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1.  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
2.  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
3.  Increasing Experience with Primary Oral Medical Therapy for Mycobacterium ulcerans Disease in an Australian Cohort 
Buruli ulcer (BU) is a necrotizing infection of subcutaneous tissue that is caused by Mycobacterium ulcerans and is responsible for disfiguring skin lesions. The disease is endemic to specific geographic regions in the state of Victoria in southeastern Australia. Growing evidence of the effectiveness of antibiotic therapy for M. ulcerans disease has evolved our practice to the use of primarily oral medical therapy. An observational cohort study was performed on all confirmed M. ulcerans cases treated with primary rifampin-based medical therapy at Barwon Health between October 2010 and December 2014 and receiving 12 months of follow-up. One hundred thirty-two patients were managed with primary medical therapy. The median age of patients was 49 years, and nearly 10% had diabetes mellitus. Lesions were ulcerative in 83.3% of patients and at WHO stage 1 in 78.8% of patients. The median duration of therapy was 56 days, with 22 patients (16.7%) completing fewer than 56 days of antimicrobial treatment. Antibiotic-associated complications requiring cessation of one or more antibiotics occurred in 21 (15.9%) patients. Limited surgical debridement was performed on 30 of these medically managed patients (22.7%). Cure was achieved, with healing within 12 months, in 131 of 132 patients (99.2%), and cosmetic outcomes were excellent. Primary rifampin-based oral medical therapy for M. ulcerans disease, combined with either clarithromycin or a fluoroquinolone, has an excellent rate of cure and an acceptable toxicity profile in Australian patients. We advocate for further research to determine the optimal and safest minimum duration of medical therapy for BU.
doi:10.1128/AAC.02853-15
PMCID: PMC4862461  PMID: 26883709
4.  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
5.  Mycobacterium ulcerans in the Elderly: More Severe Disease and Suboptimal Outcomes 
PLoS Neglected Tropical Diseases  2015;9(12):e0004253.
Background
The clinical presentation of M. ulcerans disease and the safety and effectiveness of treatment may differ in elderly compared with younger populations related to relative immune defficiencies, co-morbidities and drug interactions. However, elderly populations with M. ulcerans disease have not been comprehensively studied.
Methodology/Principal Findings
A retrospective analysis was performed on an observational cohort of all confirmed M. ulcerans cases managed at Barwon Health from 1/1/1998-31/12/2014. The cohort included 327 patients; 131(40.0%) ≥65 years and 196(60.0%) <65 years of age. Patients ≥65 years had a shorter median duration of symptoms prior to diagnosis (p<0.01), a higher proportion with diabetes (p<0.001) and immune suppression (p<0.001), and were more likely to have lesions that were multiple (OR 4.67, 95% CI 1.78–12.31, p<0.001) and WHO category 3 (OR 4.59, 95% CI 1.98–10.59, p<0.001). Antibiotic complications occurred in 69(24.3%) treatment episodes at an increased incidence in those aged ≥65 years (OR 5.29, 95% CI 2.81–9.98, p<0.001). There were 4(1.2%) deaths, with significantly more in the age-group ≥65 years (4 compared with 0 deaths, p = 0.01). The overall treatment success rate was 92.2%. For the age-group ≥65 years there was a reduced rate of treatment success overall (OR 0.34, 95% CI 0.14–0.80, p = <0.01) and when surgery was used alone (OR 0.21, 95% CI 0.06–0.76, p<0.01). Patients ≥65 years were more likely to have a paradoxical reaction (OR 2.06, 95% CI 1.17–3.62, p = 0.01).
Conclusions/Significance
Elderly patients comprise a significant proportion of M. ulcerans disease patients in Australian populations and present with more severe and advanced disease forms. Currently recommended treatments are associated with increased toxicity and reduced effectiveness in elderly populations. Increased efforts are required to diagnose M. ulcerans earlier in elderly populations, and research is urgently required to develop more effective and less toxic treatments for this age-group.
