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Drug Information Response Form
Requester Name & Title: Dr. Rossettie
Address: Hendrick Medical Center
1900 Pine Street
Abilene, TX 79601
Telephone: 325-670-2000
Email: RossettieA@HendrickMC.org

Original Question:
Should I use cefepime or pip/tazo with the vanco?

Background information about how the original question arose:

Patient related / academic (choose one)

Relevant patient information (de-identified, if applicable):
- Patient Scr: 1.8 mg/dL
- Baseline Scr: 0.8 mg/dL
- Allergies: Sulfa, fluoroquinolones
- Age: 62 years old
- Current Medications:
- Metformin IR 500 mg
- Lisinopril/HCTZ 20/12.5 mg
- Atorvastatin 40 mg
- Sertraline 50 mg

True question:
What is the difference in the incidence of AKI between piperacillin/tazobactam and cefepime when they
are given with vancomycin?

Urgency: STAT (<2hours) ASAP (<24 hours) Routine (24-48 hours)

Category (may bold ≥1):

Drug interaction Toxicology Natural product Tablet identification
Product availability Pharmacotherapy Pregnancy/lactation Product identification
Compounding Pharmacokinetics Literature search Adverse drug reaction
Off-label use Dosing Stability/compatibility Other: _____________

Last Name 1
Introduction & background information for the response:
I am responding to the request of which medication in combo with vancomycin would be best to
use in regards to incidence of acute kidney injury. Piperacillin - a penicillin derivative - is well known as
an antipseudomonal penicillin, that aims to work against HAP-producing bacteria, like Gram positive
cocci and Haemophilus influenzae. The other medication is cefepime, a fourth generation cephalosporin
that also targets Gram positive cocci and Haemophilus influenzae, as well as Pseudomonas aeruginosa,
and is known as the antipseudomonal cephalosporin According to 2016 IDSA guidelines on Hospital
acquired and ventilator-associated pneumonia, piperacillin/tazobactam or cefepime in combination with
vancomycin are both first line options for empiric use².
With piperacillin/tazobactam in combination with vancomycin, all 3 of these medications work
against bacteria to inhibit cell wall synthesis. Piperacillin/tazobactam are mainly excreted renally, with
~68% of piperacillin, and ~80% of Tazobactam both being excreted renally as unchanged drug, and their
clearance are both proportional to renal function. Cefepime is also mainly cleared renally, with ~85% of
unchanged drug being excreted via urine. Both vancomycin and piperacillin/tazobactam have potential
for nephrotoxicity alone, so combining them together may result in worsening adverse effects against
the kidneys¹. Especially with acute kidney injury, medications can have serious negative effects against
renal clearance and performance of medications that undergo renal excretion. Acute Kidney injury has
many varying definitions according to separate criteria and guidelines. RIFLE Criteria defines AKI as a
minimum of 2x serum creatinine at baseline and a urine clearance of <0.6 mL/kg/hr.⁷ AKIN Criteria
defines Stage 1 kidney injury as a minimum of 1.5x increase in creatinine clearance or increased by at
least 0.3 mg/dL, or decreased urine output.⁷ IDSA-ASHP guidelines on Vancomycin monitoring also use a
slightly modified definition, in which they describe acute kidney injury as a minimum of 0.5 mg/dL or a
50% increase of Scr at baseline, or a 50% decrease in CrCl in 2 consecutive days.⁴ In this case, outside
forces like medications can change electrolyte balances and change how the kidneys filtrate, which can
alter effects of medications in the body, and potentially cause even more harm to the patient.

Literature Search Strategy:

I performed an advanced PubMed search using advanced search settings and searched
(Nephrotoxicity) OR (acute kidney injury) AND (cefepime) AND (piperacillin/tazobactam) AND
(vancomycin). I also checked off the “Free full text” filter as well, with no limits to dates. With this search
I was able to find 23 total articles about various subjects that relate to incidence of AKI in our questioned
3 antibiotics - vancomycin,. cefepime, and piperacillin/tazobactam - where I found 3 relevant articles
pertinent for answering the question. The first article I found was a retrospective cohort study that
looked at the incidence rates of acute kidney injury to those taking cefepime or the pip/tazo in
combination with vancomycin, which is perfect for the case we are working to solve. The second article I
found was a multicenter prospective study looking at nephrotoxicity incidences with vancomycin in
combination with pip/tazo and cefepime over a 72 hour period in hospitalized patients, and compared
the incidence rates with both statistically and clinically significant numbers. The third article comprises
another retrospective cohort study that looked at incidence of acute kidney injury with at least 48 hours
of infusions of vancomycin in combination with either pip/tazo and cefepime. Using 2 prospective
cohorts and a retrospective cohort, recommendations can be made in order to solve the question of
whether zosyn with vancomycin or cefepime with vancomycin have more AKI incidence.
Literature Review:

