Maria Heaney, PharmD, is an infectious diseases clinical pharmacist at St. Joseph’s University Medical Center in Paterson, New Jersey. She completed her doctor of pharmacy degree at the University of the Sciences Philadelphia College of Pharmacy in Pennsylvania. She went on to complete her PGY-1 pharmacy residency at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania, followed by her PGY-2 pharmacy residency in infectious diseases at Temple University School of Pharmacy in Philadelphia, Pennsylvania.

Maria Heaney, PharmD

A 52-year-old man initially presented to the hospital with a diagnosis of cerebellar tumor without associated hydrocephalus. One month later he returned to the hospital with worsening neurologic symptoms and was found to have hydrocephalus. At this time he underwent extraventricular drain (EVD) placement; however, the hydrocephalus continued to worsen, prompting removal of the EVD and placement of a ventriculoperitoneal (VP) shunt. Nine days after placement, he returned to the hospital once again with a chief complaint of severe headache that had worsened over the 3 hours prior to admission with no alleviating or exacerbating factors. He also reported abdominal pain underlying the incision site from the VP shunt placement. He denied fever, chills, nausea, vomiting, and diarrhea.

The patient’s medical history included type 2 diabetes mellitus, hypertension, and cerebellar tumor. His surgical history included a craniotomy for cerebellar tumor, followed by a ventriculostomy and EVD placement the month prior to admission, as well as the VP shunt placement 9 days prior to admission.

Before admission, the patient was taking aspirin 81 mg, atorvastatin 80 mg, lisinopril 5 mg, pantoprazole 40 mg, and dexamethasone 2 mg, all daily.

The patient resided at a subacute rehabilitation facility. He had previously worked for an engineering firm but denied any chemical or toxin exposure. He also denied the use of tobacco, illicit drugs, and alcohol, and his family history was noncontributory.

Upon presenting to the hospital, the patient was awake and alert but in moderate pain. He was tachycardic, with a heart rate of 110 beats per minute, but all other vital signs were within normal limits. Staples were in place on the left side lateral occipital and posterior occipital sites from the VP shunt placement. His physical exam was remarkable for mild neck stiffness and diffuse abdominal tenderness, which was worse at the incision site where the shunt had been placed. His neurologic exam was normal.

Initial labs were significant for leukocytosis with a white blood cell (WBC) count of 18.1 cells/mm3 (4.5-11.0 cells/mm3). The remainder of the complete blood count and basic metabolic panel was unremarkable. Inflammatory markers were elevated, with a C-reactive protein level of 11.70mg/dL (<0.99 mg/dL) and an erythrocyte sedimentation rate of 40 mm/h (0-10 mm/h). A computed tomography (CT) scan of the abdomen revealed no acute pathology, and a shunt x-ray series revealed no abnormalities. A CT scan of the head revealed an extradural collection crossing the midline and resolving blood products, and a crowding of the cistern. Magnetic resonance imaging of the head showed white matter changes surrounding the posterior right ventriculostomy catheter. Blood cultures were drawn and finalized with no growth. A lumbar puncture (LP) was not attempted at the time of presentation.

Physicians in the departments of neurosurgery, surgery, gastroenterology, and infectious diseases were consulted. Vancomycin and cefepime were initiated for empiric therapy of a central nervous system (CNS) bacterial infection. Improvement in leukocytosis, headache, and abdominal pain were noted after 4 days of empiric antibiotic therapy; however, the patient complained of persistent fatigue that had begun prior to hospitalization. On hospital day 5, he reported occasional chills and became febrile to 38.3 °C. On hospital day 6, an LP was performed for suspected VP shunt infection. A cerebrospinal fluid (CSF) analysis revealed a WBC count of 65 cells/mm3 (segmented neutrophils, 70%; lymphocytes, 9%; monocytes, 21%), a red blood cell (RBC) count of 29 cells/mm3, a glucose level of 63 mg/dL (serum glucose 122 mg/dL), and a protein level of 53 mg/dL. Additionally, the Gram stain revealed Gram-negative rods. The following day vancomycin was discontinued, and cefepime was escalated to meropenem due to concern for resistant organisms. On hospital day 8 the CSF culture result was finalized, with growth of pansensitive 

; the cerebellar abscess seen on CT imaging was drained. On hospital day 10 cultures from the abscess were also finalized, with pansensitive 

, and meropenem was then de-escalated to ceftriaxone.

, VP shunt infection with ventriculitis occurred; the shunt was removed and an EVD was placed on hospital day 8. A repeat LP was performed on hospital day 14 to evaluate the CSF for pleocytosis and culture clearance. A CSF analysis revealed a WBC count of 10 cells/mm3 (differential, not reported), an RBC count of 223 cells/mm3, a glucose level of 58 mg/dL (serum glucose, 100 mg/dL), and a protein level of 38 mg/dL; a Gram stain revealed no organisms. The EVD was removed the following day. Cultures from both the CSF and EVD catheter tip grew 

. CSF culture susceptibilities were reported for caspofungin, fluconazole, and voriconazole, all of which were susceptible with minimum inhibitory concentrations of 0.12 mcg/mL, 0.5 mcg/mL, and 0.12 mcg/mL, respectively.

