Is vancomycin/zosyn the answer for everything?

Authors: Mariam Abdelghany, PA-C¹, Minela Subasic, PA-C¹, Anthony Scoccimarro, MD¹, Joel Gernsheimer, MD², and Muhammad Waseem, MD, MS^1,3 (Lincoln Medical & Mental Health Center Bronx, New York¹; SUNY Downstate Medical Center New York²; St. Georges University Grenada West Indies³) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Case:

A 65-year-old man is brought to the ED in shock. His vital signs include temperature 102 F, heart rate 132 beats/minute, respiratory rate 36 breaths/minute, blood pressure 80/50 mm Hg, and oxygen saturation 91%. His abdomen is markedly tender. After initial stabilization, he is taken to the operating room for emergency laparotomy for suspected peritonitis secondary to perforated appendicitis. Which antibiotic regimen should be administered?

Emergency Physicians are faced with the dilemma of antibiotic selection in patients with presumed sepsis or serious bacterial infection. Suspected sepsis is one of the most common causes of ED evaluation and hospital admission. Broad-spectrum agents, such as piperacillin-tazobactam (Zosyn) and vancomycin, are commonly used for empirical antibiotic coverage in suspected early sepsis and critically ill patients. Several studies show a disturbing trend toward increasing use of broad-spectrum antibiotics.[1],[2] It has been estimated that 55% of all antibiotic prescriptions may be unnecessary.[3] The broad administration of vancomycin is of special concern, as it may lead to the emergence of vancomycin resistant gram-positive cocci.[4] Appropriate antibiotic administration means that the indication for antibiotic use, the choice of the drug, timing of administration, route, dosage, frequency, and duration of administration have been carefully considered and determined to be warranted. In this article, we will discuss instances where the classic combination of vancomycin and Zosyn may be indicated, and where its use may not be warranted.

Medication Background

Before we get started, let’s go over some of the basics for Zosyn and Vancomycin.

Piperacillin/tazobactam (Zosyn)

Piperacillin/tazobactam (Zosyn) is a combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam. This antibiotic has activity against many Gram-positive, Gram-negative, and anaerobic pathogens.  It covers Streptococci, Staphylococci (but not methicillin-resistant S. aureus [MRSA]), Hemophilus, Moraxella, Enterobacteriaceae, and Pseudomonas aeruginosa.[5],[6] It is an excellent anti-anaerobic agent, but does not treat clostridium difficile infections. As an anti-pseudomonal penicillin plus a beta-lactamase inhibitor (which prevents it from being broken down by organisms that possess resistance by producing a beta-lactamase), piperacillin/tazobactam inhibits cell wall mucopeptide synthesis by binding to one or more of the penicillin-binding proteins in the cell wall.[7] It is therefore not effective against organisms that do not have a cell wall like viruses, chlamydia, mycoplasma, and rickettsia, or those with an atypical cell wall like legionella.

The recommended dosing for severe infections, other than nosocomial pneumonia, in patients with normal renal function, is 3.375 g IV Q6h (a total daily dose of 13.5 g, which comes to a total daily dose of 12 g of piperacillin and 1.5 g of tazobactam) for 7-10 days. However, in patients where severe nosocomial pneumonia is a concern, 4.5 g IV can be given in patients with normal renal function. The dose should be adjusted in patients with significant renal dysfunction.

For patients with a creatinine clearance between 20-40 mL/minute, the dose of Zosyn should be 2.25 g IV Q6h for the usual indications, and 3 g IV Q6h IV for nosocomial pneumonia.

For patients with a creatinine clearance less than 20 mL/minute, the dose should be 2.25 g IV Q8h for the usual indications, and 2.25 g IV Q6h for nosocomial pneumonia.  Zosyn should be administered IV no faster than over 30 minutes.

Indications for Piperacillin/Tazobactam Administration:

Intra-abdominal infections

Severe Sepsis (without source)

Bacteremia associated with intravascular line

Skin and skin structure infection

Postpartum/ Puerperal endometritis or pelvic inflammatory disease

Bone and joint infection

Community acquired pneumonia (severe, sepsis)

Nosocomial pneumonia

Zosyn is especially useful when a life-threatening infection with a resistant gram negative organism, particularly pseudomonas, is suspected.

