New FDA Approval: Zemdri

New FDA Approval: Zemdri

Editor’s Note: Will Towers is a P4 student from Auburn University Harrison School of Pharmacy. When he is not studying for school, he is playing video games or watching Netflix (insert Michael Scott “that’s what she said” joke). He plans on applying for a PGY1 residency and is interested in acute care and internal medicine. His dream job would include rounding, precepting students, and academia.

Stephanie Kujawski is an internal medicine clinical pharmacist and yours truly from previous tl;dr posts. She, like her co-author, enjoys the bury-your-face-in-your-couch-pillow awkwardness of Michael Scott. Unlike Will, however, she is terribly uncoordinated when it comes to video games (left hand, meet right hand). Luckily, coordination is not overly required for new drug approval posts!

Drug

Zemdri (plazomicin)

FDA-Approved Indication

Treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following organisms:

 Humans vs. multi-drug resistant bacteria  (Image)

Humans vs. multi-drug resistant bacteria (Image)

  • Escherichia coli

  • Klebsiella pneumoniae

  • Proteus mirabilis

  • Enterobacter cloacae

It should be reserved for patients who are at least 18 years old and have limited or no alternative treatment options.

How It Works

Plazomicin is an aminoglycoside antibiotic that binds to bacterial 30S ribosomes to prevent bacterial protein synthesis.

No protein synthesis = buh bye bacteria.

Kinetically speaking, plazomicin displays concentration-dependent, bactericidal activity. This means that the drug has to reach a certain concentration in order to destroy the bacteria, but it doesn’t necessarily have to stay at that concentration very long.

Well how does that work? Doesn’t the weapon have to be physically present to kill the enemy?

Interestingly, in the case of aminoglycosides, the answer is no! Aminoglycosides, along with a few other antimicrobials, exhibit a significant post-antibiotic effect. This means that even when plasma concentrations of the drug fall below the killing level, bacterial growth remains inhibited.

Wicked cool ghost antibiotic!!

For additional refreshers on aminoglycosides, please revisit the Complete Guide to Aminoglycosides and this Quick Guide to Antibiotics.  

We also made a super-spiffy Antibiotic Cheat Sheet. It’s yours FREE, just tell us where to email it.

What Makes Plazomicin Different

Most antibiotics currently available were derived from substances found in nature. Specifically, aminoglycosides were developed from a substance certain bacteria excrete to kill off their surrounding competition. But because bacteria are smart little creatures, they developed ways to overcome these naturally occurring compounds.

One of the main mechanisms of bacterial resistance is enzymatic modification (via acetyltransferases, phosphotransferase, and adenyltransferases). The bacteria use enzymes to add bulky chemical structures to the aminoglycosides’ various functional groups so that the drugs no longer have high affinity for the bacterial ribosomes.

With this in mind, plazomicin was structurally designed such that enzymatic modification by bacteria would be less likely. This resulted in a molecule that has activity against some bacteria that are resistant to other aminoglycosides. 

Other mechanisms of aminoglycoside resistance (you didn’t think that there was just one, did you?) include target alteration, porin modification that prevents entry, and/or up-regulation of efflux pumps.  

Plazomicin Spectrum of Activity

Gram positive: Weak (if any at all)! Could theoretically be used synergistically with a beta-lactam like other aminoglycosides, but there is no evidence to support this. 

Gram negative: Yes! This is where aminoglycosides, like plazomicin, thrive. More specifically, this agent would useful for infections caused by Enterobacteriaceae.

This family includes bacteria that are part of the normal human flora but are also associated with infection.

Members of pathogenic Enterobacteriaceae include E. coli, Enterobacter, Citrobacter, Klebsiella, and Proteus species. These bugs often express multiple mechanisms of resistance to beta-lactams and fluoroquinolones. 

  • Of note, plazomicin has variable activity against Pseudomonas species. It can not be trusted to reliably treat infections caused by this nasty bacteria.

(Obligate) Anaerobes: Zero! They are innately resistant. This is because aminoglycosides are pumped in through bacterial cell membranes via an oxygen-dependent mechanism, and since anaerobes are found in environments with no oxygen, aminoglycosides are unable to enter.

