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A New ExeCUTIoner: Plazomicin for complicated UTIs

Tuesday, September 18, 2018  
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Nick Hastain, PharmD Candidate 2019, Jefferson College of Pharmacy

Preceptor: Oludamilola Olugbile, PharmD, Clinical Pharmacist, Magee Rehabilitation Hospital

 

Complicated Urinary Tract Infections

Urinary tract infection (UTI) is an extremely common infection that accounted for 10.5 million ambulatory care visits, or 0.9% of all ambulatory visits in the United States in 2007.1 Additionally, the prevalence of UTIs in the inpatient setting is high. The majority of UTIs are uncomplicated, confined to the bladder, and are easily treated with short-course, empiric antibiotics.2 However, significant increases in morbidity and mortality are associated with complicated UTIs (cUTIs), which are UTIs in the setting of confounding risk factors like:

§  Pregnancy

§  Urinary tract obstruction

§  Renal failure

§  Diabetes

§  Immunosuppression

§  Male sex

The majority of UTIs are caused by Escherichia coli, an aerobic Gram-negative bacterium responsible for 74.4% of outpatient infections, 65% of hospital-acquired infections, and 47% of healthcare-associated infections.1 Other common causative Gram-negative organisms include Klebsiella species, Pseudomonas aeruginosa, and Proteus species. Streptococcus agalactiae and Staphylococcus saprophyticus are the most common Gram-positive organisms. Conversely, cUTIs are less likely the consequence of E. coli.  Enterococcus species, K. pneumoniae, Candida species, Staphylococcus, and P. aeruginosa (11%, 8%, 7%, 3%, and 2%, respectively) have a greater incidence in cUTI than uncomplicated UTI.3 Additionally, the species are more likely to be resistant.4

Although the Infectious Disease Society of America (IDSA), among other international societies, put forth guidelines for uncomplicated cystitis, pyelonephritis, and catheter-associated UTI (CA-UTI), no guidelines exist for cUTIs. This could be due in part to an inconsistent definition of cUTI across organizations. The IDSA’s approach to empiric treatment is based on the severity of illness, risk factors for resistant pathogens, host characteristics, and local resistance patterns.5 However, broader guidance exists from the European Association of Urology.4 Agents such as amoxicillin (with or without clavulanate) and trimethoprim-sulfamethoxazole are not recommended for cUTI based on current resistance patterns. Hospitalized patients should initially be treated with intravenous (IV) regimens like an aminoglycoside with amoxicillin or a 2nd or 3rd generation cephalosporin.  However, due to the emergence of multidrug-resistant (MDR) Enterobacteriaceae like extended-spectrum ß-lactamase (ESBL)- and carbapenemase-producing organisms, effective treatment has become more challenging.

Aminoglycosides may also be used in the treatment of UTIs. A recent systematic review and meta-analysis found aminoglycosides to be equally effective as ß-lactams and fluoroquinolones in attaining clinical improvement in patients with UTIs.6 In addition, aminoglycosides have been used successfully in UTIs caused by extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae.7 However, this class is also prone to resistance via aminoglycoside-modifying enzymes. Consequently, their use in infections caused by highly-resistant organisms is questionable.

Plazomicin (Zemdri™)

Plazomicin (Zemdri™) is an aminoglycoside antibiotic approved June 26th, 2018 by the FDA for the treatment of complicated urinary tract infection (cUTI), including pyelonephritis. Since only limited data is available regarding its clinical efficacy and safety, plazomicin should be reserved for patients with multi-drug resistant organisms (MDRO), those who have failed other therapies, or those with allergies and/or drug interactions to other agents.