Author Summary
Mycobacterium ulcerans is an infection that can affect all age-groups. It causes necrosis of skin and soft-tissue often resulting in severe outcomes and long-term disability. However, due to the majority of infections worldwide occurring in children and young adults, there is a paucity of information available in elderly patients. It is important that elderly patients are not neglected as the clinical presentation and treatment outcomes may differ significantly from younger patients related to relative immune defficiencies, co-morbidities and increased potential for drug interactions. We specifically examined patients with M. ulcerans disease aged ≥ 65 years and showed that they comprise a significant proportion of patients affected in Australian populations. They present with more severe and advanced disease forms, and suffer from increased toxicity and reduced effectiveness of the currently recommended treatments. Therefore, our study demonstrates that increased efforts are required to diagnose M. ulcerans disease earlier in elderly populations, and that research is urgently required to develop more effective and less toxic treatments for this age-group.
doi:10.1371/journal.pntd.0004253
PMCID: PMC4667883  PMID: 26630648
6.  Candida Infective Endocarditis: an Observational Cohort Study with a Focus on Therapy 
Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis.
doi:10.1128/AAC.04867-14
PMCID: PMC4356766  PMID: 25645855
7.  Mycobacterium Ulcerans Treatment – Can Antibiotic Duration Be Reduced in Selected Patients? 
PLoS Neglected Tropical Diseases  2015;9(2):e0003503.
Introduction
Mycobacterium ulcerans (M. ulcerans) is a necrotizing skin infection endemic to the Bellarine Peninsula, Australia. Current treatment recommendations include 8 weeks of combination antibiotics, with adjuvant surgery if necessary. However, antibiotic toxicity often results in early treatment cessation and local experience suggests that shorter antibiotic courses may be effective with concurrent surgery. We report the outcomes of patients in the Barwon Health M. ulcerans cohort who received shorter courses of antibiotic therapy than 8 weeks.
Methodology / Principal findings
A retrospective analysis was performed of all M. ulcerans infections treated at Barwon Health from March 1, 1998 to July 31, 2013. Sixty-two patients, with a median age of 65 years, received < 56 days of antibiotics and 51 (82%) of these patients underwent concurrent surgical excision. Most received a two-drug regimen of rifampicin combined with either ciprofloxacin or clarithromycin for a median 29 days (IQR 21–41days). Cessation rates were 55% for adverse events and 36% based on clinician decision. The overall success rate was 95% (98% with concurrent surgery; 82% with antibiotics alone) with a 50% success rate for those who received < 14 days of antibiotics increasing to 94% if they received 14–27 days and 100% for 28–55 days (p<0.01). A 100% success rate was seen for concurrent surgery and 14–27 days of antibiotics versus 67% for concurrent surgery and < 14 days of antibiotics (p = 0.12). No previously identified risk factors for treatment failure with surgery alone were associated with reduced treatment success rates with < 56 days of antibiotics.
Conclusion
In selected patients, antibiotic treatment durations for M. ulcerans shorter than the current WHO recommended 8 weeks duration may be associated with successful outcomes.
Author Summary
Buruli ulcer is a necrotizing skin and subcutaneous tissue infection caused by Mycobacterium ulcerans and is the third most common mycobacterial infection, behind tuberculosis and leprosy, world-wide. In recent years, the World Health Organisation has modified its guidelines for M. ulcerans treatment, moving from predominantly surgical to predominantly medical based management. It now recommends the combination of oral rifampicin and intramuscular streptomycin for a period of eight weeks as first-line therapy, with surgery as adjunctive therapy if necessary. The Barwon Health experience from south-eastern Australia has demonstrated that the entirely oral combination of rifampicin with either ciprofloxacin or clarithromycin for eight weeks can be an effective treatment option. However, these antibiotics are often toxic leading to early cessation, especially in the elderly. In addition, clinicians have been using a shorter duration of therapy for smaller lesions that have also been surgically managed. This study reviews our experience treating M. ulcerans with antibiotic durations of less than 8 weeks and demonstrates that successful outcomes can be achieved in selected patients, with success rates influenced by the duration of treatment and the use of surgical excision. This finding needs confirmation in further studies, but could have significant benefits in terms of reducing toxicity and improving adherence associated with Buruli ulcer antibiotic treatment.
doi:10.1371/journal.pntd.0003503
PMCID: PMC4319776  PMID: 25658304
8.  Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial 
Trials  2015;16:24.