Vancomycin

Vancomycin is a glycopeptide that inhibits cell-wall biosynthesis.[8] Intravenous vancomycin is indicated for serious infections with gram positive organisms, such as staphylococcus (specifically MRSA), streptococcus, and most strains of enterococcus. Intravenous vancomycin remains the drug of choice for serious deep seated MRSA infections.[9] It is also indicated for possible meningitis in children and adults, pending the results of CSF cultures, as it has excellent coverage against pneumococcus, including forms resistant to penicillins and cephalosporins. Vancomycin is poorly absorbed in the GI tract and cannot be used orally, except for treating serious or resistant clostridium difficile infections. It can also be instilled in the peritoneal cavity as part of the dialysate in patients who have peritonitis from peritoneal dialysis.

The recommended dose includes 15-20 mg/kg (actual body weight) every 8-12 hours in patients with normal renal function, with a maximum of 2 g IV. In critically ill patients, a loading dose of 25-30 mg/kg can be administered (though the maximum dose remains the same).[10],[11] Vancomycin should never be administered faster than over one hour in both children and adults. In adults, it should not be administered faster than 10 mg per minute. Administering vancomycin too rapidly may cause a “Red Man Syndrome” with flushing, erythema, pruritis, and even hypotension.

Vancomycin/piperacillin-tazobactam regimen indications               

Vancomycin and piperacillin-tazobactam is a good antibiotic combination to use in critically ill patients with an unclear source of infection, sepsis, or septic shock.  Empiric antibiotic therapy should be started as early as possible and should cover all likely pathogens.  If possible, obtain blood cultures and other appropriate cultures before starting the medications, but if the patient is sick, provide broad spectrum coverage first. The regimen can be modified based on the specific pathogen shown on culture and sensitivity reports when available (this is more for the ICU/floor). [12] Decisions to continue empiric antimicrobial should be based on both clinical assessment and culture results.[13] When possible antibiotics with very broad-spectrum coverage, such as the combination of Zosyn and vancomycin, should be changed to an antibiotic regimen with a narrower spectrum in order to prevent the emergence of resistant organisms to these very important medications.

Consider combination therapy with the following conditions:

1. Severe intra-abdominal infections: for patients with complicated infections, particularly those who have had recent intra-abdominal surgery, as they are more likely to have MRSA infection that requires Vancomycin, rather than just gram negative and anaerobic infection that usually could be treated with Zosyn alone.[14]
2. Bacteremia associated with the presence of an intravascular line: if the patient is extremely ill, neutropenic, possesses a line in the femoral area, or in the setting of resistant microbe. If the patient is not too ill, then some experts might use Vancomycin alone initially.[15]
3. Hospital Acquired Pneumonia: Most experts would agree on combination therapy, especially if the patient is severely ill.[16]
4. Neutropenic fever: If the patient is very ill and the source may be from a line or skin source, then Vancomycin should be added to a gram-negative drug like Zosyn or Cefepime to cover MRSA. If the patient is not severely ill and if a line or skin source is not suspected, then some experts would just use Zosyn or Cefepime without adding Vancomycin.[17]

Vancomycin/piperacillin-tazobactam coverage

Vancomycin /piperacillin-tazobactam regimen spectrum of activity includes:

–Gram positives: MRSA, strep viridans, strep pneumoniae, beta-hemolytic streptococci, coagulase negative staphylococcus, MSSA, E. Faecalis

–Gram negatives: pseudomonas, Enterobacter spp, serratia spp, proteus spp., klebsiella spp, E. coli, H. Influenzae

–Anaerobes – oral and abdominal

-This regimen has great penetration at the following sites: lungs, abdomen, skin, soft tissues, and urine

When is vancomycin/piperacillin-tazobactam not the answer?

