Does Vancomycin In Combination With Piperacillin/Tazobactam Place Patients At Risk For Acute Kidney Injury?
Diabetic foot infections (DFIs) account for approximately one in five hospital admissions in the United States and are the most common cause of diabetes-related admissions. Typically, treatment of these patients requires antibiotic therapy and may or may not include surgical intervention.1 In most cases, if admission is required, the patient will most likely receive intravenous (IV) antibiotic treatment.2
The current Infectious Diseases Society of America (IDSA) recommendation for severe soft tissue infection is an empiric IV antibiotic regimen against gram-positive cocci, common gram-negative and obligate anaerobic organisms, and methicillin-resistant Staphylococcus aureus (MRSA).2 The broad recommendation regarding choice of antibiotic is vancomycin plus one of the following: ceftazidime; cefepime; piperacillin-tazobactam; aztreonam; or a carbapenem. Additional coverage for anaerobes may result from selection of ceftazidime, cefepime, or aztreonam.2 Due to its broad coverage and availability, vancomycin and piperacillin/tazobactam (VPT) combination therapy is a commonly utilized empiric regimen chosen by physicians from various specialties. However, studies recently identified VPT combination therapy as an independent risk factor for the development of acute kidney injury (AKI) in hospitalized patients.3-6
Ezebuenyi and colleagues in 2018 performed a retrospective study looking at admissions over two years for severe soft tissue infection and tallied the chosen empiric antibiotic regimen. They revealed that up to 53.4 percent of patients received VPT.7 While it is well-known that both these agents carry the risk of nephrotoxicity, the association AKI with VPT is a relatively recent finding, and, as such, many physicians are not aware of it. The purpose of this review is to bring attention to this issue so that prescribing physicians can appropriately weigh the risks and benefits associated with VPT and potentially opt for a different antibiotic regimen if possible.
What You Should Know About Vancomycin And Piperacillin/ Tazobactam
Vancomycin is a glycopeptide antibiotic introduced in 1953 for the treatment of gram-positive infections. It works by inhibiting bacterial cell wall synthesis by blocking glycopeptide polymerization through binding tightly to D-alanyl-D-alanine. Its common indication is for the treatment of serious methicillin-resistant Staphylococcus aureus infections.8 In 1983, Sorrell and team produced a study demonstrating its effectiveness against MRSA infections,8 which caused its increasing popularity over the years, although not without caution. Vancomycin has associated complications such as neutropenia, thrombocytopenia, nephrotoxicity, ototoxicity, and “red man” syndrome (caused by rapid infusion). High serum levels of the antibiotic contribute to nephrotoxicity and ototoxicity.8,9 For this reason, one closely monitors serum peaks and troughs in patients receiving vancomycin to reduce the risks of said complications and ensure successful therapeutic outcomes. Other risk factors that increase the risk of complications, other than dose and rate of administration, are pre-existing kidney dysfunction and concomitant administration with other nephrotoxic drugs, such as piperacillin/tazobactam.8,9
Piperacillin/tazobactam is a fourth-generation penicillin approved by the Food and Drug Administration (FDA) in 1993 to treat severe infections. Piperacillin inhibits bacterial wall synthesis by binding to penicillin-binding proteins. The addition of tazobactam inhibits many beta-lactamases and prevents the destruction of piperacillin, thus enhancing its activity. When used alone, piperacillin/tazobactam does not have any serious side effects and is a relatively safe, inexpensive, and readily available treatment option for DFI. Piperacillin/ tazobactam does not provide coverage of MRSA but does offer coverage of most gram-positives, including Enterococcus spp, anaerobes and gram-negatives, including Pseudomonas aeruginosa.8,9
What Does The Research Say About Acute Kidney Injury Risk?
VPT provides effective broad-spectrum coverage for DFI, but also comes with severe potential risks and complications. Recent literature implicates this antibiotic combination with the increased risk of AKI. In 2016, Giuliano and team performed a meta-analysis of articles on the association of AKI with VPT therapy.6 They identified 15 studies with a total of 3258 patients. The incidence of AKI in patients treated with VPT was 5.5 to 46 percent. This was significantly higher than those treated with just vancomycin or vancomycin combined with a different beta-lactam.3 Additionally, Anderson and colleagues (2017) looked at the incidence of AKI in vancomycin monotherapy versus VPT in noncritically ill patients. Of 253 patients reviewed, 17 percent of patients on VPT therapy developed AKI, while just 11 percent of those on vancomycin did.4 O’Callaghan and coworkers (2020) specifically looked at the risk of AKI in intensive care unit (ICU) patients treated with VPT therapy. They retrospectively evaluated 270 patients, 168 of which received VPT and 92 received vancomycin with either cefepime or meropenem. They noted AKI in 27 percent of admissions, with statistically significantly more occurring in the VPT group compared to the others.5 In addition, McLaren and colleagues (2020) looked at 211 patients treated with vancomycin and piperacillin-tazobactam for skin and soft tissue infections and not only identified the combination as an independent risk factor for AKI, but they also identified duration of therapy as an additional risk factor.6
Although recent research suggests that VPT combination therapy strongly associates with AKI development, the mechanism by which this happens is not clearly understood. Piperacillin-tazobactam acts on the proximal renal tubule and, as a result, can cause acute interstitial nephritis. A possible explanation for the development of AKI is the addition of vancomycin-associated cellular necrosis in the proximal renal tubule. Another theory centers on accumulation of vancomycin due to decreased clearance caused by piperacillin/tazobactam.3-6
What Alternative Options Exist?