Background
Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.
Methods/Design
The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.
Trial registration
The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0541-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-014-0541-9
PMCID: PMC4311465  PMID: 25623485
Extended-spectrum beta-lactamase; ESBL; Plasmid-AmpC; Therapy; Resistance; Beta-lactam/beta-lactamase inhibitor; Carbapenem; Clinical trial
9.  Community-Onset Escherichia coli Infection Resistant to Expanded-Spectrum Cephalosporins in Low-Prevalence Countries 
By global standards, the prevalence of community-onset expanded-spectrum-cephalosporin-resistant (ESC-R) Escherichia coli remains low in Australia and New Zealand. Of concern, our countries are in a unique position, with high extramural resistance pressure from close population and trade links to Asia-Pacific neighbors with high ESC-R E. coli rates. We aimed to characterize the risks and dynamics of community-onset ESC-R E. coli infection in our low-prevalence region. A case-control methodology was used. Patients with ESC-R E. coli or ESC-susceptible E. coli isolated from blood or urine were recruited at six geographically dispersed tertiary care hospitals in Australia and New Zealand. Epidemiological data were prospectively collected, and bacteria were retained for analysis. In total, 182 patients (91 cases and 91 controls) were recruited. Multivariate logistic regression identified risk factors for ESC-R among E. coli strains, including birth on the Indian subcontinent (odds ratio [OR] = 11.13, 95% confidence interval [95% CI] = 2.17 to 56.98, P = 0.003), urinary tract infection in the past year (per-infection OR = 1.430, 95% CI = 1.13 to 1.82, P = 0.003), travel to southeast Asia, China, the Indian subcontinent, Africa, and the Middle East (OR = 3.089, 95% CI = 1.29 to 7.38, P = 0.011), prior exposure to trimethoprim with or without sulfamethoxazole and with or without an expanded-spectrum cephalosporin (OR = 3.665, 95% CI = 1.30 to 10.35, P = 0.014), and health care exposure in the previous 6 months (OR = 3.16, 95% CI = 1.54 to 6.46, P = 0.02). Among our ESC-R E. coli strains, the blaCTX-M ESBLs were dominant (83% of ESC-R E. coli strains), and the worldwide pandemic ST-131 clone was frequent (45% of ESC-R E. coli strains). In our low-prevalence setting, ESC-R among community-onset E. coli strains may be associated with both “export” from health care facilities into the community and direct “import” into the community from high-prevalence regions.
doi:10.1128/AAC.02052-13
PMCID: PMC4023745  PMID: 24468775
10.  Iatrogenic Meningitis Caused by Neisseria sicca/subflava after Intrathecal Contrast Injection, Australia 
Emerging Infectious Diseases  2014;20(6):1023-1025.
We report a case of invasive Neisseria sicca/subflava meningitis after a spinal injection procedure during which a face mask was not worn by the proceduralist. The report highlights the importance of awareness of, and adherence to, guidelines for protective face mask use during procedures that require sterile conditions.
doi:10.3201/eid2006.131117
PMCID: PMC4036775  PMID: 24856004
Iatragenic; bacteria; bacterial meningitis; Neisseria sicca/subflava; commensal; lumbar puncture; myelography; intrathecal; facemask; face mask; Australia
11.  Clinical Features and Risk Factors of Oedematous Mycobacterium ulcerans Lesions in an Australian Population: Beware Cellulitis in an Endemic Area 
Introduction
Oedematous lesions are a less common but more severe form of Mycobacterium ulcerans disease. Misdiagnosis as bacterial cellulitis can lead to delays in treatment. We report the first comprehensive descriptions of the clinical features and risk factors of patients with oedematous disease from the Bellarine Peninsula of south-eastern Victoria, Australia.
Methods
Data on all confirmed Mycobacterium ulcerans cases managed at Barwon Health, Victoria, were collected from 1/1/1998–31/12/2012. A multivariate logistic regression model was used to assess associations with oedematous forms of Mycobacterium ulcerans disease.