The rationale for combination therapy includes prevention of resistance to a single agent, treatment of polymicrobial infection, empiric therapy for immunocompromised and critically ill patients, and using synergistic antibiotics to treat a serious, hard to treat infection due to relatively resistant organisms, such as endocarditis. Double beta-lactam therapy in most situations is not needed. In fact, if it is deemed necessary to add a second antibiotic to a beta-lactam drug, it is usually recommended to add an antibiotic from another drug class.

According to the Antimicrobial Stewardship program, the practice of giving two agents to cover anaerobes (double coverage) accounts for 20% of interventions although this practice is not supported by susceptibility profiles.[18] One common instance of this is in the case of intra-abdominal infections. According to the Infectious Disease Society of America (IDSA) guidelines, piperacillin-tazobactam is appropriate as monotherapy, as it has excellent gram negative and anaerobic coverage.[19] The exception to this would be intra-abdominal infections secondary to a biliary etiology (e.g. cholangitis), in which case it is recommended to add metronidazole.

For gram negative organisms, a carbapenem by itself usually gives very effective coverage, including coverage against organisms that produce an extended spectrum beta lactamase (ESBL). Carbapenems also have excellent coverage for most anaerobes and gram positive organisms. Third and fourth generation cephalosporins have excellent gram negative coverage, as does aztreonam. However, for life threatening infections with gram positive organisms that may be resistant to beta-lactams antibiotics, including MRSA and resistant pneumococci, vancomycin is usually needed. Other antibiotics that can be used to treat life-threatening infections caused by MRSA are Linezolid and Daptomycin. Bactrim, doxycycline, and clindamycin can be used orally to treat less serious community acquired MRSA infections. IV Clindamycin may be used as an addition to other antibiotics (such as vancomycin/pipercillin-tazobactam) to treat necrotizing soft tissue infections by helping to block toxin production.

Decisions to use broad spectrum antimicrobials should include clinical assessment with a range of diagnostic information which includes, but is not limited to, culture-based microbiology if available.[20]

In a recent study, up to 12% of the total antibiotic costs could have been avoided if all prescriptions were optimal.[21] In this study, Infectious Disease consultants evaluated the appropriateness of antibiotic selection using a modification of Kunin’s criteria, which are a set of validated criteria for antibiotic use.[22] This study reviewed antibiotic selection for both admitted and discharged patients from the emergency department. In another study 29% of empiric antibiotic administration was inappropriate in surgical and trauma patients.[23] In terms of indications, studies have noted increased association between inappropriate antibiotic selection and peritoneal, urinary tract, catheter-associated, and bloodstream infections.[24-26]

Finally, it should go without saying that not all causes of sepsis and septic shock are bacterial: the clinician should also consider adding anti-viral and anti-fungal antimicrobials where appropriate.

Vancomycin/piperacillin-tazobactam: what does it not cover?

-Vancomycin-resistant Enterococcus

-Fungal, viral, and parasitic infections

-Atypical infections including illness caused by: chlamydia, mycoplasma, legionella

-Organisms that produce extended spectrum beta-lactamases (ESBLs) – some strains of Escherichia coli (E. coli) and Klebsiella. The risk factors for an infection with an ESBL producing organism are recurrent UTIs, hospitalizations, urinary tract instrumentation, elderly, and being male.

-Infection caused by an abscess or infected line if not drained or removed, respectively.

It should be emphasized again that Zosyn is a broad-spectrum antibiotic that covers many gram positive, gram negative (including pseudomonas), and anaerobic organisms. When anaerobic and pseudomonal coverage is not needed, it may be better to use a drug like ceftriaxone, that has excellent gram negative coverage, but no significant anti-anaerobic or anti-pseudomonal activity. When it is believed that infection with pseudomonas is present, but there is no need for anaerobic coverage, then Cefepime may be a more appropriate choice. These types of decisions should be made on the basis of the patient’s clinical status, the possible site of infection, whether the patient is at risk for nosocomial acquired infections, and the antibiograms of the institution. Vancomycin has great gram positive coverage, and it is especially useful for treating serious infections with MRSA. When it is believed that infection with MRSA is unlikely, then another antibiotic with excellent gram positive coverage like a penicillin, cephalosporin, or clindamycin may be used. Again this should be based on the considerations noted above.

