5) versus CC45 strains (n = 5). Fibronectin-binding receptors on CC5 formed stronger bonds with immobilized fibronectin (P < 0.001). The fnbA gene was expressed at higher levels in CC45, whereas fnbB was found in only CC5 isolates. The fnbB gene was not sequenced because all CC45 isolates lacked this gene. Instead, comparisons were made for fnbA, which was present in all 10 isolates. Sequencing of fnbA revealed discrete differences within high-affinity, fibronectin-binding repeats (FnBRs) of FnBPA that included (i) 5-amino-acid polymorphisms in FnBR-9, FnBR-10, and FnBR-11 involving charged or polar side chains, (ii) an extra, 38-amino-acid repeat inserted between FnBR-9 and FnBR-10 exclusively seen in CC45 isolates, and (iii) CC5 isolates had the SVDFEED epitope in FnBR-11 (a sequence shown to be essential for fibronectin binding), while this sequence was replaced in all CC45 isolates with GIDFVED (a motif known to favor host cell invasion at the cost of reduced fibronectin binding). These complementary sequence and binding data suggest that differences in fnbA and fnbB, particularly polymorphisms and duplications in FnBPA, give S. aureus two distinct advantages in human endovascular infections: (i) FnBPs similar to that of CC5 enhance ligand binding and foster initiation of disease, and (ii) CC45-like FnBPs promote cell invasion, a key attribute in persistent endovascular infections.
doi:10.1128/IAI.01074-15
PMCID: PMC4645417  PMID: 26416903
18.  Clinical Management of Staphylococcus aureus Bacteremia 
JAMA  2014;312(13):1330-1341.
Importance
Several management strategies may improve outcomes in patients with Staphylococcus aureus bacteremia (SAB). The strength of evidence supporting these management strategies, however, varies widely.
Objective
To perform a systematic review of the evidence for two unresolved questions involving management strategies for SAB: 1) is transesophageal echocardiography (TEE) necessary in all cases of SAB; and 2) what is the optimal antibiotic therapy for methicillin resistant Staphylococcus aureus (MRSA) bacteremia?
Evidence acquisition
A PubMed search from inception through May 2014 was performed to find studies that addressed the role of TEE in SAB. A second search of PubMed, EMBASE, and The Cochrane Library from 1/1/1990 to 5/28/2014 was performed to find studies that addressed antibiotic treatment of MRSA bacteremia. Studies that reported outcomes of systemic antibiotic therapy for MRSA bacteremia were included. All searches were augmented by review of bibliographic references from included studies. The quality of evidence was assessed using the GRADE system by consensus of independent evaluations by at least two authors.
Results
In 9 studies with a total of 3513 patients, use of TEE was associated with higher rates of diagnosis of endocarditis (14–25%) when compared with TTE (2–14%). Five studies proposed criteria to identify patients in whom TEE might safely be avoided. Only one high-quality trial of antibiotic therapy for MRSA bacteremia was identified from the 83 studies considered.
Conclusions and relevance
Most contemporary management strategies for SAB are based upon low quality evidence. TEE is indicated in most patients with SAB. It may be possible to identify a subset of SAB patients for whom TEE can be safely avoided. Vancomycin and daptomycin are the first-line antibiotic choices for MRSA bacteremia. Well-designed studies to address the management of SAB are desperately needed.
doi:10.1001/jama.2014.9743
PMCID: PMC4263314  PMID: 25268440
19.  Impact of therapy and strain type on outcomes in urinary tract infections caused by carbapenem-resistant Klebsiella pneumoniae 
Objectives
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an important healthcare-associated pathogen. We evaluated the impact of CRKP strain type and treatment on outcomes of patients with CRKP bacteriuria.
Patients and methods
Physician-diagnosed CRKP urinary tract infection (UTI)—defined as those patients who received directed treatment for CRKP bacteriuria—was studied in the multicentre, prospective Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle) cohort. Strain typing by repetitive extragenic palindromic PCR (rep-PCR) was performed. Outcomes were classified as failure, indeterminate or success. Univariate and multivariate ordinal analyses to evaluate the associations between outcome, treatment and strain type were followed by binomial analyses.