Results
Seventeen of 238 (7%) patients had oedematous Mycobacterium ulcerans lesions. Their median age was 70 years (IQR 17–82 years) and 71% were male. Twenty-one percent of lesions were WHO category one, 35% category two and 41% category three. 16 (94%) patients were initially diagnosed with cellulitis and received a median 14 days (IQR 9–17 days) of antibiotics and 65% required hospitalization prior to Mycobacterium ulcerans diagnosis. Fever was present in 50% and pain in 87% of patients. The WCC, neutrophil count and CRP were elevated in 54%, 62% and 75% of cases respectively. The median duration of antibiotic treatment was 84 days (IQR 67–96) and 94% of cases required surgical intervention. On multivariable analysis, there was an increased likelihood of a lesion being oedematous if on the hand (OR 85.62, 95% CI 13.69–535.70; P<0.001), elbow (OR 7.83, 95% CI 1.39–43.96; p<0.001) or ankle (OR 7.92, 95% CI 1.28–49.16; p<0.001), or if the patient had diabetes mellitus (OR 9.42, 95% CI 1.62–54.74; p = 0.02).
Conclusions
In an Australian population, oedematous Mycobacterium ulcerans lesions present with similar symptoms, signs and investigation results to, and are commonly mistakenly diagnosed for, bacterial limb cellulitis. There is an increased likelihood of oedematous lesions affecting the hand, elbow or ankle, and in patients with diabetes.
Author Summary
The oedematous form of Buruli ulcer, caused by Mycobacterium ulcerans, is less common representing 7% of cases over a 15 year period in a patient cohort from the Bellarine Peninsula of south-eastern Victoria, Australia. In this study, for oedematous Buruli ulcer cases, fever and pain were usually present and investigations showed leucocytosis, neutrophilia and a raised serum CRP. This is in contrast to other forms of Buruli ulcer which are classically painless and not associated with systemic symptoms. As a result oedematous cases were usually misdiagnosed and treated as bacterial cellulitis leading to delays in diagnosis, progression of disease, increased morbidity and increased complexity of treatment. Compared with non-oedematous forms of Buruli ulcer, we found that oedematous lesions were strongly associated with being located on the dorsum of the hand, the elbow and the ankle, and with patients who had diabetes mellitus. This study aims to increase the awareness of odematous Buruli ulcer disease, and improve the understanding of its clinical presentation and risk factors, to aid clinicians to diagnose and treat early Mycobacterium ulcerans infection when managing patients with cellulitis who have been exposed to areas endemic for Buruli ulcer.
doi:10.1371/journal.pntd.0002612
PMCID: PMC3879256  PMID: 24392172
12.  Incidence, clinical spectrum, diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections 
BMC Infectious Diseases  2013;13:416.
Background
Paradoxical reactions from antibiotic treatment of Mycobacterium ulcerans have recently been recognized. Data is lacking regarding their incidence, clinical and diagnostic features, treatment, outcomes and risk factors in an Australian population.
Methods
Data was collected prospectively on all confirmed cases of M. ulcerans infection managed at Barwon Health Services, Australia, from 1/1/1998-31/12/2011. Paradoxical reactions were defined on clinical and histological criteria and cases were determined by retrospectively reviewing the clinical history and histology of excised lesions. A Poisson regression model was used to examine associations with paradoxical reactions.
Results
Thirty-two of 156 (21%) patients developed paradoxical reactions a median 39 days (IQR 20-73 days) from antibiotic initiation. Forty-two paradoxical episodes occurred with 26 (81%) patients experiencing one and 6 (19%) multiple episodes. Thirty-two (76%) episodes occurred during antibiotic treatment and 10 (24%) episodes occurred a median 37 days after antibiotic treatment. The reaction site involved the original lesion (wound) in 23 (55%), was separate to but within 3 cm of the original lesion (local) in 11 (26%) and was more than 3 cm from the original lesion (distant) in 8 (19%) episodes. Mycobacterial cultures were negative in 33/33 (100%) paradoxical episodes. Post-February 2009 treatment involved more cases with no antibiotic modifications (12/15 compared with 11/27, OR 5.82, 95% CI 1.12-34.07, p = 0.02) and no further surgery (9/15 compared with 2/27, OR 18.75, 95% CI 2.62-172.73, p < 0.001). Six severe cases received prednisone with marked clinical improvement. On multivariable analysis, age ≥ 60 years (RR 2.84, 95% CI 1.12-7.17, p = 0.03), an oedematous lesion (RR 3.44, 95% CI 1.11-10.70, p=0.03) and use of amikacin in the initial antibiotic regimen (RR 6.33, 95% CI 2.09-19.18, p < 0.01) were associated with an increased incidence of paradoxical reactions.