What are the consequences of inappropriate antibiotic administration?

-Increased duration of antibiotic treatment

-Development of multidrug-resistant (MDR) organisms

-Increased hospital length of stay

-Increased cost

-Adverse drug effects: nausea/vomiting, diarrhea, rash (SJS, TENS, etc.), renal toxicity, and many others

Is piperacillin-tazobactam nephrotoxic?

This question has been one of considerable debate in the FOAM world, especially in the last year.[27],[28] Piperacillin-tazobactam has been associated with risk of developing AKI.[29]  Other studies have also shown no association with AKI[30] or the need for renal replacement therapy.[31]  Although the exact mechanism for AKI due to beta-lactams and vancomycin is not known, the most common proposed mechanism is acute interstitial nephritis or toxic effects on the renal tubule. Four independent risk factors for AKI have been identified.[32]

• Gram-positive infection
• Sepsis (the greater the severity, the higher the risk of AKI)
• Administration of Vancomycin loading dose. However, in another report initial dosing of vancomycin > 20 mg/kg was not associated with an increased rate of nephrotoxicity.[33]
• Administration of any other nephrotoxic agent

It is suggested that piperacillin-tazobactam is associated with an increased creatinine due to a reduction in tubular creatinine secretion. In a retrospective analysis by Jensen et. al, the use of piperacillin-tazobactam was identified as a cause of delayed renal recovery in critically ill patients.[34] Interestingly, after the piperacillin/tazobactam was discontinued, the subgroup had more rapid recovery of glomerular filtration rates.

There remains considerable debate as to whether piperacillin-tazobactam is nephrotoxic in its own right or in combination with vancomycin, or if it is a matter of elevating serum creatinine by a mechanism similar to trimethoprim or probenecid.

Is Vancomycin nephrotoxic?

Many believe that vancomycin induced nephrotoxicity is overstated.[35] A recent study has suggested that vancomycin is minimally nephrotoxic and has a similar nephrotoxic profile as compared with linezolid when appropriate dosing is used, even among critically ill patients.[36] The trough serum vancomycin concentrations and duration of therapy are associated with increased risk of nephrotoxicity.[37] Other studies have identified following factors linked with vancomycin-associated nephrotoxicity.[38]

• Total daily dose > 4 grams
• Trough levels > 20 mg/L
• Therapy exceeding 6 days
• Concurrent use of other nephrotoxic agents
• Preexisting renal disease
• Obesity
• Hypotensive episodes
• Severe illness

There is also concern for higher risk of acute kidney injury with combined use of vancomycin/piperacillin-tazobactam.[39]

Summary / Pearls

-Vancomycin/piperacillin-tazobactam should be used judiciously in order to limit the emergence of resistant organisms.

-Vancomycin should be administered in suspected or proven serious MRSA infections.

– Most intra-abdominal infections do not require coverage for MRSA, unless the patient has had recent abdominal surgery or instrumentation, such as catheter insertion.

– Coverage against pseudomonas and other very resistant gram negative organisms is often not needed in patients with uncomplicated intra-abdominal infections, who are otherwise healthy, not had recent intra-abdominal procedures, not recently been on antibiotics, and not life-threateningly ill.

–Do not delay administering Vancomycin/piperacillin-tazobactam to severely ill patients when the source of infection is not known.

-Give piperacillin-tazobactam before Vancomycin, as Zosyn possesses broader coverage and can be given more rapidly than vancomycin.

-Concomitant use of Vancomycin and piperacillin-tazobactam may increase the incidence of acute kidney injury.

–Correct dosing of vancomycin is also important.