Mechanism of Action

Plazomicin binds to the 30S ribosomal subunit, resulting in a faulty bacterial cell membrane and inhibition of protein synthesis. Like the other aminoglycosides, its bactericidal effect is concentration-dependent. This antibiotic is structurally modified to protect itself from certain aminoglycoside modifying enzymes (AMEs). The modification was completed through alteration of the natural product sisomicin to provide protection against AMEs that impart resistance via N-acetylation, O-adenylylation, or O-phosphorylation. Plazomicin retained antibacterial activity against 15 of 17 different AME strains in one study.8

Spectrum of Activity

Zemdri™ has been shown to be clinically active against the following aerobic, Gram-negative bacteria, with a susceptibility breakpoint of < 2 mcg/mL9:

ü  Escherichia coli

ü  Klebsiella pneumoniae

ü  Proteus mirabilis

ü  Enterobacter cloacae

Additionally, plazomicin exhibits in vitro activity against multidrug-resistant (MDR) Enterobacteriaceae, including extended-spectrum ß-lactamase- (ESBL) producing strains. Carbapenem-resistant Enterobacteriaceae (CRE) and methicillin-resistant Staphylococcus aureus are also susceptible to plazomicin.

Plazomicin has limited activity against isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, as well as Streptococcus and Enterococcus species.10

Pharmacokinetics10

There is no appreciable amount of metabolism that plazomicin undergoes, and it is excreted primarily by the kidneys. Additionally, the drug does not seem to interfere with the CYP450 enzyme system and most membrane transporters (renal or hepatic) besides MATE1 inhibition.

Dosing11

Renal

 

Creatinine clearance (CrCl)

Dosing and administration (IV)

Dosing Interval

> 60 mL/min

15 mg/kg over 30 minutes

Every 24 hours

30-59 mL/min

10 mg/kg over 30 minutes

Every 24 hours

15-29 mL/min

10 mg/kg over 30 minutes

Every 48 hours

< 15 mL/min, ESRD, CRRT

No recommendation

No recommendation

 

Weight

Dosage should be calculated using total body weight (TBW). In those patients with TBW 1.25-times greater than their ideal body weight (IBW), use adjusted body weight (ABW) for dosing.

Storage, Preparation, and Administration

Plazomicin is supplied as a 50 mg/mL solution in a 10 mL single-dose vial, and the required volume for each dose should be diluted in 0.9% sodium chloride or lactated ringer’s for a final volume of 50 mL. Single-dose vials should be refrigerated at 2-8ºC. After dilution, the product for administration is stable at room temperature for 24 hours, and should be infused intravenously over 30 minutes.

Therapeutic Drug Monitoring11

In patients with CrCl 15-89 mL/min, therapeutic drug monitoring (TDM) is recommended with a target trough concentration < 3 mcg/mL. A plazomicin peak should be drawn within 30 minutes of administration of the second dose. For levels > 3 mcg/mL, the dosing interval should be extended to 36 hours if dosed every 24 hours, and 72 hours if dosed every 48 hours.

Adverse Drug Events11

Boxed Warnings

Ø  Nephrotoxicity

Ø  Ototoxicity

Ø  Neuromuscular blockade

Ø  Fetal harm

 

Other reported adverse events

Ø  Hypersensitivity reactions

Ø  Clostridium difficile-associated diarrhea

Ø  Hyper- and hypotension

Ø  Nausea and vomiting

Ø  Headache

Cost12

The average wholesale price of Zemdri® is $37.80/mL, so each 10 mL single-dose vial costs $378.00. For a 150 lb (68 kg) person with good renal function (CrCl > 60 mL/min), a single dose of plazomicin (1023 mg) would necessitate the use of two vials and therefore $756.00.  

Important Clinical Trials

Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis (EPIC)13

Methods: 609 patients with cUTI or acute pyelonephritis (AP) were randomized 1:1 to IV plazomicin or IV meropenem for 4-7 days, with the option for an oral switch (levofloxacin or appropriate alternative) for a total of 7-10 days of therapy. Microbiological eradication, clinical cure, and composite cure (combined microbiological eradication and clinical cure) rates were assessed at the end of IV therapy (days 4-7) and test-of-cure (days 15-19).

