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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.  Building Sustainable Capacity for Cardiovascular Care at a Public Hospital in Western Kenya 
Cardiovascular disease deaths are increasing in low- and middle-income countries and are exacerbated by health care systems that are ill-equipped to manage chronic diseases. Global health partnerships, which have stemmed the tide of infectious diseases in low- and middle-income countries, can be similarly applied to address cardiovascular diseases. In this review, we present the experiences of an academic partnership between North American and Kenyan medical centers to improve cardiovascular health in a national public referral hospital. We highlight our stepwise approach to developing sustainable cardiovascular services using the health system strengthening World Health Organization Framework for Action. The building blocks of this framework (leadership and governance, health workforce, health service delivery, health financing, access to essential medicines, and health information system) guided our comprehensive and sustainable approach to delivering subspecialty care in a resource limited setting. Our experiences may guide the development of similar collaborations in other settings.
doi:10.1016/j.jacc.2015.09.086
PMCID: PMC4680855  PMID: 26653630
cardiovascular disease; global health partnership; limited resources; sub-Saharan Africa
5.  A randomized, double-blind, placebo controlled safety, tolerability, and pharmacokinetic dose escalation study of a gentamicin vancomycin gel in patients undergoing colorectal surgery 
Background
Despite numerous interventions promulgated by the Surgical Care Improve Project (SCIP) and other organizations, surgical site infection (SSI) continues to be a significant medical problem. DFA-02 is a novel bioresorbable modified-release gel consisting of both gentamicin (16.8 mg/mL) and vancomycin (18.8 mg/mL) to be applied during surgical incision closure for the prevention of SSIs. The following double-blind phase 2a trial was designed to test the safety and tolerability of DFA-02.
Methods
At six US sites, the study planned to randomize 40 subjects undergoing colorectal surgery (30 with DFA-02, and eight with placebo gel) in four ascending dose cohorts (10-, 20-, 30-, and 40-mL study drug per wound). Safety was ascertained and serum pharmacokinetics (PK) was determined.
Results
Study enrollment was discontinued after the first three dose cohorts (10, 20, and 30 mL) as even very large incisions could not accommodate more than 20 mL of gel, leaving no scientific justification for the 40-mL cohort. DFA-02 was well tolerated and showed no evidence of local tissue reaction or impairment of wound healing. No serious AEs were deemed related to study drug. Systemic exposure to gentamicin and vancomycin remained well below levels considered to be at higher risk for oto- or nephrotoxicity. The maximal gentamicin and vancomycin levels observed were 2.36 and 0.684 μg/mL at 6 h, which were well below the prespecified stopping criteria of 12 and 20 μg/mL, respectively.
Conclusions
In this small phase 2a study, the study drug was well tolerated and appeared to be free of serious adverse effects. Consistent with these findings, the PK values were consistent with gradual release of the antibiotics from the gel in the surgical site.
Trial registration
ClinicalTrials.gov, NCT01496352
doi:10.1186/s13741-016-0043-2
PMCID: PMC4910209  PMID: 27313846
Surgical site infection; Colorectal; Topical antibiotic; Gentamicin; Vancomycin
6.  Potential Role for Telavancin in Bacteremic Infections Due to Gram-Positive Pathogens: Focus on Staphylococcus aureus 
Experimental models and limited clinical data support a potential role for telavancin, a bactericidal lipoglycopeptide antibiotic, for treatment of Staphylococcus aureus bacteremia (SAB). Additional clinical experience is needed to fully assess use of telavancin for SAB.
Staphylococcus aureus bacteremia (SAB) is one of the most common serious bacterial infections and the most frequent invasive infection due to methicillin-resistant S. aureus (MRSA). Treatment is challenging, particularly for MRSA, because of limited treatment options.
Telavancin is a bactericidal lipoglycopeptide antibiotic that is active against a range of clinically relevant gram-positive pathogens including MRSA. In experimental animal models of sepsis telavancin was shown to be more effective than vancomycin.