  • Of course, beware the facultative anaerobes… They can make do in both aerobic and anaerobic conditions, so it’s possible for aminoglycosides to have activity against these.

Recommended Dosing 

The suggested dosing schedule for plazomicin is based on extended interval aminoglycoside dosing (aka once daily administration). This high mg/kg once daily dosing allows for bactericidal concentrations to be achieved while also allowing for sufficient clearance from the plasma. This helps to prevent the drug accumulation that could possibly lead to toxicity. 

Creatinine ClearanceDose
> 90 mL/min15 mg/kg Q24h and TDM* is not required**
60-89 mL/min15 mg/kg Q24h with TDM
30-59 mL/min10 mg/kg Q24h with TDM
15-29 mL/min10 mg/kg Q48h with TDM
< 15 mL/min***Avoid use
* Therapeutic drug monitoring (TDM)
** Per manufacturer
*** Also avoid in hemodialysis or continual renal replacement therapy

Therapeutic Drug Monitoring (TDM)

Plazomicin is monitored by obtaining a trough concentration after the first dose in order to adjust therapy and avoid toxicity. The monitoring plan is much simpler compared to that seen with traditional dosing of alternative aminoglycosides. 

The trough concentration is a blood sample obtained 30 minutes before administration of the second dose. If this trough concentration is > 3 mcg/mL, then the dosing interval must be lengthened by 1.5 fold (e.g., Q48h —> Q72h).

The manufacturer does not indicate that further monitoring is required, but a change in renal function or prolonged therapy would certainly justify it!

How It Got Approved

In the phase 3 EPIC study, plazomicin’s manufacturer (Achaogen) sought to prove that its new medication was noninferior to (aka just as good as) meropenem for the treatment of complicated UTI or pyelonephritis. In this randomized controlled trial, 388 patients were treated with 4-7 days of either IV plazomicin or meropenem. This IV course was followed by optional oral levofloxacin for a total of 7-10 days of therapy.

The co-primary endpoints were the composite cure rates (aka clinical cure and microbiological eradication) at day 5 and then at a test-of-cure visit between days 15-19. The noninferiority margin was set at 15%.

Based on the preliminarily reported results (full publication pending at the time of this posting), the plazomicin group had an 88% composite cure rate vs 91.4% in the meropenem group at day 5 of therapy (difference -3.4%, 95% CI -10 to 3.1), meeting the primary noninferiority objective. At the later test-of-cure visit, plazomicin’s composite cure rate was significantly higher than meropenem’s (81.7% vs 70.1%, difference 11.6, 95% CI 2.7 to 20.3).

Numbers also indicated increased microbiologic eradication and decreased relapse with plazomicin, and although the raw numbers seemed to show more patients with increased serum creatinine with plazomicin, most patients had fully recovered by their final follow up visit.

Sounds pretty good, right?

In several ways, it is. First, a large proportion of the patients had an ESBL pathogen on culture, and of those patients who had one of these resistant bacteria, the eradication rate at the test-of-cure visit was ~80% in the plazomicin group. Not too shabby.

Second, this trial used a "microbiologic mITT" design that only included patients in the final analysis who had bugs that were susceptible to both plazomicin and meropenem. Maybe not the most externally valid/generalizable population design but certainly useful when you want to go head to head on susceptibility and clinical outcomes.

Third, a good portion of patients with various degrees of renal function were included. We’re dealing with an aminoglycoside, so of course, as pharmacists, we’re curious about how plazomicin performs in a variety of kidneys. About a third of the patients in each group had CrCl 30-60 ml/min, and about a third had CrCl 60-90 ml/min. So at least they weren’t all young’ns with CrCl >100 ml/min!

Fourth, the population was fairly sick. About 20% in each group were considered to be septic, and ~12% were bacteremic.