Conclusions
Paradoxical reactions occur frequently during or after antibiotic treatment of M. ulcerans infections in an Australian population and may be increased in older adults, oedematous disease forms, and in those treated with amikacin. Recognition of paradoxical reactions led to changes in management with less surgery, fewer antibiotic modifications and use of prednisolone for severe reactions.
doi:10.1186/1471-2334-13-416
PMCID: PMC3854792  PMID: 24007371
Mycobacterium ulcerans; Paradoxical reactions; Antibiotics; Predictors; Incidence; Clinical; Diagnosis; Treatment
13.  Forgotten but not gone - Scrofuloderma in a migrant student from India 
The Australasian Medical Journal  2013;6(7):371-373.
A 34-year-old Indian student who immigrated to Australia five years ago presented with a four-week history of neck pain. Physical examination revealed two firm fixed cervical lymph nodes in the anterior triangle and midline region which were tender on palpation and erythematous on inspection. Cording phenomenon was found on ZN staining of FNA sample and mycobacterium tuberculosis (M.tb ) PCR confirmed the diagnosis with incomplete resistance to isoniazid. Patient was treated with other three first line antituberculosis medications for nine months with an excellent outcome. Prednisolone was also used as adjunctive therapy and tapered during the course of treatment.
doi:10.4066/AMJ.2013.1759
PMCID: PMC3737763  PMID: 23940498
Scrofuloderma; Tuberculosis; Cording phenomenon
14.  Impact of Hiv-Associated Conditions on Mortality in People Commencing Anti-Retroviral Therapy in Resource Limited Settings 
PLoS ONE  2013;8(7):e68445.
Objectives
To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS).
Design, Setting
Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010.
Subjects, Participants
36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55–2.27).
Outcome Measures
Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation.
Results
There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21–5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97–2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74–4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80–3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80–3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi’s sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates.
Conclusions
A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research.
doi:10.1371/journal.pone.0068445
PMCID: PMC3720807  PMID: 23935870
15.  Mycobacterium ulcerans Disease: Experience with Primary Oral Medical Therapy in an Australian Cohort 
Background
Mycobacterium ulcerans (MU) is responsible for disfiguring skin lesions and is endemic on the Bellarine peninsula of southeastern Australia. Antibiotics have been shown to be highly effective in sterilizing lesions and preventing disease recurrences when used alone or in combination with surgery. Our practice has evolved to using primarily oral medical therapy.
Methods
From a prospective cohort of MU patients managed at Barwon Health, we describe those treated with primary medical therapy defined as treatment of a M. ulcerans lesion with antimicrobials either alone or in conjunction with limited surgical debridement.
Results
From 1/10/2010 through 31/12/11, 43 patients were treated with exclusive medical therapy, of which 5 (12%) also underwent limited surgical debridement. The median patient age was 50.2 years, and 86% had WHO category 1 and 91% ulcerative lesions. Rifampicin was combined with ciprofloxacin in 30 (70%) and clarithromycin in 12 (28%) patients. The median duration of antibiotic therapy was 56 days, with 7 (16%) receiving less than 56 days. Medication side effects requiring cessation of one or more antibiotics occurred in 7 (16%) patients. Forty-two (98%) patients healed without recurrence within 12 months, and 1 patient (2%) experienced a relapse 4 months after completion of 8 weeks of antimicrobial therapy.