In clinically evaluable patients enrolled in a pilot study of uncomplicated SAB, cure rates were 88% for telavancin and 89% for standard therapy. Among patients with infection due to only gram-positive pathogens enrolled in the 2 phase 3 studies of telavancin for treatment of hospital-acquired pneumonia, cure rates for those with bacteremic S. aureus pneumonia were 41% (9/22, telavancin) and 40% (10/25, vancomycin) with identical mortality rates. These data support further evaluation of telavancin in larger, prospective studies of SAB.
doi:10.1093/cid/ciu971
PMCID: PMC4329924  PMID: 25472944
Staphylococcus aureus; MRSA; bacteremia; telavancin; experimental
7.  An open-label, pragmatic, randomized controlled clinical trial to evaluate the comparative effectiveness of daptomycin versus vancomycin for the treatment of complicated skin and skin structure infection 
BMC Infectious Diseases  2015;15:503.
Background
Treatment of complicated skin and skin structure infection (cSSSI) places a tremendous burden on the health care system. Understanding relative resource utilization associated with different antimicrobials is important for decision making by patients, health care providers, and payers.
Methods
The authors conducted an open-label, pragmatic, randomized (1:1) clinical study (N = 250) to compare the effectiveness of daptomycin with that of vancomycin for treatment of patients hospitalized with cSSSI caused by suspected or documented methicillin-resistant Staphylococcus aureus infection. The primary study end point was infection-related length of stay (IRLOS). Secondary end points included health care resource utilization, cost, clinical response, and patient-reported outcomes. Patient assessments were performed daily until the end of antibiotic therapy or until hospital discharge, and at 14 days and 30 days after discharge.
Results
No difference was found for IRLOS, total LOS, and total inpatient cost between cohorts. Hospital LOS contributed 85.9 % to the total hospitalization cost, compared with 6.4 % for drug costs. Daptomycin showed a nonsignificant trend toward a higher clinical success rate, compared with vancomycin, at treatment days 2 and 3. In the multivariate analyses, vancomycin was associated with a lower likelihood of day 2 clinical success (odds ratio [OR] = 0.498, 95 % confidence interval [CI], 0.249–0.997; P < 0.05).
Conclusion
This study did not provide conclusive evidence of the superiority of one treatment over the other in terms of clinical, economic, or patient outcomes. The data suggest that physician and patient preference, rather than drug acquisition cost, should be the primary driver of initial antibiotic selection for hospitalized patients with cSSSI.
Trial registration
ClinicalTrials.gov: NCT01419184 (Date: August 16, 2011)
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1261-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-015-1261-9
PMCID: PMC4637139  PMID: 26547411
Daptomycin; Vancomycin; Complicated skin and skin structure infection; Pragmatic randomized clinical trial; Antimicrobial; Effectiveness
8.  Prolonged Use of Oritavancin for Vancomycin-Resistant Enterococcus faecium Prosthetic Valve Endocarditis 
Open Forum Infectious Diseases  2015;2(4):ofv156.
Oritavancin is a novel lipoglycopeptide with activity against Gram-positive organisms including streptococci, methicillin-resistant Staphylococcus aureus, vancomycin-resistant S aureus (VRSA), and vancomycin-resistant enterococci (VRE) [1–3]. The US Food and Drug Administration approved oritavancin as a single intravenous dose of 1200 mg for the treatment of acute bacterial skin and skin structure infections on the basis of 2 clinical trials demonstrating noninferiority compared with vancomycin [4, 5].
