What The Recent Literature Reveals About Antibiotic Use And Multi-Drug Resistant Gram Negative Rods

Warren S. Joseph DPM FIDSA

I confess that I have been a bit lackadaisical in my scanning through the journals I receive each month. This point hit home the other day when I went to find room on my desk to put some work and realized it was totally covered with stacks of journal back issues I had put aside with all good intentions to eventually read through. It was time to start clearing my desk with the side benefit of realizing I could probably come up with some interesting articles to blog about. Well, I did. In fact, I think I have enough for a few upcoming posts.

Those of you who have heard me lecture on methicillin resistant Staphylococcus aureus (MRSA) know that I am not a big fan of the use of trimethoprim/sulfamethoxazole (Septra, GlaxoSmithKline) for the treatment of even mild outpatient infections. My main objection has been increased toxicity of this drug versus other options. Potential issues include: Stevens-Johnson syndrome, renal toxicity, allergies, drug-drug interactions, etc.

However, I have also questioned the evidence supporting its use and have frequently stated that we don’t even know the proper dosing. Most clinicians use this drug at the “standard” dose of one DS tablet bid (160 mg/800 mg). However, some authorities have argued that dose is too low for MRSA and one should use an increased dose of two DS tabs bid. This has always concerned me because of the potential risk for increased adverse events with the higher dose.

A study published in the December 2011 (I told you I was behind on my reading) Antimicrobial Agents and Chemotherapy by Cadena and colleagues compared the two dosing regimens.1 The authors found no difference in outcomes with those treated with the higher dose versus those treated with the lower “standard” dose. There was no difference in patient and infection characteristics or in clinical response. Seventy-three percent (121 patients) of the high dose group had a clinical response versus 75 percent (170 patients) of the low dose group having a clinical response. Although they did not specifically look at the number of adverse events in each group, Cadena and co-workers do comment that none occurred with either group “… although one might anticipate a higher rate of adverse events in those who received the higher dose.” None of this has changed my mind. I still prefer doxycycline or minocycline to the use of TMP/SMX although I do see situations in which this drug would be useful.

What You Should Know About Vancomycin Dosing And Trough Levels

Another huge area of debate on which I have commented a number of times — both here in the blog and when I speak on the topic — is this concept of increasing vancomycin dosing to keep trough levels between 15 to 20 mg/mL. I strongly believe that this is not only unnecessary for all skin and skin structure infections (it may be necessary for blood stream or pneumonia but that is outside my scope), it is extremely dangerous. I do not think vancomycin improves outcomes and not only believe but have seen increased cases of nephrotoxicity (aka “acute kidney injury or AKI” in current parlance). For a more thorough discussion on my reasoning, just search www.leinfections.com for the term “vancomycin” and you can see my posts on the matter.

I always like seeing new papers that support my opinion on something. In the December 2011 issue of Antimicrobial Agents and Chemotherapy, Bosso and colleagues prospectively assessed nephrotoxicity in relation to trough concentrations in patients with MRSA treated with vancomycin.2 They found that “Nephrotoxicity was observed for 42 patients (29.6%) with trough concentrations >15 mg/mL and for 13 (8.9%) with trough concentrations =15 mg/mL.” They concluded that the increased trough concentrations were associated with (a) threefold increased risk of nephrotoxicity.

When will this nonsense stop? The entire concept of increasing doses of vancomycin is based on a pharmacodynamic model known as the area under the curve/minimum inhibitory concentration (AUC/MIC) ratio. There is essentially no evidence to show that the AUC/MIC increases efficacy of vancomycin for the infections we treat in the lower extremity but it is more toxic. Yet I frequently hear of clinicians and clinical pharmacists pushing for this higher dosing even in skin and skin structure infections. This dosing, by the way, is not supported by the Infectious Diseases Society of America MRSA guidelines. If you feel you need to push vancomycin this high, then consider alternative agents such as linezolid (Zyvox, Pfizer), daptomycin (Cubicin, Cubist Pharmaceuticals) or ceftaroline (Teflaro, Forest Laboratories).

Are Multi-Drug Resistant Gram Negative Rods The Organisms Of The Future?

To change tone completely, I was recently giving some lectures in Florida. I spoke in Miami, Ft. Lauderdale, Hialeah and Lakeland. Nothing like the heat and humidity of August in the Sunshine State to make me appreciate the heat and relative dryness (I can’t believe I am saying that) of August in Philadelphia. Little did I know that my visit may have put me at risk for exposure to extended spectrum beta-lactamases (ESBLs).

The May 2012 issue of Antimicrobial Agents and Chemotherapy contains an article by Poirel and colleagues on “Wild coastline birds as reservoirs of broad spectrum β lactamase producing Enterobacteriaceae in Miami Beach, Florida.”3 The investigators collected 53 fecal samples of wild seagulls and 10 specimens from pelicans. They obtained a total of 10 Enterobacteriaceae isolates containing ESBLs from eight (14 percent) specimens. They go on to discuss the exact phenotypes and the cross-resistance between various antibiotics. The authors conclude that “… beaches may play a significant role for dissemination of various resistance determinants and may be a source of (ESBL) community acquired infections.”

I could make some light of this and compare this report to what the movie Jaws did to destroy beach towns back in the 1970s, but I will show restraint. This is actually a serious issue. Multi-drug resistant gram negative rods are, in my opinion, the organisms of the future. Unlike MRSA, for which we have a number of different viable antibiotic choices, we have precious few resources to use against these organisms. To see that they can be found in bird droppings at one of the top beach destinations in the world only adds to the urgency that we do more to fight these bugs.

That is all for now. As promised, I still have plenty left.


1. Cadena J, Nair S, Henao-Martinez AF, et al. Dose of trimethoprim-sulfamethoxazole to treat skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011; 55(12):5430-2.

2. Bosso JA, Nappi J, Rudisill C, et al. Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial. Antimicrob Agents Chemother. 2011; 55(12):5475-9.

3. Poirel L, Potron A, De La Cuesta C, et al. Wild coastline birds as reservoirs of broad spectrum β lactamase producing Enterobacteriaceae in Miami Beach, Florida. Antimicrob Agents Chemother. 2012; 56(5):2756-8.

Editor’s note: This blog was originally published at http://www.leinfections.com/antibiotics/whats-new-interesting-in-the-inf... and has been adapted with permission from Warren Joseph, DPM, FIDSA, and Data Trace Publishing Company. For more information about the Handbook of Lower Extremity Infections, visit www.leinfections.com/.

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