Gomes et. al conducted a retrospective cohort study that compared incidences of AKI in those using
vancomycin in combination with either piperacillin/tazobactam or cefepime.²
This study included patient records of those who were over 18 years of age with a baseline serum
creatinine within 1 day of admission, had at least one trough level for vancomycin, and was treated with
either of the two medications in combination with vancomycin for at least 48 hours during the
admission period, having started on either vancomycin or the two studied medications no more than 48
hours from each other. Patients that were excluded from the study had a baseline creatinine clearance
of 60 mL/min or worse or were on dialysis, had a history of chronic kidney disease (CKD) of stage III or
higher, or structural kidney disease.²
The study looked at patients that were admitted to the UF Health Jacksonville from January 21, 2012 to
October 15, 2012, and looked at patients that have received the combination of vancomycin and
piperacillin/tazobactam or cefepime during their admission. Once the full group of patients has been
made, a match pair is made using propensity scores on patients to create the groups.² The primary
endpoint for this study was the incidence of AKI and differences of rates of AKI between the two study
groups. The length of stay for patients as well as the time from initiation and AKI incidence are
secondary points.²
A total of 112 patients in the unmatched pair analysis were grouped into the 2 treatment groups, with
the piperacillin/tazobactam group on average being slightly older (52 yr Zosyn vs. 50 yr Cefepime), a
baseline Scr or 0.79, but a higher Crcl in Zosyn + vanco (~141) vs cefepime + vanco (~139) . In the
unmatched group, incidence of AKI was found to be higher in those taking piperacillin/tazobactam with
vancomycin (34.8%) than those that took cefepime and vancomycin (12.5%) (odds ratio [OR] 3.74, 95%
confidence interval [CI] 1.89–7.39, p<0.0001).² No difference was found in the length of stay as well as
the initiation of treatment and AKI incidence, however.
In the incidence of AKI with piperacillin/tazobactam in combination with vancomycin, the chances of
acquiring AKI is significantly higher than those taking other antimicrobials like cefepime with
vancomycin.

Brandon Mullins et. al. performed a multicenter, prospective observational study that looked at the
incidence of AKI in those that received vancomycin in combination with either cefepime, meropenem, or
piperacillin/tazobactam.⁵ However, Meropenem’s statistical numbers are not relevant to our question
and thus will not be discussed.
Patients 18 years or older that received IV vancomycin in combination with piperacillin/tazobactam,
cefepime, or meropenem for at least 72 hours were included in the study, with antibiotic overlap being
for at least 48 hours.⁵ Those that were excluded from the study if they had history of CKD, AKI prior to
initiation in hospital, having a baseline Scr ≥1.5 mg/L, having a vancomycin trough <10 mg/L before
discontinuation of therapy, and those who have suffered cardiac arrest before initiation of antibiotics.⁵
Patient data was collected from 4 different medical institutions from December 2014 to August 2016,
with various infections including upper respiratory infections or skin infections.⁵ The primary endpoint
of this study was the difference of incidence of AKI between the 3 treatment groups, and comparing risk
factors to AKI and AKI incidence was determined to be the secondary endpoint.⁵
242 patients were officially included in the study, with an average baseline Scr at 0.85 mg/dL, an average
baseline Crcl of ~78 mL/min, and an average age of ~66 years old. 94 patients received vancomycin in
combination with piperacillin/tazobactam, and 101 patients received vancomycin with cefepime.⁵
Incidence of AKI with the group that received piperacillin/tazobactam was significantly higher than that
of cefepime combination with vancomycin, with incidence rates of the cefepime group having less
incidence than the piperacillin/tazobactam group (29.8% VPT versus 5.9% VC, P < 0.001).⁵ The study
also found that concomitant use of certain medications like loop diuretics ( Odds Ratio [OR] 3.27, 95% CI
1.42-7.53, P= 0.005) or vasopressors (OR 5.04, 95% CI 1.66-15.35, P=0.004) further increases the risk of
AKI developing while on any of these antibiotics.⁵
This study can show an association between vancomycin combined with piperacillin/tazobactam and AKI
incidence. Certain concomitant medications as well are risk factors to the development of acute kidney
injury