There are limited options for treatment of serious VRE infections. Monotherapy with daptomycin or tigecycline or linezolid may be sufficient in some cases, but combination therapy is often indicated for severe or complicated infections such as endocarditis. Several antibiotic combinations have been used in isolated case reports with some efficacy, including the following: high-dose ampicillin with an aminoglycoside [6], ampicillin with ceftriaxone or imipenem [7, 8], high-dose daptomycin with ampicillin and gentamicin [9] or with gentamicin and rifampin [10], daptomycin with tigecycline [11, 12], quinupristin-dalfopristin with high-dose ampicillin [13] or doxycycline and rifampin [14], and linezolid with tigecycline [15]. The limited efficacy, limited susceptibility, and extensive toxicities with many of these agents and combinations present barriers to effective treatment. Additional treatment options for VRE endocarditis would be valuable. Although oritavancin has been shown to have in vitro activity against some isolates of VRE, clinical data are lacking. We describe the first use of a prolonged course of oritavancin in the treatment of a serious VRE infection, prosthetic valve endocarditis.
doi:10.1093/ofid/ofv156
PMCID: PMC4677157  PMID: 26677455
endocarditis; enterococci; oritavancin; vancomycin-resistant; VRE
9.  Analysis of the Impact of Early Surgery on In-hospital Mortality of Native Valve Endocarditis: Use of Propensity Score and Instrumental Variable Methods to Adjust for Treatment Selection Bias 
Circulation  2010;121(8):1005-1013.
Background
The impact of early surgery on mortality in patients with native valve endocarditis (NVE) is unresolved. This study seeks to evaluate valve surgery compared to medical therapy for NVE, and to identify characteristics of patients who are most likely to benefit from early surgery.
Methods and Results
Using a prospective, multinational cohort of patients with definite NVE, the effect of early surgery on in-hospital mortality was assessed using propensity-based matching adjusting for survivor bias, and instrumental variable analysis. Patients were stratified by propensity quintile, paravalvular complications, valve perforation, systemic embolization, stroke, Staphylococcus aureus infection and congestive heart failure.
Of the 1552 patients with NVE, 720 (46%) underwent early surgery and 832 (54%) were treated with medical therapy. Compared to medical therapy, early surgery was associated with a significant reduction in mortality in the overall cohort (12.1% [87/720] vs. 20.7% [172/832]) and after propensity-based matching and adjustment for survivor bias (absolute risk reduction (ARR) = -5.9 %; p<0.001). Using a combined instrument, the instrumental variable adjusted ARR in mortality associated with early surgery was -11.2% (p<0.001). In sub-group analysis, surgery was found to confer a survival benefit compared to medical therapy among patients with a higher propensity for surgery (ARR= -10.9% for quintiles 4 and 5; p=0.002); those with paravalvular complications (ARR= -17.3 %; p<0.001), systemic embolization (ARR= -12.9%; p=0.002), S aureus NVE (ARR= -20.1%; p<0.001) and stroke (ARR= -13%; p=0.02) but not with valve perforation or congestive heart failure.
Conclusions
Early surgery for NVE is associated with an in-hospital mortality benefit compared to medical therapy alone.
doi:10.1161/CIRCULATIONAHA.109.864488
PMCID: PMC3597944  PMID: 20159831
early surgery; infective endocarditis; medical therapy; in hospital mortality
10.  Telavancin for Acute Bacterial Skin and Skin Structure Infections, a Post Hoc Analysis of the Phase 3 ATLAS Trials in Light of the 2013 FDA Guidance 
Antimicrobial Agents and Chemotherapy  2015;59(10):6170-6174.
Two phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. This post hoc analysis included patients with lesion sizes of ≥75 cm2 and excluded patients with ulcers or burns (updated all-treated population; n = 1,127). Updated day 3 (early) clinical response was defined as a ≥20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of-cure (TOC) clinical response was defined as a ≥90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of −4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, −0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin.