Liposomal amphotericin B 400 mg (4 mg/kg) intravenously every 24 hours and flucytosine 2 g (30 mg/kg) orally every 6 hours were initiated on hospital day 16 for treatment of 

ventriculitis. The patient refused flucytosine doses intermittently. After 7 days of this regimen, he was transitioned to fluconazole 1200 mg (12 mg/kg) IV every 24 hours. On hospital day 42, 16 days after antifungal therapy initiation, he was transitioned to oral fluconazole 800 mg every 24 hours. The fluconazole dose was further reduced to 400 mg every 24 hours on hospital day 57 due to QTc prolongation. Fluconazole was discontinued on hospital day 64, completing 38 days of antifungal therapy. Ceftriaxone for the 

shunt infection was also discontinued at this time.

The patient experienced various complications throughout his hospital stay, including a 4-day admission to the medical intensive care unit (MICU) for intubation for airway protection, and bilateral pulmonary emboli for which he was treated with enoxaparin.Upon returning to the neurology floor from the MICU, he received physical therapy, occupational therapy, and speech therapy. He was discharged to a rehabilitation facility on hospital day 69 in stable condition.

The reported incidence of infections involving CNS drainage devices varies from 5% to 41%. Fungi account for only 2.7% of such infections in the United States, with a mortality rate of 11% to 33%.1,2 Newborns and children are most commonly affected, although adults may also develop these infections as postoperative neurosurgery complications or as disseminated disease. Neurosurgical procedures directly disrupt the blood-brain barrier, increasing its permeability and causing a reduction in immunity. This facilitates the fungi’s penetration into the CNS. In addition to neurosurgery, recent bacterial meningitis and the use of broad-spectrum antibiotics were risk factors that may have contributed to infection in the patient discussed in this case. Other risk factors for CNS candidiasis include abdominal complications and immunosuppression. Patients with these infections often present with headache, lethargy, fever, abdominal tenderness, and a change in mental status.1 Diagnosis is heavily dependent on CSF cultures. A CSF analysis may not accurately detect infection, as abnormalities could also be related to neurosurgery or the underlying indication for catheter placement.1,3,4 Normal values also may not rule out infection, as a study by Conan et al reported that 20% of adults with shunt-associated infection presented with normal CSF WBC counts and lactate concentrations.1,5

Although the Infectious Diseases Society of America developed a clinical practice guideline for the treatment of CNS candidiasis, there is limited high-quality supporting evidence. Guidelines currently recommend initial treatment with liposomal amphotericin B, with or without flucytosine.1,6 This combination works synergistically to increase fungal cell uptake of flucytosine.7-9 Therapy is subsequently transitioned to oral fluconazole after patients exhibit clinical improvement.6 Fluconazole achieves higher CSF concentrations and CSF to plasma ratios compared with other azole agents;1,7,8 however, it is not recommended in the first line as monotherapy because therapeutic failure has been documented.1,10-13 Avoiding the use of itraconazole and posaconazole for CNS candidiasis is recommended due to inadequate CNS penetration.1,6,7 Echinocandins also are not recommended because of findings from a pharmacokinetic study in a rabbit model demonstrating low CSF concentrations of micafungin.1,6,14 Results of animal studies may not translate to clinical outcomes in humans, but data on the use of echinocandins for CNS infections in humans are lacking.

Current literature describing CNS fungal infections reports varying results without a clearly defined treatment duration. Notably, this patient received 1 week of amphotericin B plus flucytosine prior to stepping down to fluconazole, which is inconsistent with the guideline recommendation suggesting that several weeks of initial amphotericin B plus flucytosine may be necessary.1,6 Based on the evidence available, the impact of early step-down to an azole is unclear. Additionally, it is not clear whether the approximate 6-week total of antifungals the patient received is adequate for cure. In a case series describing therapy for 

 CNS infections in 10 patients, 8 were treated with various combinations of amphotericin B, flucytosine, and fluconazole, with treatment durations ranging from 14 days to 2 months.7 At the time the patient in this case completed therapy and was discharged, his neurologic status had improved, his WBC count was within normal limits, and he denied headache, fever, abdominal pain, nausea, and vomiting. Although it is prudent to evaluate the pharmacokinetic literature and case studies in addition to guideline recommendations to direct therapy for patients with CNS candidiasis, further clinical data will assist in optimizing treatment regimens and defining an adequate duration.

Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. 

Hasbun R, Rosenthal N, Balada-Llasat, et al. Epidemiology of Meningitis and Encephalitis in the United States, 2011-2014. 