Navalkele et. al. performed a retrospective , matched cohort study that compared the incidence of acute
kidney injury between piperacillin/tazobactam and cefepime in combination with vancomycin. They also
looked at the relationship of acute kidney injury onset and levels of vancomycin
Patients were included in the study if they were given piperacillin/tazobactam or cefepime with
vancomycin for at least 48 hours, and had both the antibiotics initiated within 24 hours of each other,
and were at least 18 years old.⁶ If patients had multiple regimens, only the first regiment of the combo
antibiotics were included. However, if patients required renal therapy prior to initiation or had a
baseline serum creatinine >1.2 mg/dL, they were excluded from the study.
The study was conducted in Detroit, Michigan at Detroit Medical center, comprising 5 acute care centers
around the city. Patients were divided into two therapy groups: vancomycin with
piperacillin/tazobactam and vancomycin with cefepime, and matched together, comparing variables
that are associated with kidney injury together to determine differences between the two. The study
was conducted from December 1, 2011 to December 31, 2013.⁶ Comparing the rates of AKI between
piperacillin/tazobactam and cefepime was the primary endpoint for this study, along with studying
vancomycin trough levels to determine if there is a relationship between the incidence of AKI and
vancomycin trough levels. The time from first dose to incidence of AKI was noted as a secondary
endpoint.
A total of 558 patients - with an average age of 55.9 years old (± 16.6) and a baseline Scr of 0.86 mg/dL -
were included in the final study population that matched using 5 key variables: sepsis severity, similar
daily dose of vancomycin, status of ICU patients, the duration of therapy, and a number of concomitant
nephrotoxic agents.⁶ These patients took either Vancomycin + Piperacillin/tazobactam (VPT) or
Vancomycin + Cefepime (VC), and both study groups were equally 278 patients.⁶ Using the RIFLE criteria
to determine AKI, the study showed that 81 patients in the VPT group would develop AKI, and only 31
patients in the VC group (29.0% vs 11.1%; hazard ratio [HR] = 4.0; 95% confidence interval [CI], 2.6–6.2;
P < .0001).⁶ Additionally, the VPT group also developed AKI at a quicker rate, with a mean rate in VPT
being 3 days, and 5 days in VC.⁶ The researchers also discovered no significant association vancomycin
trough levels and AKI incidence in the VPT group. On the other hand, they found that in the VC group
there was a significant risk of those developing AKI if their vancomycin trough levels where above 15
mg/dL - where those who had trough levels over 15 mg/dL had an incidence rate of 5%, and those with
trough levels >20 mg/dL had an incidence rate of 21% (P = 0.003).⁶
The authors concluded that there was a four-fold increased risk of AKI with concurrent use of
vancomycin and piperacillin/tazobactam, and at a quicker rate.
Conclusion & Recommendations:

All 3 of the studies reviewed have the commonality of significant evidence of AKI incidence with
vancomycin + piperacillin/tazobactam. Both retrospective studies revealed the same results with varying
conditions as well as varying definitions of AKI.⁵⁺⁶ Regardless, the use of piperacillin/tazobactam with
vancomycin has shown nephrotoxic effects compared to safer options like cefepime or even
meropenem.⁵ Especially in patients with concomitant medications that are known to have an effect on
renal function, piperacillin/tazobactam with vancomycin should only be considered a viable option in
situations where other options are unavailable². Finally, incidence of AKI using piperacillin/tazobactam
in combination with vancomycin occurred at quicker rates than cefepime in combination with
vancomycin.⁶ In regards to use of piperacillin/tazobactam use in combination with vancomycin, it should
not be used in patients with a history of acute kidney injury, or have risk factors that may lead to acute
kidney injury. With regards to cefepime use, cefepime should be used with caution in those susceptible
or have risk factors for acute kidney injury. However, cefepime should be preferred over
piperacillin/tazobactam with the use of vancomycin, if possible. When considering empiric treatments
for HAP/VAP patients, cefepime is a safer option in regards to safety for the kidneys and has a better
overall adverse effect profile than that of piperacillin/tazobactam in combination with vancomycin, and
should be favored. To answer the question of whether cefepime or piperacillin/tazobactam would be
better to use in combination with vancomycin for patients at risk of acute kidney injury, cefepime 2 g IV
every 8 hours is a safer option and should be preferred.

Response prepared by: Dominic L. Pitre

Time spent: 6+ hours
Response reviewed by:
Time spent:

References:

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combined with vancomycin: should it be a concern?. Int J Antimicrob Agents. 2018;52(2):180-
184. doi:10.1016/j.ijantimicag.2018.03.024
2. Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment
with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy.
2014;34(7):662-669. doi:10.1002/phar.1428
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Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases
Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111.
doi:10.1093/cid/ciw353
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Vancomycin in Combination With Cefepime, Meropenem, or Piperacillin/Tazobactam: A
Prospective, Multicenter Study. Ann Pharmacother. 2018;52(7):639-644.
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6. Navalkele B, Pogue JM, Karino S, et al. Risk of Acute Kidney Injury in Patients on Concomitant
Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime. Clin
Infect Dis. 2017;64(2):116-123. doi:10.1093/cid/ciw709
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