Results
One-hundred-and-fifty-seven patients with physician-diagnosed CRKP UTI were included. After adjustment for CDC/National Healthcare Safety Network (NHSN)-defined UTI, critical illness and receipt of more than one active antibiotic, patients treated with aminoglycosides were less likely to fail therapy [adjusted OR (aOR) for failure 0.34, 95% CI 0.15–0.73, P = 0.0049]. In contrast, patients treated with tigecycline were more likely to fail therapy (aOR for failure 2.29, 95% CI 1.03–5.13, P = 0.0425). Strain type data were analysed for 55 patients. The predominant clades were ST258A (n = 18, 33%) and ST258B (n = 26, 47%). After adjustment for CDC/NHSN-defined UTI and use of tigecycline and aminoglycosides, infection with strain type ST258A was associated with clinical outcome in ordinal analysis (P = 0.0343). In multivariate binomial models, strain type ST258A was associated with clinical failure (aOR for failure 5.82, 95% CI 1.47–28.50, P = 0.0113).
Conclusions
In this nested cohort study of physician-diagnosed CRKP UTI, both choice of treatment and CRKP strain type appeared to impact on clinical outcomes.
doi:10.1093/jac/dku495
PMCID: PMC4356203  PMID: 25492391
carbapenem-resistant Enterobacteriaceae; MDR; UTIs; aminoglycosides; tigecycline
20.  No Survival Benefit with Empirical Vancomycin Therapy for Coagulase-negative Staphylococcal Bloodstream Infections in Infants 
Background
Coagulase-negative Staphylococcus (CoNS) is the most common cause of bloodstream infections (BSI) in hospitalized infants. CoNS BSI is most reliably treated with vancomycin; however, concerns about side effects and promoting resistance often delay empirical vancomycin therapy until culture results become available.
Methods
All infants with CoNS BSI discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2012 were identified. Empirical vancomycin therapy was defined as vancomycin exposure on the day of the first positive blood culture. Delayed vancomycin therapy was defined as vancomycin exposure 1–3 days after the first positive blood culture. We used multivariable logistic regression with random effects for site to evaluate the association between the use of empirical vancomycin therapy vs. delayed vancomycin therapy and 30-day mortality, controlling for gestational age, small-for-gestational age status, postnatal age on the day of the first positive culture, oxygen requirement, ventilator support, and inotropic support on the day the first positive culture was obtained.
Results
Of the 4364 infants with CoNS BSI, 2848 (65%) were treated with empirical vancomycin. The median postnatal age at first positive culture was 14 days (interquartile range: 9, 21). Unadjusted 30-day mortality was similar for infants treated with empirical vancomycin and infants treated with delayed vancomycin therapy (166/2848 [6%] vs. 69/1516 [4%]; p=0.08). There was no significant difference in 30-day mortality on multivariable analysis (odds ratio: 1.14 [0.84, 1.56]). The median duration of bacteremia was 1 day longer for infants with delayed vancomycin therapy (4 days [interquartile range 2, 6] vs. 3 days [2, 5]; p<0.0001).
Conclusions
The median duration of bacteremia was 1 day longer in infants with CoNS BSI who received delayed vancomycin therapy. Despite this finding, empirical vancomycin therapy for CoNS BSI was not associated with improved mortality.
doi:10.1097/INF.0000000000000573
PMCID: PMC4357312  PMID: 25760564
late-onset sepsis; NICU
21.  Renal systems biology of patients with systemic inflammatory response syndrome 
Kidney international  2015;88(4):804-814.
A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular weight proteins and acute phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and n-acetylaspartate were inversely correlated with the majority of significantly down-regulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness.
doi:10.1038/ki.2015.150
PMCID: PMC4591107  PMID: 25993322
acute kidney injury; chronic kidney disease; gene expression; hemodialysis; sepsis
22.  CAMERA2 – combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: study protocol for a randomised controlled trial 
Trials  2016;17:170.
Background
Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20–50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia.
Methods/Design
We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint.
Discussion
Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.