Because of the identification of VPT therapy as an independent risk factor for AKI, numerous studies specifically compare it to other combination therapies with similar microbial coverage in order to recommend possible alternatives. In 2017, Peyko and team compared patients who received vancomycin with either piperacillin/tazobactam, cefepime, or meropenem in a single-center prospective study.10 They evaluated 85 patients and found that 37.3 percent of those who received VPT developed AKI, while only 7.7 percent of those with vancomycin and either cefepime or meropenem did.10 Buckley and colleagues (2021) did a very similar study comparing the nephrotoxicity of VPT versus vancomycin in combination with either cefepime or meropenem. Researchers included a total of 1138 patients, and their results demonstrated a significantly higher incidence of AKI with VPT (21.9 percent) compared to the other combination therapy (16.8 percent). Incidentally, they also identified that the mean time to AKI was shorter for the patients treated with VPT (4.3 days) than with the other combinations (5.8 days).11 Jeon and coworkers in 2017 did another similar study looking at increased AKI risk with piperacillin-tazobactam compared with cefepime, looking at baseline kidney function. They included 5335 patients in their study, of which 1980 (37.11 percent) received piperacillin-tazobactam, and 3355 (62.89 percent) received cefepime, both in combination with vancomycin therapy. AKI ensued in 398 (19.68 percent) patients in the piperacillin-tazobactam group, and 546 (16.27 percent) of the patients who received cefepime. They found this difference to be statistically significant and concluded that vancomycin in combination with piperacillin-tazobactam carried an increased risk for AKI when compared to vancomycin with cefepime.12
According to the data presented, there is a statistically significant difference in AKI occurrence associated with VPT compared with any other monotherapy or combination therapy. Physicians prescribing empiric antibiotics should keep this in mind and consider alternatives that do not carry this risk and that can provide similar coverage. Karino and colleagues in 2016 studied the incidence of AKI in patients treated with vancomycin versus VPT. While they also came to the same conclusion as all the prior studies, that VPT had a higher risk of AKI than just vancomycin, they also identified additional patient factors that may put them at risk. The purpose of this additional analysis was to identify patients in whom VPT should not be a first-line therapy. The main three factors they identified were receiving a vancomycin loading dose, concomitant nephrotoxin use, and a longer duration of therapy.13
As stated above, cefepime and meropenem have a significantly lower risk of AKI and provides similar coverage to piperacillin/tazobactam. Cefepime is a fourth-generation cephalosporin that has been shown to cover both gram-positive and gram-negative bacteria, including Pseudomonas. The only coverage it does not provide in comparison to piperacillin/tazobactam is for anaerobic bacteria.14 Off-label cefepime effectively treats infections including but not limited to: gram-negative bacteremia; moderate-to-severe diabetic foot infections; osteomyelitis; prosthetic joint infection; sepsis; and septic arthritis. Cefepime, along with all other cephalosporins, only have nephrotoxicity at high doses.14 Meropenem is a beta-lactamase inhibitor that provides coverage against most gram-negative and gram-positive bacteria. Except for Enterococcus spp, meropenem provides similar coverage to that of piperacillin/tazobactam. Meropenem has indication for individuals with skin and soft tissue infections, intra-abdominal infections, animal or human bite wound infections, pneumonia, gram-negative bacteremia, moderate-to-severe diabetic foot infections, osteomyelitis, prosthetic joint infection, and sepsis. Meropenem combined with vancomycin is associated with AKI more so than cefepime; however, both combinations provide a lower risk of AKI than VPT.15,16
In Conclusion
Acquiring broad-spectrum antibiotic coverage in the presence of a severe soft tissue infection is paramount in managing the severe soft tissue infection and preventing sepsis. In combination with piperacillin/tazobactam, vancomycin is a common broad-spectrum antibiotic regimen many physicians choose due to multiple factors, including availability, bacterial coverage, IDSA guidelines, and individual local hospital antibiotic algorithms. However, there is a strong association between this medication combination and AKI development in hospitalized patients. As an alternative, both cefepime (except for anaerobic coverage) and meropenem can provide similar empiric bacterial coverage as piperacillin/ tazobactam but do not carry the same increased risk of the development of AKI. As experts in treating diabetic foot infections, podiatrists should be aware of the risks of this frequently prescribed regimen when recommending antibiotic treatment and consider alternatives whenever possible.
Dr. Ptak is a first-year resident with the Podiatric Medicine and Surgery Residency Program at Intermountain Medical Center in Murray, UT.
Dr. Ray is a second-year resident with the Podiatric Medicine and Surgery Residency Program at Intermountain Medical Center in Murray, UT.
Dr. Read is a second-year resident with the Podiatric Medicine and Surgery Residency Program at Scripps Memorial Hospital Encinitas in Encinitas, CA.
Dr. Larsen is the Residency Director at the Podiatric Medicine and Surgery Residency Program at Intermountain Medical Center in Murray, UT.
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