Conclusion
Our experience demonstrates the efficacy and safety of primary oral medical management of MU infection with oral rifampicin-based regimens. Further research is required to determine the optimal and minimum durations of antibiotic therapy, and the most effective antibiotic dosages and formulations for young children.
Author Summary
Mycobacterium ulcerans (MU) is responsible for disfiguring skin infections which are challenging to treat. The recommended treatment for MU has continued to evolve from surgery to remove all involved tissue, to the use of effective combination oral antibiotics with surgery as required. Our study describes the oral medical treatment utilised for consecutive cases of MU infection over a 15 month period at our institution, in Victoria, Australia. Managing patients primarily with oral antibiotics results in high cure rates and excellent cosmetic outcomes. The success with medical treatment reported in this study will aid those treating cases of MU infection, and will add to the growing body of knowledge about the relative roles of antibiotics and surgery for treating this infection.
doi:10.1371/journal.pntd.0002315
PMCID: PMC3715400  PMID: 23875050
16.  A case of Kingella kingae endocarditis complicated by native mitral valve rupture 
The Australasian Medical Journal  2013;6(4):172-174.
We report a case of Kingella kingae endocarditis in a patient with a history of recent respiratory tract infection and dental extraction. This case is remarkable for embolic and vasculitic phenomena in association with a large valve vegetation and valve perforation. Kingella kingae is an organism known to cause endocarditis, however early major complications are uncommon. Our case of Kingella endocarditis behaved in a virulent fashion necessitating a combined approach of intravenous antibiotic therapy and a valve replacement. It highlights the importance of expedited investigation for endocarditis in patients with Kingella bacteraemia.
doi:10.4066/AMJ.2013.1577
PMCID: PMC3650306  PMID: 23671460
Kingella kingae; Endocarditis; Mitral Valve Rupture
17.  Successful Outcomes with Oral Fluoroquinolones Combined with Rifampicin in the Treatment of Mycobacterium ulcerans: An Observational Cohort Study 
Background
The World Health Organization currently recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. Alternatives are needed when these are not tolerated or accepted by patients, contraindicated, or neither accessible nor affordable. Despite in vitro effectiveness, clinical evidence for fluoroquinolone antibiotic use against Mycobacterium ulcerans is lacking. We describe outcomes and tolerability of fluoroquinolone-containing antibiotic regimens for Mycobacterium ulcerans in south-eastern Australia.
Methodology/Principal Findings
Analysis was performed of prospectively collected data including all primary Mycobacterium ulcerans infections treated at Barwon Health between 1998 and 2010. Medical treatment involved antibiotic use for more than 7 days; surgical treatment involved surgical excision of a lesion. Treatment success was defined as complete lesion healing without recurrence at 12 months follow-up. A complication was defined as an adverse event attributed to an antibiotic that required its cessation. A total of 133 patients with 137 lesions were studied. Median age was 62 years (range 3–94 years). 47 (34%) had surgical treatment alone, and 90 (66%) had combined surgical and medical treatment. Rifampicin and ciprofloxacin comprised 61% and rifampicin and clarithromycin 23% of first-line antibiotic regimens. 13/47 (30%) treated with surgery alone failed treatment compared to 0/90 (0%) of those treated with combination medical and surgical treatment (p<0.0001). There was no difference in treatment success rate for antibiotic combinations containing a fluoroquinolone (61/61 cases; 100%) compared with those not containing a fluoroquinolone (29/29 cases; 100%). Complication rates were similar between ciprofloxacin and rifampicin (31%) and rifampicin and clarithromycin (33%) regimens (OR 0.89, 95% CI 0.27–2.99). Paradoxical reactions during treatment were observed in 8 (9%) of antibiotic treated cases.
Conclusions
Antibiotics combined with surgery may significantly increase treatment success for Mycobacterium ulcerans infections, and fluoroquinolone combined with rifampicin-containing antibiotic regimens can provide an effective and safe oral treatment option.