References / Further Reading

[1] Steinman MA, Landefeld CS, Gonzales R. Predictors of broad spectrum antibiotic prescribing for acute respiratory tract infections in adult primary care. JAMA 2003; 289:719-725

[2] Roumie CL, Halasa NB, Grijalva CG. Trends in antibiotic prescribing for adults in the United States-1995 to 2002. J Gen Intern Med 2005;20:697-702

[3] Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States.  Clin Infect Dis.2001; 33:757-762

[4] Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin—United States, 2002. MMWR Morb Mortal Wkly Rep2002; 51:565-567

[5] http://www.fda.gov/ohrms/dockets/dockets/06p0195/06P-0195-EC1-Attach-1.pdf Last accessed December 16, 2016

[6] Chambers H.F.: Other B-lactam antibiotics. In (eds): Philadelphia: Churchill Livingstone, 2000. pp. 291-299

[7] http://reference.medscape.com/drug/zosyn-piperacillin-tazobactam-342485#10 Last Accessed December 16, 2016

[8] http://reference.medscape.com/drug/vancocin-vancomycin-342573#10 Last Accessed December 16, 2016

[9] Barbara E. Murray, Cesar A. Arias, Esteban C. Nannini. Glycopeptides (Vancomycin and Teicoplanin), Streptogramins (Quinupristin-Dalfopristin), Lipopeptides (Daptomycin), and Lipoglycopeptides (Telavancin Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition, 2015: 30, 377-400.e4 Saunders

[10] Wang JT, Fang CT, Chen YC, et al: Necessity of a loading dose when using vancomycin in critically ill patients. J Antimicrob Chemother 2001; 47:246

[11]  Truong J, Levkovich BJ, and Padiglione AA: Simple approach to improving vancomycin dosing in intensive care: a standardized loading dose results in earlier therapeutic levels. Int Med J 2012; 42: 23-29

[12] Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM; Infectious Diseases Society of America.; Society for Healthcare Epidemiology of America. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007 Jan 15;44(2):159-177

[13] Shallcross LJ, Freemantle N, Nisar S, Ray D. A cross-sectional study of blood cultures and antibiotic use in patients admitted from the Emergency Department: missed opportunities for antimicrobial stewardship. BMC Infect Dis. 2016 Apr 18;16:166

[14] Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, O’Neill PJ, Chow AW, Dellinger EP, Eachempati SR, Gorbach S, Hilfiker M, May AK, Nathens AB, Sawyer RG, Bartlett JG. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010 Jan 15;50(2):133-64

[15] Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP, Raad II, Rijnders BJ, Sherertz RJ, Warren DK. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009 Jul 1;49(1):1-45

[16] Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O’Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL.Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-e11

[17] Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011 Feb 15;52(4): e56-93

[18] Double Anaerobic Coverage: What is the role in clinical practice?  Available at http://www.nebraskamed.com/App_Files/pdf/careers/education-programs/asp/DoubleAnaerobicCoverage.pdf. Last Accessed January 13, 2017

[19] Solomkin, J. S., Mazuski, J. E., Bradley, J. S., Rodvold, K. A., Goldstein, E. J., Baron, E. J., & Gorbach, S. (2010). Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surgical infections, 11(1), 79-109

[20] Shallcross LJ, Freemantle N, Nisar S, Ray D. A cross-sectional study of blood cultures and antibiotic use in patients admitted from the Emergency Department: missed opportunities for antimicrobial stewardship. BMC Infect Dis. 2016 Apr 18;16(1):166

[21] Ojeniran M, Shouval R, Miskin IN, Moses AE, Shmueli Costs of appropriate and inappropriate use of antibiotics in the emergency department. Isr Med Assoc J. 2010 Dec;12(12):742-476

[22] Vlahovic-Palcevski V, Francetic I, Palcevski G, Novak S, Abram M, Bergman U. Antimicrobial use at a university hospital: appropriate or misused? A qualitative study. Int J Clin Pharmacol Ther. 2007; 45(3): 169-174

[23] Davies SW, Efird JT, Guidry CA, Hranjec T, Metzger R, Swenson BR, Sawyer RG. Characteristics of surgical patients receiving inappropriate empiric antimicrobial therapy. J Trauma Acute Care Surg. 2014 Oct;77(4):546-554