Trial registration
ClinicalTrials.gov Identifier: NCT02365493. Registered 24 February 2015.
doi:10.1186/s13063-016-1295-3
PMCID: PMC4815121  PMID: 27029920
Staphylococcus aureus; Methicillin-resistant; MRSA; Vancomycin; Combination; Randomised controlled trial; Daptomycin; Flucloxacillin; Cloxacillin; Cefazolin; Nafcillin
23.  Clinical MRSA isolates from skin and soft tissue infections show increased in vitro production of phenol soluble modulins 
The Journal of infection  2015;71(4):447-457.
Summary
Background
Phenol-soluble modulins (PSMs) are amphipathic, pro-inflammatory proteins secreted by most Staphylococcus aureus isolates. This study tested the hypothesis that in vitro PSM production levels are associated with specific clinical phenotypes.
Methods
177 methicillin-resistant S. aureus (MRSA) isolates from infective endocarditis (IE), skin and soft tissue infection (SSTI), and hospital-acquired/ventilator-associated pneumonia (HAP) were matched by geographic origin, then genotyped using spa-typing. In vitro PSM production was measured by high performance liquid chromatography/mass spectrometry. Statistical analysis was performed using Chi-squared or Kruskal–Wallis tests as appropriate.
Results
Spa type 1 was significantly more common in SSTI isolates (62.7% SSTI; 1.7% IE; 16.9% HAP; p < 0.0001) while HAP and IE isolates were more commonly spa type 2 (0% SSTI; 37.3% IE; 40.7% HAP; p < 0.0001). USA300 isolates produced the highest levels of PSMs in vitro. SSTI isolates produced significantly higher quantities of PSMα1-4, PSMβ1, and δ-toxin than other isolates (p < 0.001). These findings persisted when USA300 isolates were excluded from analysis.
doi:10.1016/j.jinf.2015.06.005
PMCID: PMC4816458  PMID: 26079275
Phenol soluble modulin; MRSA; Skin and soft tissue infection; Pneumonia; Endocarditis
24.  Virulence of Endemic Nonpigmented Northern Australian Staphylococcus aureus Clone (Clonal Complex 75, S. argenteus) Is Not Augmented by Staphyloxanthin 
The Journal of Infectious Diseases  2013;208(3):520-527.
Staphylococcus aureus clonal complex 75 (herein referred to as S. argenteus) lacks the carotenoid pigment operon, crtOPQMN, responsible for production of the putative virulence factor, staphyloxanthin. Although a common cause of community-onset skin infections among Indigenous populations in northern Australia, this clone is infrequently isolated from hospital-based patients with either bacteremic or nonbacteremic infections. We hypothesized that S. argenteus would have attenuated virulence compared to other S. aureus strains due to its staphyloxanthin “deficiency.” Compared to prototypical S. aureus strains, S. argenteus was more susceptible to oxidative stress and neutrophil killing in vitro and had reduced virulence in murine sepsis and skin infection models. Transformation with pTX-crtOPQMN resulted in staphyloxanthin expression and increased resistance to oxidative stress in vitro. However, neither resistance to neutrophil killing nor in vivo virulence was increased. Thus, reduced virulence of S. argenteus in these models is due to mechanisms unrelated to lack of staphyloxanthin production.
doi:10.1093/infdis/jit173
PMCID: PMC3699000  PMID: 23599317
Staphylococcus aureus; staphyloxanthin; virulence; Australia; carotenoid pigment
25.  Application of Whole-Genome Sequencing to an Unusual Outbreak of Invasive Group A Streptococcal Disease 
Open Forum Infectious Diseases  2016;3(1):ofw042.
Whole-genome analysis was applied to investigate atypical point-source transmission of 2 invasive group A streptococcal (GAS) infections. Isolates were serotype M4, ST39, and genetically indistinguishable. Comparison with MGAS10750 revealed nonsynonymous polymorphisms in ropB and increased speB transcription. This study demonstrates the usefulness of whole-genome analyses for GAS outbreaks.
doi:10.1093/ofid/ofw042
PMCID: PMC4800461  PMID: 27006966
group A Streptococcus; invasive disease; speB; Streptococcuspyogenes; whole-genome sequencing

Results 1-25 (97)