All useful information. But now let’s look at the other side…

Intravenous therapy was assessed at day 5 for the primary outcome; however, IV therapy was allowed for 4-7 days. As a pharmacist, do you think getting 4 days of IV therapy is the same as a full week? And if the patients were assessed at day 5 but could have received 2 additional days of IV, could that mean that the patients who received a full 7 days were at an advantage for efficacy? Or a detriment for safety?

Unfortunately, the average duration of IV therapy in each group is not (yet) reported, so we don’t really have a great way to interpret this.

Next, about 80% of patients in the plazomicin group compared to ~77% in the meropenem cohort were transitioned to oral levofloxacin. An interesting choice for a UTI or pyelo, right?

While there is some recent data about the utility of levofloxacin in ESBL infections, it’s not yet clear whether it is a completely trustworthy agent in this scenario. Interestingly, in this study, the composite cure rate in the plazomicin group only increased by about 4% when oral levofloxacin was tacked onto IV.

That aside, at least a similar number of patients in each group transitioned to oral therapy. But we’re still left in the dark as far as duration of mop up therapy (7 versus 10 days) between groups, which could have impacted clinical cure, microbiological eradication, and/or safety results.

Finally, let’s think about renal function and safety. The manufacturer noted “comparable” incidences of increases in serum creatinine by at least 0.5 mg/dL while on IV therapy (3.7% in plazomicin vs 3% in meropenem). No associated p-values.

They also note “full recovery” to be serum creatinine values no more than 0.5 mg/dL above baseline. Well, by golly, I certainly hope full recovery entails being no more than 0.5 mg/dL above baseline! Actually let’s hope it’s closer than that for “full recovery”.

Remember KDIGO guidelines for acute kidney injury, which is defined in part by a rise in serum creatinine of at least 0.3 mg/dL above baseline?! Mmhmm. Makes that *recovery* definition a little more difficult to interpret, doesn’t it…

Bottom line is that this phase 3 EPIC study demonstrated there’s another medication for complicated UTIs and pyelonephritis cases caused by resistant (e.g., ESBL) bacteria.

Serious Adverse Effects

Nephrotoxicity: Aminoglycosides are well known for their negative effects on the kidneys, and plazomicin is no exception. To monitor for this, renal function (serum creatinine, urine output, etc) should be assessed daily.

Those at higher risk for nephrotoxicity include elderly patients, those with pre-existing renal dysfunction, patients receiving concomitant nephrotoxins, and patients who present with acute kidney injury. (Probably wouldn’t want to use plazomicin in that last group anyway…)

Ototoxicity: Again, this is another hallmark toxicity of aminoglycosides. Often manifesting as hearing loss, tinnitus, and/or vertigo, these effects are considered irreversible and are normally undetectable until it is too late. Ototoxicity is exposure dependent and is more likely in those on prolonged regimens.

Common Adverse Reactions

Decreased renal function (4%), hypertension (2%) or hypotension (1%), headache (1%), nausea (1%), vomiting (1%), and diarrhea (2%)

 Think of aminoglycosides as the hulk. They usually take care of the bad guy, but there is a definite chance of collateral damage (kidneys and ears). Also, it would be a good idea to watch him closely!  (Image)

Think of aminoglycosides as the hulk. They usually take care of the bad guy, but there is a definite chance of collateral damage (kidneys and ears). Also, it would be a good idea to watch him closely! (Image)

Notable Drug Interactions

Increased risk of nephrotoxicity: foscarnet, carboplatin, systemic cyclosporine, tenofovir products, amphotericin B, NSAIDs, loop diuretics, and vancomycin (and the list goes on for nephrotoxins…).

If given concomitantly, renal function and aminoglycoside serum levels should be monitored closely.

Place in Therapy

Currently, plazomicin is approved for use in cUTI due to multi-drug resistant gram negative bacteria, particularly ESBLs. Our usual choices for ESBL cUTI or pyelonephritis cases are the carbapenems. (Ahhh, this is why the EPIC phase 3 study compared plazomicin to meropenem!)

So let’s take a quick look at the competition. Meropenem is typically dosed 3 times a day in normal renal function. Fine for in the hospital…but a little harder as an outpatient. So in patients who need to complete IV therapy after discharge, providers often turn to meropenem’s cousin: ertapenem.