doi:10.1128/AAC.00471-15
PMCID: PMC4576104  PMID: 26248356
12.  New developments in the management of severe skin and deep skin structure infections – focus on tedizolid 
Tedizolid, a novel oxazolidinone, is approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs). Tedizolid offers several potential advantages over current ABSSSI treatment options. First, tedizolid has a prolonged half-life, which allows for once-daily dosing. Second, tedizolid has broad spectrum activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, and enterococci. Third, tedizolid, available in both intravenous and oral formulations, has high oral bioavailability, allowing for easy oral step-down therapy. Fourth, in patients who have been prescribed selective serotonin reuptake inhibitors or monoamine oxidase inhibitors, tedizolid may have fewer drug interactions than linezolid. Finally, tedizolid may have fewer or comparatively delayed onset side effects than linezolid, including thrombocytopenia and nausea. This review covers the microbiology, pharmacology, mode of action, and pharmacokinetics of tedizolid as well as patient-focused perspectives such as quality of life, patient satisfaction/acceptability, adherence, and uptake and provides expert opinion on the current use of tedizolid for ABSSSIs and potential future therapeutic applications.
doi:10.2147/TCRM.S64553
PMCID: PMC4447168  PMID: 26045667
cellulitis; new antibiotics; oxazolidinones; infectious diseases; MRSA
14.  An integrated transcriptome and expressed variant analysis of sepsis survival and death 
Genome Medicine  2014;6(11):111.
Background
Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.
Methods
The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes.
Results
The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.
Conclusions
The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies.
Trial registration
ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0111-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-014-0111-5
PMCID: PMC4274761  PMID: 25538794
15.  Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections 
Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by Staphylococcus aureus. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%; P = 0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P = 0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P = 0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.)
doi:10.1128/AAC.03688-14
PMCID: PMC4335893  PMID: 25421472
16.  Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study 
Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA.
doi:10.1128/AAC.50.3.862-867.2006
PMCID: PMC1426424  PMID: 16495243
17.  A randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study 
BMC Infectious Diseases  2014;14:289.
Background
Staphylococcus aureus bacteremia is a common infection associated with significant morbidity and mortality. Telavancin is a bactericidal lipoglycopeptide active against Gram-positive pathogens, including methicillin-resistant S. aureus (MRSA). We conducted a randomized, double-blind, Phase 2 trial in patients with uncomplicated S. aureus bacteremia.
Methods
Patients were randomized to either telavancin or standard therapy (vancomycin or anti-staphylococcal penicillin) for 14 days. Continuation criteria were set to avoid complicated S. aureus bacteremia. The primary end point was clinical cure at 84 days.
Results
In total, 60 patients were randomized and 58 received ≥1 study medication dose (all-treated), 31 patients fulfilled inclusion/exclusion and continuation criteria (all-treated target [ATT]) (telavancin 15, standard therapy 16), and 17 patients were clinically evaluable (CE) (telavancin 8, standard therapy 9). Mean age (ATT) was 60 years. Intravenous catheters were the most common source of S. aureus bacteremia and ~50% of patients had MRSA. A similar proportion of CE patients were cured in the telavancin (88%) and standard therapy (89%) groups. All patients with MRSA bacteremia were cured and one patient with MSSA bacteremia failed study treatment in each group. Although adverse events (AEs) were more common in the telavancin ATT group (90% vs. 72%), AEs leading to drug discontinuation were similar (7%) in both treatment arms. Potentially clinically significant increases in serum creatinine (≥1.5 mg/dl and at least 50% greater than baseline) were more common in the telavancin group (20% vs. 7%).
Conclusions
This study suggests that telavancin may have utility for treatment of uncomplicated S. aureus bacteremia; additional studies are warranted. (Telavancin for Treatment of Uncomplicated Staphylococcus Aureus Bacteremia (ASSURE); NCT00062647).
doi:10.1186/1471-2334-14-289
PMCID: PMC4048626  PMID: 24884578
Bacteremia; Staphylococcus aureus; Telavancin; Vancomycin
18.  Effect of vancomycin serum trough levels on outcomes in patients with nosocomial pneumonia due to Staphylococcus aureus: a retrospective, post hoc, subgroup analysis of the Phase 3 ATTAIN studies 
BMC Infectious Diseases  2014;14:183.