Results: As seen in Figure 1, Plazomicin achieved higher composite cure rates than meropenem in both cUTI and AP, which was driven by higher microbiological eradication rates. Additionally, plazomicin was well tolerated, with similar incidence of adverse events compared to meropenem. The most common adverse events were diarrhea, hypertension, headache, nausea, and vomiting. According to an FDA briefing document evaluating plazomicin, this study supports the conclusion that plazomicin is noninferior to meropenem for cUTIs including AP.10

Figure 1. Efficacy outcomes for plazomicin vs meropenem assessed at the end-of-IV-therapy (EOIV) and at test-of-cure (TOC)13

 

A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis14

Methods: 145 patients were randomized to plazomicin 10 mg/kg, 15 mg/kg, or levofloxacin 750 mg (1:4:2) once daily for 5 days, and were stratified according to infection type. The primary efficacy endpoint was microbiological eradication at test-of-cure by primary diagnosis (cUTI or AP). 

Results: The microbiological eradication rates at test-of-cure were similar across treatment groups, with nonsignificant differences. Table 1 shows that microbiological eradication was achieved in > 85% of patients treated with plazomicin. Additionally, a lower rate of recurrence 1 month after the last dose of study drug (plazomicin 15 mg/kg) vs. levofloxacin was found. Plazomicin was well-tolerated overall with mild, reversible elevations in serum creatinine in some patients.

Table 1. Microbiological outcome at test-of-cure (TOC) for plazomicin vs levofloxacin14

 

Conclusion

Plazomicin is a novel aminoglycoside that provides coverage of resistant organisms in cUTIs. Its efficacy as monotherapy, in addition to its once-daily dosing, makes it an attractive option for physicians and nurses. Caution should still be utilized, as it possesses similar adverse effects to the other aminoglycosides. Pharmacists should be aware of the renal dose adjustments, as well as therapeutic drug monitoring, for certain patients. Due to its limited data regarding efficacy, plazomicin is a viable option for complicated patients with limited therapeutic options.

References:

1.      Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin N Am. 2014;28(1):1-13.

2.      Dielubanza E, Mazur D, Schaeffer A. Management of non-catheter-associated complicated urinary tract infection. Infect Dis Clin N Am. 2014;28(1):121-34.

3.      Flores-Mireles A, Walker J, Caparon M, Hultgren S. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-84.

4.      G. Bonkat, R. Pickard, R. Bartoletti, et al. Infections. 2018. Available at: http://uroweb.org/guideline/urological-infections/#1

5.      Gupta K, Hooton TM, Naber KG, et al. Infectious Diseases Society of America, European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103.

6.      Vidal L, Gafter-Gvili A, Borok S, et al. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2007;60(2):247-57.

7.      Ipekci T, Seyman D, Berk H, Celik O. Clinical and bacteriological efficacy of amikacin in the treatment of lower urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae. J Infect Chemother. 2014;20(12):762.

8.      Cox G, Ejim L, Stogios PJ, et al. Plazomicin retains antibiotic activity against most aminoglycoside modifying enzymes. ACS Infect Dis. 2018;4(6):980-987.

9.      Sakoulas G. Plazomicin approved for complicated urinary tract infections. NEJM Journal Watch. 2018. Available at: https://www.jwatch.org/na47108/2018/07/18/plazomicin-approved-complicated-urinary-tract-infections

10.  Food and Drug Administration. Plazomicin sulfate Injection Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC). https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM606039.pdf. May 2018.

11.  Zemdri [package insert]. San Francisco, CA: Achaogen, Inc; 2018.

12.  Plazomicin. Lexi-Drugs. Hudson, OH: Lexicomp, 2015. http://online.lexi.com/. Updated August 2, 2018. Accessed September 5, 2018.

13.  Cloutier DJ, Komirenko AS, Cebrik DS, et al. Plazomicin compared with meropenem for the treatment of complicated urinary tract infection (cUTI) including acute pyelonephritis (AP).  Poster presented at: IDWeek; October, 2017; San Diego, CA.

14.  Connolly LE, Riddle V, Cebrik D, et al. A multicenter, randomized, double-blind, phase 2 study of the efficacy and safety of plazomicin compared with levofloxacin in the treatment of complicated urinary tract infection and acute pyelonephritis. Antimicrob Agents Chemother. 2018;62(4).


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