Author Summary
Buruli ulcer is a necrotizing infection of skin and subcutaneous tissue caused by Mycobacterium ulcerans and is the third most common mycobacterial disease worldwide (after tuberculosis and leprosy). In recent years its treatment has radically changed, evolving from a predominantly surgically to a predominantly medically treated disease. The World Health Organization now recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. However, alternatives are needed where recommended antibiotics are not tolerated or accepted by patients, contraindicated, or not accessible nor affordable. This study describes the use of antibiotics, including oral fluoroquinolones, in the treatment of Mycobacterium ulcerans in south-eastern Australia. It demonstrates that antibiotics combined with surgery are highly effective in the treatment of Mycobacterium ulcerans. In addition, oral fluoroquinolone-containing antibiotic combinations are shown to be as effective and well tolerated as other recommended antibiotic combinations. Fluoroquinolone antibiotics therefore offer the potential to provide an alternative oral antibiotic to be combined with rifampicin for Mycobacterium ulcerans treatment, allowing more accessible and acceptable, less toxic, and less expensive treatment regimens to be available, especially in resource-limited settings where the disease burden is greatest.
doi:10.1371/journal.pntd.0001473
PMCID: PMC3260310  PMID: 22272368
18.  Candida Infective Endocarditis 
Purpose
Candida infective endocarditis (IE) is uncommon but often fatal. Most epidemiologic data are derived from small case series or case reports. This study was conducted to explore epidemiology, treatment patterns, and outcomes of patients with Candida IE.
Methods
We compared 33 Candida IE cases to 2716 patients with non-fungal IE in the International Collaboration on Endocarditis - Prospective Cohort Study. Patients were enrolled and data collected from June 2000 until August 2005.
Results
Patients with Candida IE were more likely to have prosthetic valves (p<0.001), short term indwelling catheters (p<0.0001), and have healthcare-associated infection (p<0.001). Reasons for surgery differed between the two groups: myocardial abscess (46.7% vs. 22.2% p=0.026) and persistent positive blood cultures (33.3% vs. 9.9%, p=0.003) were more common among those with Candida IE. Mortality at discharge was higher in patients with Candida IE (30.3%) when compared to non-fungal cases (17%, p=0.046). Among Candida patients, mortality was similar in patients who received combination surgical and antifungal therapy versus antifungal therapy alone (33.3% vs. 27.8%, p=0.26). New antifungal drugs, particularly echinocandins, were used frequently.
Conclusions
These multi-center data suggest distinct epidemiologic features of Candida IE when compared to non-fungal cases. Indications for surgical intervention are different and mortality is increased. Newer antifungal treatment options are increasingly used. Large, multi-center studies are needed to help better define Candida IE.
doi:10.1007/s10096-008-0466-x
PMCID: PMC2757733  PMID: 18283504
19.  Genotypic Diversity of Coagulase-Negative Staphylococci Causing Endocarditis: a Global Perspective▿  
Journal of Clinical Microbiology  2008;46(5):1780-1784.
Coagulase-negative staphylococci (CNS) are important causes of infective endocarditis (IE), but their microbiological profiles are poorly described. We performed DNA target sequencing and susceptibility testing for 91 patients with definite CNS IE who were identified from the International Collaboration on Endocarditis—Microbiology, a large, multicenter, multinational consortium. A hierarchy of gene sequences demonstrated great genetic diversity within CNS from patients with definite endocarditis that represented diverse geographic regions. In particular, rpoB sequence data demonstrated unique genetic signatures with the potential to serve as an important tool for global surveillance.
doi:10.1128/JCM.02405-07
PMCID: PMC2395089  PMID: 18367572
20.  Successful treatment of Mycobacterium ulcerans osteomyelitis with minor surgical debridement and prolonged rifampicin and ciprofloxacin therapy: a case report 
Introduction
Treatment for osteomyelitis-complicating Mycobacterium ulcerans infection typically requires extensive surgery and even amputation, with no reported benefit from adjunctive antibiotics.
Case presentation
We report a case of an 87-year-old woman with M. ulcerans osteomyelitis that resolved following limited surgical debridement and 6 months of therapy with rifampicin and ciprofloxacin.