Background
Existing data are not consistently supportive of improved clinical outcome when vancomycin dosing regimens aimed at achieving target trough levels are used. A retrospective, post hoc, subgroup analysis of prospectively collected data from the Phase 3 ATTAIN trials of telavancin versus vancomycin for treatment of nosocomial pneumonia was conducted to further investigate the relationship between vancomycin serum trough levels and patient outcome.
Methods
Study patients were enrolled in 274 study sites across 38 countries. A total of 98 patients had Staphylococcus aureus nosocomial pneumonia and vancomycin serum trough levels available. These patients were grouped according to their median vancomycin trough level; < 10 μg/mL, 10 μg/mL to < 15 μg/mL, and ≥ 15 μg/mL.
Results
Clinical cure rates in the < 10 μg/mL, 10 μg/mL to < 15 μg/mL, and ≥ 15 μg/mL vancomycin trough level groups were 70% (21/30), 55% (18/33), and 49% (17/35), respectively (p = 0.09), and the frequencies of patient death were 10% (3/30), 15% (5/33), and 20% (7/35), respectively (p = 0.31). Renal adverse events were more frequent in the ≥ 15 μg/mL (17% [6/35]) than the < 10 μg/mL (0%) and 10 μg/mL to < 15 μg/mL (3% [1/33]) trough level groups (p < 0.01). When patients with acute renal failure or vancomycin exposure within 7 days prior to study medication were excluded, clinical cure rates in the < 10 μg/mL, 10 μg/mL to < 15 μg/mL, and ≥ 15 μg/mL vancomycin trough level groups (71% [12/17], 60% [9/15], and 27% [3/11], respectively; p = 0.04) and the number of deaths (12% [2/17], 20% [3/15], and 45% [5/11], respectively; p = 0.07) demonstrated a trend towards worse outcomes in the higher vancomycin trough level groups.
Conclusions
The findings of our study suggest that higher vancomycin trough levels do not result in improved clinical response but likely increase the incidence of nephrotoxicity.
Trial registration
NCT00107952 and NCT00124020
doi:10.1186/1471-2334-14-183
PMCID: PMC4101862  PMID: 24708675
Vancomycin; Trough levels; Nosocomial pneumonia; Staphylococcus aureus
19.  Telavancin for Hospital-Acquired Pneumonia: Clinical Response and 28-Day Survival 
U.S. Food and Drug Administration draft guidance for future antibiotic clinical trials of bacterial nosocomial pneumonia recommends the use of diagnostic criteria according to American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines and the use of a primary endpoint of 28-day all-cause mortality. The effect of applying these guidelines on outcomes of phase III nosocomial pneumonia studies of telavancin was evaluated in a post hoc analysis. ATS/IDSA criteria were applied in a blind fashion to the original all-treated (AT) group. Clinical cure rates at final follow-up were determined in the refined AT and clinically evaluable (CE) groups (ATS/IDSA-AT and ATS/IDSA-CE, respectively). The exploratory endpoint of 28-day survival was evaluated for the ATS/IDSA-AT group. Noninferiority of telavancin versus vancomycin was demonstrated, with similar cure rates in the ATS/IDSA-AT (59% versus 59%) and ATS/IDSA-CE (83% versus 80%) groups. Cure rates favored telavancin in ATS/IDSA-CE patients where Staphylococcus aureus was the sole pathogen (86% versus 75%). Overall, 28-day survival rates were similar in the telavancin (76%) and vancomycin (77%) groups but lower in telavancin-treated patients with preexisting moderate-to-severe renal impairment (creatinine clearance [CLCR] of <50 ml/min). Telavancin should be administered to patients with moderate-to-severe renal impairment only if treatment benefit outweighs the risk or if no suitable alternatives are available.
doi:10.1128/AAC.02330-13
PMCID: PMC4023742  PMID: 24419353
20.  An integrated clinico-metabolomic model improves prediction of death in sepsis 
Science translational medicine  2013;5(195):195ra95.
Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.
doi:10.1126/scitranslmed.3005893
PMCID: PMC3924586  PMID: 23884467
21.  Epidemiology and outcome of major postoperative infections following cardiac surgery: Risk factors and impact of pathogen type 
Background
Major postoperative infections (MPIs) are poorly understood complications of cardiac surgery. We examined the epidemiology, microbiology, and outcome of MPIs occurring after cardiac surgery.
Methods
The study cohort was drawn from the Society of Thoracic Surgeon National Cardiac Database and comprised adults who underwent cardiac surgery at 5 tertiary hospitals between 2000 and 2004. We studied the incidence, microbiology, and risk factors of MPI (bloodstream or chest wound infections within 30 days after surgery), as well as 30-day mortality. We used multivariate regression analyses to evaluate the risk of MPI and mortality.
Results
MPI was identified in 341 of 10,522 patients (3.2%). Staphylococci were found in 52.5% of these patients, gram-negative bacilli (GNB) in 24.3%, and other pathogens in 23.2%. High body mass index, previous coronary bypass surgery, emergency surgery, renal impairment, immunosuppression, cardiac failure, and peripheral/cerebrovascular disease were associated with the development of MPI. Median postoperative duration of hospitalization (15 days vs 6 days) and mortality (8.5% vs 2.2%) were higher in patients with MPIs. Compared with uninfected individuals, odds of mortality were higher in patients with S aureus MPIs (adjusted odds ratio, 3.7) and GNB MPIs (adjusted odds ratio, 3.0).
Conclusions
Staphylococci accounted for the majority of MPIs after cardiac surgery. Mortality was higher in patients with Staphylococcus aureus- and GNB-related MPIs than in patients with MPIs caused by other pathogens and uninfected patients. Preventive strategies should target likely pathogens and high-risk patients undergoing cardiac surgery.
doi:10.1016/j.ajic.2012.01.012
PMCID: PMC3535474  PMID: 22609237
Wound infection; Sepsis; Cardiac surgical procedures; Morbidity; Mortality
22.  HACEK Infective Endocarditis: Characteristics and Outcomes from a Large, Multi-National Cohort 
PLoS ONE  2013;8(5):e63181.
The HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) are rare causes of infective endocarditis (IE). The objective of this study is to describe the clinical characteristics and outcomes of patients with HACEK endocarditis (HE) in a large multi-national cohort. Patients hospitalized with definite or possible infective endocarditis by the International Collaboration on Endocarditis Prospective Cohort Study in 64 hospitals from 28 countries were included and characteristics of HE patients compared with IE due to other pathogens. Of 5591 patients enrolled, 77 (1.4%) had HE. HE was associated with a younger age (47 vs. 61 years; p<0.001), a higher prevalence of immunologic/vascular manifestations (32% vs. 20%; p<0.008) and stroke (25% vs. 17% p = 0.05) but a lower prevalence of congestive heart failure (15% vs. 30%; p = 0.004), death in-hospital (4% vs. 18%; p = 0.001) or after 1 year follow-up (6% vs. 20%; p = 0.01) than IE due to other pathogens (n = 5514). On multivariable analysis, stroke was associated with mitral valve vegetations (OR 3.60; CI 1.34–9.65; p<0.01) and younger age (OR 0.62; CI 0.49–0.90; p<0.01). The overall outcome of HE was excellent with the in-hospital mortality (4%) significantly better than for non-HE (18%; p<0.001). Prosthetic valve endocarditis was more common in HE (35%) than non-HE (24%). The outcome of prosthetic valve and native valve HE was excellent whether treated medically or with surgery. Current treatment is very successful for the management of both native valve prosthetic valve HE but further studies are needed to determine why HE has a predilection for younger people and to cause stroke. The small number of patients and observational design limit inferences on treatment strategies. Self selection of study sites limits epidemiological inferences.
doi:10.1371/journal.pone.0063181
PMCID: PMC3656887  PMID: 23690995
23.  TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections 
Antimicrobial Agents and Chemotherapy  2012;56(11):5476-5483.