Ertapenem is a lovely, once daily, 30 minute infusion that doesn’t require TDM (other than perhaps a periodic metabolic panel depending on duration of treatment). So as long as Pseudomonas coverage isn’t required, ertapenem is on the table.

So why on earth would we choose a potentially toxic, therapeutically monitored aminoglycoside when we can order a much easier, generally well-tolerated carbapenem??

We can think of maybe 2 specific cases:

  1. Resistance to carbapenems but susceptibility to plazomicin. (Likely a rare scenario at this point in time.)

  2. Allergies/intolerances. (And even this is negotiable with desensitization depending on the severity of the beta lactam reaction.)

Clinical Scenario

Let’s apply plazomicin to a short patient case.

Subjective/Objective: You receive an antibiotic consult for TL. She is a 55 year old female diagnosed with non-catheter related pyelonephritis 5 days after being admitted to the hospital for treatment of an acute ischemic stroke. After obtaining a urine sample for culture, she is placed on empiric ceftriaxone 1 gram IV every 24 hours. The following day, culture and sensitivity data show the following results:

Source: Urine
Organism #1: KPC* E. coli
> 100,000 CFU/mL
Agents TestedSusceptibilities (MIC)
AmpicillinResistant
Ampicillin/SulbactamResistant
CefazolinResistant
CetriaxoneResistant
LevofloxacinIntermediate
MeropenemResistant
NitrofurantoinResistant
PlazomicinSusceptible
Piperacillin/TazobactamResistant
Trimethoprim/SulfamethoxazoleIntermediate
*Klebsiella pneumoniae carbapenemase

Pertinent Values

  • Height: 170 cm

  • Weight: 70 kg

  • Temperature: 102.4 F

  • Blood pressure: 115/72 mmHg

  • Heart rate: 87 BPM

  • Respiratory rate: 14 breaths/min

  • SCr, BUN: 0.9 mg/dL, 15 mg/DL

  • White blood cell count: 21,000/μL

All blood cultures are negative. 

Assessment: This patient has complicated pyelonephritis caused by MDR E. coli. This pesky bug is producing a Klebsiella pneumoniae carbapenemase. Essentially, this KPC enzyme chops up and inactivates most (we’re looking at you, Vabomere) beta lactams.

It is also expressing some sort of resistance to fluoroquinolones - another indicator that we are dealing with a real problem bug. OMG, with those susceptibility results, this patient is a perfect candidate for plazomicin therapy! It is almost like it was planned… *wink wink.

Plan: First, we need to estimate creatinine clearance, which is ~75 mL/min by Cockcroft-Gault. Therefore, according to the plazomicin dosing recommendations, TL should receive 15 mg/kg every 24 hours with TDM.

  • 15mg/kg x 70 kg = 1050 mg —> rounded to 1000 mg (supplied as 500 mg vials…and we do not want our techs to hate us) 

  • FYI, according to AWP pricing, this single 1000 mg dose would cost $756. Compare that to meropenem, which may cost around $150 per day and displays similar cure rates for most infections! 

TL shows clinical signs of improvement and is maintaining normal renal function. A trough level is obtained before administration of the second dose, and it returns as 4 mcg/mL.

Remember, for trough levels > 3 mcg/mL, the dosing interval must be lengthened by 1.5 fold.

In TL’s case, we would simply change the frequency from 1000 mg every 24 hours to 1000 mg every 36 hours (24 x 1.5 = 36). Per current guidelines, TL would need a total of 5-7 days of therapy for her pyelonephritis.

In this time, we would need to continue monitor clinical status, renal function, and signs of ototoxicity.

And we are done! Not too complicated, huh? 

Conclusion 

Plazomicin is an aminoglycoside antibiotic that has the potential to cause all the usual adverse effects associated with the class. It is highly dependent on renal function for its clearance and should only be used for the treatment of cUTI caused by bad@$$ Enterobacteriaceae, such as ESBLs, when other treatment options are unavailable. 

Managing Diabetes with Insulin Pumps

Managing Diabetes with Insulin Pumps