Conclusion
M. ulcerans osteomyelitis can be successfully treated with limited surgical debridement and adjunctive oral antibiotics.
doi:10.1186/1752-1947-2-123
PMCID: PMC2396654  PMID: 18439310
21.  Case Cluster of Necrotizing Fasciitis and Cellulitis Associated with Vein Sclerotherapy 
Emerging Infectious Diseases  2008;14(1):180-181.
doi:10.3201/eid1401.070250
PMCID: PMC2600178  PMID: 18258105
Group A Streptococcus; necrotizing fasciitis; sclerotherapy; polidocanol; varicose vein; letter
22.  Risk Factors for Mycobacterium ulcerans Infection, Southeastern Australia 
Emerging Infectious Diseases  2007;13(11):1661-1666.
Epidemiologic evidence shows that mosquitoes play a role in transmission to humans.
Buruli/Bairnsdale ulcer (BU) is a severe skin and soft tissue disease caused by Mycobacterium ulcerans. To better understand how BU is acquired, we conducted a case–control study during a sustained outbreak in temperate southeastern Australia. We recruited 49 adult patients with BU and 609 control participants from a newly recognized BU-endemic area in southeastern Australia. Participants were asked about their lifestyle and insect exposure. Odds ratios were calculated by using logistic regression and were adjusted for age and location of residence. Odds of having BU were at least halved for those who frequently used insect repellent, wore long trousers outdoors, and immediately washed minor skin wounds; odds were at least doubled for those who received mosquito bites on the lower legs or lower arms. This study provides new circumstantial evidence that implicates mosquitoes in the transmission of M. ulcerans in southeastern Australia.
doi:10.3201/eid1311.061206
PMCID: PMC3375781  PMID: 18217548
Mycobacterium ulcerans; Mycobacterium infections; atypical; communicable diseases; lifestyle; insect vectors; case-control studies; Australia; epidemiology; research
23.  Personal Protective Equipment and Antiviral Drug Use during Hospitalization for Suspected Avian or Pandemic Influenza1 
Emerging Infectious Diseases  2007;13(10):1541-1547.
In a pandemic, many current national stockpiles of PPE and antiviral medications are likely inadequate.
For pandemic influenza planning, realistic estimates of personal protective equipment (PPE) and antiviral medication required for hospital healthcare workers (HCWs) are vital. In this simulation study, a patient with suspected avian or pandemic influenza (API) sought treatment at 9 Australian hospital emergency departments where patient–staff interactions during the first 6 hours of hospitalization were observed. Based on World Health Organization definitions and guidelines, the mean number of “close contacts” of the API patient was 12.3 (range 6–17; 85% HCWs); mean “exposures” were 19.3 (range 15–26). Overall, 20–25 PPE sets were required per patient, with variable HCW compliance for wearing these items (93% N95 masks, 77% gowns, 83% gloves, and 73% eye protection). Up to 41% of HCW close contacts would have qualified for postexposure antiviral prophylaxis. These data indicate that many current national stockpiles of PPE and antiviral medication are likely inadequate for a pandemic.
doi:10.3201/eid1310.070033
PMCID: PMC2851524  PMID: 18258004
Influenza; avian; pandemic; antivirals; health resources; infection control; healthcare workers; disease transmission; research
24.  Peritonitis Due to Curvularia inaequalis in an Elderly Patient Undergoing Peritoneal Dialysis and a Review of Six Cases of Peritonitis Associated with Other Curvularia spp. 
Journal of Clinical Microbiology  2005;43(8):4288-4292.
Fungal peritonitis due to Curvularia species in patients undergoing peritoneal dialysis is a very rare problem. We report a case of peritonitis caused by Curvularia inaequalis. This is the first report in the English literature of this species causing human infection. We also review the six previously reported cases of continuous ambulatory peritoneal dialysis peritonitis caused by other Curvularia species.
doi:10.1128/JCM.43.8.4288-4292.2005
PMCID: PMC1233934  PMID: 16082004
25.  Melioidosis in Tsunami Survivors 
Emerging Infectious Diseases  2005;11(10):1638-1639.
doi:10.3201/eid1110.050740
PMCID: PMC3366758  PMID: 16355505
tsunami; pneumonia; melioidosis; letter

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