{"id":1543,"date":"2015-06-12T11:03:46","date_gmt":"2015-06-12T15:03:46","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1543"},"modified":"2015-06-13T16:37:21","modified_gmt":"2015-06-13T20:37:21","slug":"vancomycin-vs-tmpsmx-for-mrsa-not-the-final-word","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/06\/12\/1543\/vancomycin-vs-tmpsmx-for-mrsa-not-the-final-word\/","title":{"rendered":"Vancomycin vs TMP\/SMX for MRSA \u2013 Not the Final Word"},"content":{"rendered":"
\"vanquish\"<\/a>
…the etymology of vancomycin reflects marketing hype and irrational exuberance…<\/span><\/figcaption><\/figure>\n

Vancomycin got a bad reputation since the early 90ies when it became clear that it\u00a0was slow to provide clinical improvement and microbiologic cure in MRSA patients. \u00a0It was associated with prolonged bacteremia even when combined with rifampin\u00a0[1]<\/a>. \u00a0And for MSSA, anti-staph penicillins like nafcillin were always the better choice.<\/p>\n

Then, in a series of trials comparing vancomycin to linezolid (LZD), the oxazolidinone showed superior outcomes.\u00a0 Well, because these studies were registration trials which individually only showed non-inferiority with a trend towards superiority, the label of LZD is what it is and vancomycin still can claim non-inferiority[2]<\/a>.\u00a0 However, with vancomycin\u2019s poor penetration into pulmonary tissues and consistently lower clinical response rates in several large well-controlled trials, most pulmonologists and ID specialists would choose to treat S.aureus pneumonia with LZD today.<\/p>\n

To add insult to injury, a heightened awareness of \u2018red neck syndrome\u2019, or \u2018red man syndrome\u2019 and the need for therapeutic drug monitoring (TDM) made vancomycin even less popular.<\/p>\n

There was always interest in using TMP\/SMX (trimethoprim\/sulfamethoxazole) for serious MRSA\u00a0infections\u00a0[3]<\/a>.\u00a0 Susceptibility data suggest that most MRSA in the US remain susceptible.\u00a0 So, it seems only logical to use this combination before resorting to the newer but much more expensive antibiotics like ceftaroline\/Teflaro, dalbavancin\/Dalvance, oritavancin\/Orbactiv or daptomycin\/Cubicin. \u00a0However, comparative clinical data for the two old drugs were not available.<\/p>\n

So, the recently published clinical trial by Paul,\u00a0a side-by-side comparison of vancomycin and TMP\/SMX in patients with severe MRSA infections,\u00a0fills an important gap.[4]<\/a>.<\/p>\n

The authors report on 252 patients enrolled at 4 centers in Israel between 2007 and 2014.\u00a0 Half of the patients had post-surgical infections, and 1\/3 of cases had bacteremia.\u00a0 This was a randomized but open-label trial in which\u00a0treatment success or failure was determined on Day 7 by a blinded adjudication committee.<\/p>\n

The study finding\u00a0was surprising.\u00a0 Despite a large 15% non-inferiority\u00a0margin, TMP\/SMX was inferior to vancomycin, in particular in the subgroup of bacteremic patients.\u00a0 The authors felt that\u00a0TMP\/SMX could not be recommended for severe MRSA infections.<\/p>\n

Several caveats are in order before accepting their\u00a0conclusions.\u00a0 This was what the authors describe as a \u2018practical\u2019 study.\u00a0 In many aspects it did not meet the quality markers of the linezolid trials mentioned above.\u00a0 As an open trial which allowed concomitant anti-staphylococcal medicines up to 48 hrs prior to enrolment, it is certainly not registration-quality even by 2007 standards.\u00a0 A 15% NI margin may seem generous, but FDA would have insisted on a double-blinded comparison, two-sided alpha and an adjustment for the 2 interim analyses performed a la Pocock or more likely, the O\u2019Brien Fleming alpha-spending method.\u00a0

It is hard\u00a0to do a practical study, but even harder to do a well-controlled study<\/span><\/p>\n<\/div><\/p>\n

There are other methodologic concerns which detract from the value of this study.\u00a0 The effect of concomitant surgeries (in approx. 75% of patients) during the initial 7 days of treatment is hard to ignore: Were these wound debridements?\u00a0 Were topical antibiotics administered? \u00a0And some very basic questions remain: What was the MIC distribution of organisms?\u00a0 Why were there so many polymicrobial infections (37%)?<\/p>\n

30-Day mortality is an efficacy and a safety endpoint.\u00a0 The fact that no difference in survival between the 2 groups at this nor at the 7-day efficacy time point was observed should be noted.\u00a0 Hospitalization was of equal length in both treatment arms. \u00a0Makes you wonder whether the 2 antibiotics are\u00a0really all that different.<\/p>\n

My take-away: Admittedly, it is hard to do a practical study, but it is even harder to do a well-controlled study.\u00a0 Because the trial fails to meet these higher standards, it is not the last word on TMP\/SMX.\u00a0 If the authors had compared it to LZD, presumably there would have been clear difference in efficacy.<\/p>\n

Then again, without sponsors to finance a more definitive\u00a0study of these two off-patent drugs, the Paul study may be the last word for a long time.<\/p>\n

 <\/p>\n

References:
\n<\/strong>[1]<\/a> D Levine Ann Int Med. 1991; 115:674
\n[2]<\/a> R Wunderink CID 2012; 54:621
\n[3]<\/a> N Markowitz AAC. 1983; 23:450
\n[4]<\/a> M Paul BMJ 2015;350:h2219 doi: 10.1136\/bmj.h2219<\/p>\n","protected":false},"excerpt":{"rendered":"

Vancomycin got a bad reputation since the early 90ies when it became clear that it\u00a0was slow to provide clinical improvement and microbiologic cure in MRSA patients. \u00a0It was associated with prolonged bacteremia even when combined with rifampin\u00a0[1]. \u00a0And for MSSA, anti-staph penicillins like nafcillin were always the better choice. Then, Continue reading Vancomycin vs TMP\/SMX for MRSA \u2013 Not the Final Word<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1558,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[227,3,18],"tags":[403,691,828,229,66,85,228,1056,5,1057,72,83,1053,1054,153,1055,1059,234,67,1058,1061,1060,979,829,980,767,48],"class_list":["post-1543","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_news","category-the_viewpoint","tag-antibiotic-blog","tag-bacteremia","tag-ceftaroline","tag-cubicin","tag-dalbavancin","tag-dalvance","tag-daptomycin","tag-delta","tag-fda","tag-interim-analysis","tag-linezolid","tag-mrsa","tag-mssa","tag-nafcillin","tag-non-inferiority","tag-non-inferiority-margin","tag-obrien-fleming","tag-orbactiv","tag-oritavancin","tag-pocock","tag-red-man-syndrome","tag-red-neck-syndrome","tag-tdm","tag-teflaro","tag-therapeutic-drug-monitoring","tag-tmpsmx","tag-vancomycin"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/06\/MRSA-slider-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-oT","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":3116,"url":"https:\/\/allphasepharma.com\/dir\/2017\/01\/30\/3116\/txa-709-kid-qidp-block\/","url_meta":{"origin":1543,"position":0},"title":"TXA-709 –\u00a0 New Kid on the Block","author":"Harald","date":"January 30, 2017","format":false,"excerpt":"When searching for FtsZ inhibitors on PubMed, there are 187 hits. 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