When the Antibiotic Combination “Vosyn” Isn’t Enough for Sepsis

Emergency physicians are frequently shamed by hospital antibiotic stewards for overprescribing vancomycin and Zosyn (piperacillin/tazobactam), a combination so frequently used that it’s been nicknamed “vosyn.”

The concern is that this antibiotic regimen is overly broad-spectrum for most infections and that its excessive use will lead to selective pressure promoting antimicrobial resistance in the hospital. To their credit, the principal stewards, infectious diseases specialists, have pushed back on the one-hour bundle proposed by the Surviving Sepsis Campaign’s (SSC), the latest SSC overreach. As in the past, yet another SSC policy appears destined to eventually be determined either dangerous, ineffective, or both (see “How the Surviving Sepsis Campaign Got Almost Everything Wrong” in the March 2018 issue of ACEP Now). But when it comes to “sepsis,” even antibiotic stewards seem to be giving a pass to vosyn, which has become the emergency department’s go-to.

With sepsis now redefined by the Society of Critical Care Medicine as “real” sepsis with organ dysfunctions (and not the bogus systemic inflammatory response syndrome type), it is worth considering whether the first antibiotics we reach for are the right ones. With the rapidly increasing prevalence of resistant bacteria, we have arrived at a place where vosyn, the paragon of ED overprescription, may actually not be enough in some situations. Knowing when to deviate from sepsis order sets can be lifesaving.

Sepsis Treatment Overview

Overall, Gram-negative sepsis, due to urinary and gastrointestinal sources, is the most common type of sepsis. You are probably familiar with the emergence of extended-spectrum β-lactamase (ESBL)-producing E. coli, first noting more ciprofloxacin-resistant isolates and then observing that they were also ceftriaxone-resistant. Together, this spells an ESBL.

ESBLs are resistant to all commonly used cephalosporins and often to many other antibiotic classes, like fluoroquinolones. My colleagues and I monitored urosepsis patients admitted through U.S. emergency departments in 2018, and our data suggest that around 20 percent of patients are infected with ESBLs. In some places, the rate is lower, but in others, rates are as high as 50 percent. The changing resistance patterns underscore the importance of routine urine cultures for pyelonephritis.

Antimicrobial susceptibility results usually show that ESBLs are susceptible to Zosyn, so you’d think vosyn would do the trick. However, recent research casts doubt on Zosyn’s clinical effectiveness for ESBL infections. In 2018, JAMA published a pivotal randomized controlled trial (the “Merino trial”) comparing Zosyn and meropenem (Merrem, a carbapenem) in treating 380 patients with ESBL-producing E. coli or Klebsiella bacteremia.¹ Mortality was lower with meropenem than Zosyn, 3 percent versus 12 percent, respectively, and meropenem was associated with an increased rate of microbiological eradication and a reduced rate of subsequent infections. The explanation is that antibiotics sometimes work differently in patients than in test tubes due to higher bacterial concentrations than used for microbiological assays.

This paper is a game-changer, with implications for empirical ED treatment of patients suspected of Gram-negative sepsis who are at risk of ESBL infection.

ESBL risk factors include many of the traditional ones—antibiotic and hospital/long-term care exposure in the last few months—and one you may not have considered—a past ESBL infection. Routinely check the electronic medical record before initiating empirical antibiotic treatment. Foreign travel outside North America is also a risk factor.

If your emergency department is now seeing ceftriaxone-resistance (ESBL) rates near 20 percent or greater, it’s time to change to a carbapenem, such as meropenem, from Zosyn for empirical treatment of patients with severe sepsis/septic shock who have a suspected Gram-negative (urosepsis) infection or unknown source and for less-sick patients with ESBL risk factors. It is crucial to get this right, as it often coincides with patients in whom the risk of being wrong is likely to be of the greatest significance. Many places still rely on ceftriaxone or ciprofloxacin/levofloxacin for initial treatment of patients with pyelonephritis. Ertapenem, a daily carbapenem, which lacks typically unneeded Pseudomonas activity, would be preferred. Fortunately, carbapenemase-producing isolates are still rare.

That could make our empirical regimen something like “vonem” for these cases, with vancomycin included for the possibility of a Gram-positive infection. However, for some circumstances, vancomycin might not be the ideal antibiotic for anticipated Gram-positive sepsis. Here I’ll offer evidence of better outcomes with vancomycin-alternative Gram-positive regimens for some special presentations.

Treatment Recommendations

Some septic patients are at very high risk of Staphylococcus aureus bacteremia. These include patients with a chronic venous catheter/fistula (eg, dialysis patients) and cancer patients with an infected port site. Of S. aureus isolates, some will be methicillin-sensitive S. aureus (MSSA); some, methicillin-resistant S. aureus (MRSA). MSSA is susceptible to oxacillin and nafcillin (anti-staphylococcal β-lactams); MRSA is not.

While vancomycin is active in vitro against both, for MSSA bacteremia, studies demonstrate reduced mortality associated with oxacillin and nafcillin. In one case-control study with patients matched for outcome confounders, mortality was 37 percent with vancomycin compared to 11 percent for β-lactams.² So after blood cultures, ordering nafcillin in addition to vancomycin will give your patient the best chance.

Finally, there’s evidence that for MRSA pneumonia, linezolid leads to superior clinical outcomes when compared to vancomycin. Randomized controlled trials comparing linezolid and vancomycin for pneumonia found that, among the subgroup of patients with MRSA, survival was significantly greater with linezolid, 80 percent versus 63.5 percent.³ Another randomized controlled trial targeting MRSA pneumonia patients confirmed improved clinical response with linezolid.⁴ Risk factors for MRSA etiology of pneumonia include the following: severe illness, imaging suggestive of cavities, abscesses or empyema, and history of MRSA infection. Linezolid is also active against pneumococcus, the most common cause of severe community-acquired pneumonia, and MSSA. Of note, linezolid is not indicated for primary bloodstream infections (eg, endocarditis). In septic patients with pneumonia who are at risk for MRSA, linezolid would be a better empirical choice than vancomycin.

While these recommendations are evidence-based and supported by survival and clinical improvement data, hospital antibiotic stewards will fear emergency physicians overgeneralizing these broadened regimens. It’s always best to engage and seek consensus with your infectious disease specialists.

So, for your next ED patient with sepsis, before reaching for vosyn, take a moment to think about ESBL, MSSA bloodstream, and MRSA pneumonia infections as exceptions. There’s no shame in knowing more.

Dr. Talan is professor of emergency medicine and medicine (infectious diseases) in the departments of emergency medicine at Ronald Reagan UCLA Medical Center, Olive View-UCLA Medical Center, and The David Geffen School of Medicine at UCLA, in Los Angeles.