TD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of −7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistant Staphylococcus aureus at baseline (n = 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n = 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection.
doi:10.1128/AAC.00712-12
PMCID: PMC3486540  PMID: 22869571
24.  Clinical Presentation, Etiology and Outcome of Infective Endocarditis in the 21st Century: The International Collaboration on Endocarditis-Prospective Cohort Study 
Archives of internal medicine  2009;169(5):463-473.
Background
The aim of this study was to provide a contemporary picture of the presentation, etiology and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide.
Methods
Prospective cohort study of 2781 adults with definite IE admitted to 58 hospitals in 25 countries between June 2000 and September 2005.
Results
The median age of the cohort was 57.9 (IQR 43.2–71.8) years and 72% had native valve IE. Most (77%) patients presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health-care exposure was found in one quarter of patients. Staphylococcus aureus was the most common pathogen (31%). Mitral (41%) and aortic (38%) valves were infected most commonly. Complications were common: stroke (17%); embolization other than stroke (23%); heart failure (32%) and intracardiac abscess (14%). Surgical therapy was common (48%) and in-hospital mortality remained high (18%). Prosthetic valve involvement (OR 1.47, 95%CI 1.13–1.90), increasing age (OR 1.30, 95%CI 1.17–1.46 per 10-year interval), pulmonary edema (OR 1.79, 95%CI 1.39–2.30), S. aureus infection (OR 1.54, 95%CI 1.14–2.08), coagulase-negative staphylococcal infection (OR 1.50, 95%CI 1.07–2.10), mitral valve vegetation (OR 1.34, 95%CI 1.06–1.68), and paravalvular complications (OR 2.25, 95%CI 1.64–3.09) were associated with increased risk of in-hospital death, while viridans streptococcal infection (OR 0.52, 95%CI 0.33–0.81) and surgery (OR 0.61, 95%CI 0.44–0.83) were associated with decreased risk.
Conclusions
In the early 21st century, IE is more often an acute disease, characterized by a high rate of S. aureus infection. Mortality remains relatively high.
doi:10.1001/archinternmed.2008.603
PMCID: PMC3625651  PMID: 19273776
25.  Heterogeneous Vancomycin-Intermediate Susceptibility Phenotype in Bloodstream Methicillin-Resistant Staphylococcus aureus Isolates from an International Cohort of Patients with Infective Endocarditis: Prevalence, Genotype, and Clinical Significance 
The Journal of infectious diseases  2009;200(9):1355-1366.
Background
The significance of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is unknown. Using a multinational collection of isolates from methicillin-resistant S. aureus (MRSA) infective endocarditis (IE), we characterized IE patients with and without hVISA, and genotyped the infecting strains.
Methods
MRSA bloodstream isolates from 65 patients with definite IE from 8 countries underwent PCR for 31 virulence genes, pulsed-field gel electrophoresis, and multilocus sequence typing. hVISA was defined using population analysis profiling (PAP).
Results
Nineteen (29.2%) of 65 MRSA IE isolates exhibited hVISA by PAP. Isolates from Oceania and Europe were more likely to exhibit hVISA than isolates from the United States (77.8% vs. 35.0% vs. 13.9%; P < .001). The prevalence of hVISA was higher among isolates with a vancomycin minimum inhibitory concentration of 2 mg/L (P = .026). hVISA-infected patients were more likely to have persistent bacteremia (68.4% vs. 37.0%; P = .029) and heart failure (47.4% vs. 19.6%; P = .033). Mortality of hVISA- and non-hVISA-infected patients did not differ (42.1% vs. 34.8%, P = .586). hVISA and non-hVISA isolates were genotypically similar.
Conclusions
In these analyses, hVISA occurred in over one-quarter of MRSA IE isolates, was associated with certain IE complications, and varied in frequency by geographic region.
doi:10.1086/606027
PMCID: PMC3600359  PMID: 19811099
hVISA; Methicillin-resistant Staphylococcus aureus; endocarditis; genotype

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