[24] Kawanami GH, Fortaleza CM. Factors predictive of inappropriateness in requests for parenteral antimicrobials for therapeutic purposes: a study in a small teaching hospital in Brazil. Scand J Infect Dis. 2011; 43 (6–7): 528-535

[25] Edelsberg J, Berger A, Schell S, Mallick R, Kuznik A, Oster G. Economic consequences of failure of initial antibiotic therapy in hospitalized adults with complicated intra-abdominal infections. Surg Infect (Larchmt). 2008; 9 (3): 335-347

[26] Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999; 115 (2): 462-474

[27] Hayes, B. (2016, April 16). Piperacillin/Tazobactam and Risk of Acute Kidney Injury with Vancomycin (Web log post). Retrieved from https://www.aliem.com/2014/piperacillin-tazobactam-acute-kidney-injury/

[28] Farkas, J. (2016, July 9). PulmCrit Wee: Is piperacillin-tazobactam nephrotoxic? (Web log post).  Retrieved from <http://emcrit.org/pulmcrit/piperacillin-tazobactam-nephrotoxic/

[29] Peyko V, Smalley S, Cohen H. Prospective Comparison of Acute Kidney Injury During Treatment With the Combination of Piperacillin-Tazobactam and Vancomycin Versus the Combination of Cefepime or Meropenem and Vancomycin. J Pharm Pract. 2016 Feb 23

[30] Davies, S. W., Efird, J. T., Guidry, C. A., Dietch, Z. C., Willis, R. N., Shah, P. M., & Sawyer, R. G. (2016). Top Guns: The “Maverick” and “Goose” of Empiric Therapy. Surgical infections, 17(1), 38-47

[31] Hammond, D. A., Smith, M. N., Painter, J. T., Meena, N. K., & Lusardi, K. (2016). Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin‐Tazobactam or Cefepime: A Retrospective Cohort Study. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 36(5), 463-471

[32] Karino S, et al. Epidemiology of Acute Kidney Injury Among Patients Receiving Concomitant Vancomycin and Piperacillin/tazobactam: Opportunities for Antimicrobial Stewardship. Antimicrob Agents Chmother. 2016 Apr 11.

[33] Rosini JM, Davis JJ, Muenzer J, Levine BJ, Papas MA, Comer D, Arnold R. High Single-dose Vancomycin Loading Is Not Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients. Acad Emerg Med. 2016 Jun;23(6):744-746

[34] Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr T, Andersen MH, Thornberg KJ, Løken J, Steensen M, Fox Z, Tousi H, Søe-Jensen P, Lauritsen AØ, Strange DG, Reiter N, Thormar K, Fjeldborg PC, Larsen KM, Drenck NE, Johansen ME, Nielsen LR, Ostergaard C, Kjær J, Grarup J, Lundgren JD; Procalcitonin And Survival Study (PASS) Group. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomized trial. BMJ Open. 2012 Mar 11;2(2):e000635

[35] Moffett BS, Kim S, Edwards M. Vancomycin nephrotoxicity may be overstated. J Pediatr. 2011 May;158(5):865-866

[36] Davies SW, Guidry CA, Petroze RT, Hranjec T, Sawyer RG. Vancomycin and nephrotoxicity: just another myth? J Trauma Acute Care Surg. 2013 Nov;75(5):830-835

[37] Hanrahan TP, Harlow G, Hutchinson J, Dulhunty JM, Lipman J, Whitehouse T, Roberts JA. Vancomycin-associated nephrotoxicity in the critically ill: a retrospective multivariate regression analysis. Crit Care Med. 2014 Dec;42(12):2527-36

[38] Mergenhagen KA, Borton AR. Vancomycin nephrotoxicity: a review. J Pharm Pract. 2014 Dec;27(6):545-553

[39] Hellwig TR, Hammerquist R, Loecker B, et al. Retrospective evaluation of the the incidence of Vancomycin and/or piperacillin-tazobactam induced acute renal failure. Crit Care Med 2011:39 (supp)301