Forgacs P, Geyer CA, Freidberg SR. Characterization of chemical meningitis after neurological surgery. 

Schade RP, Schinkel J, Roelandse FW, et al. Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis. 

Conen A, Walti LN, Merlo A, Fluckiger U, Battegay M, Trampuz A. Characteristics and treatment outcome of cerebrospinal fluid shunt-associated infections in adults: a retrospective analysis over an 11-year period. 

Pappas PG, Kaffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. 

Bellmann R, Smuszkiewicz P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients. 

Coulter KS, Bariola JR. Current Antifungal Agents for Treatment of Central Nervous System Infections. 

Medoff G, Kobayashi GS, Kwan CN, et al. Potentiation of Rifampicin and 5-Fluorocytosine as Antifungal Antibiotics by Amphotericin B. 

Sanchez-Portocarrero J, Perez-Cecilia E, Corral O, et al. The central nervous system and infection by Candida species. 

Chen TL, Chen HP, Fung CP, et al. Clinical characteristics, treatment and prognostic factors of candidal meningitis in a teaching hospital in Taiwan. 

Aleixo MJ, Caldeira L, Ferreira ML. Candida albicans meningitis: clinical case. 

Epelbaum S, Laurent C, Morin G, Berquin P, Piussan C. Failure of fluconazole treatment in Candida meningitis. 

Hope WW, Mickiene D, Petraitis V, et al. The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: implications for echinocandin therapy in neonates. 

Chen M, Chen C, Yang Q, et al. Candida meningitis in neurosurgical patients: a single-institute study of nine cases over 7 years. 

Geers TA, Gordon SM. Clinical Significance of Candida species Isolated from Cerebrospinal Fluid Following Neurosurgery. 

Montero A, Romero J, Vargas JA, et al. Candida Infection of Cerebrospinal Fluid Shunt Devices: Report of Two Cases and Review of the Literature. 

O’Brien D, Stevens NT, Liam CH, et al. Candida infection of the central nervous system following neurosurgery: a 12-year review. 

Articles

Rare cases of health care–associated meningitis and ventriculitis in adults caused by Candida species are associated with recent bacterial meningitis and broad-spectrum antibiotic use.

A Case of Candida Albicans Ventriculitis Secondary to E Coli Ventriculoperitoneal Shunt Infection

Tetracycline development began in the 1940s with the discovery of the natural product, chlortetracycline. One of the first agents termed “broad spectrum,” chlortetracy&shy;cline became widely used in humans because of its activity against rickettsiae and other organisms with no thera&shy;peutic options prior to its discovery. Following identifica&shy;tion of the 4-ring core structure, which coined the class name “tetracycline antibiotics” in the 1950s, the first of the semisynthetic agents, tetracycline, was introduced.

 Derived from chlortetracycline, tetracycline has a higher potency and stability and more favorable adverse effect profile.

 The second-generation semisynthetic compounds, doxycy&shy;cline and minocycline, were developed via modification of the tetracycline core in the 1960s and 1970s, respectively.

Shortly after the development of minocycline, resis&shy;tance mechanisms to tetracyclines were identified: efflux pumps that eliminate drug molecules from within the cell and ribosomal protection mechanisms that reduce tetra&shy;cycline-ribosomal binding. As with many other classes of antibiotics, resistance to tetracyclines increased over time; however, it was not until the early 2000s that minocycline was structurally modified to derive tigecycline.

 Although tigecycline offers a broad spectrum of activity that includes organisms resistant to tetracycline, its high rate of gastroin&shy;testinal toxicity, a US Food and Drug Administration (FDA) warning of increased mortality compared with other agents, and large volume of distribution preclude its use in many patients. These factors left the door open for novel tetracy&shy;cline antibiotics with activity against organisms possessing tetracycline-resistance mechanisms and a more favorable adverse effect profile to come to market.

In 2018, 2 new tetracyclines, omadacycline and erava&shy;cycline, were approved by the FDA. Similar to tigecycline, these agents were designed to have activity specifically against tetracycline-resistant organisms. This article discusses omadacycline, a semisynthetic tetracycline derived from minocycline that has an aminomethyl group added to the C9 position of the tetracyclic core allowing it to overcome efflux systems and ribosomal protection mecha&shy;nisms that confer resistance to older tetracyclines.

 It was approved by the FDA on October 2, 2018, for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs).

Omadacycline is a broad-spectrum agent active against gram-positive organisms, including vancomycin-resistant 

; gram-negative organisms, including some extend&shy;ed-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae and 

 It is not active against the “MP3” of 

Morganella morganii, Proteus mirabilis, Providencia 

In an in vitro surveillance study, omadacycline had a minimum inhibitory concentration for 90% of the isolates (MIC90) of 0.5 μg/mL for 

, 0.5 μg/mL for VRE, and ≤0.06 μg/mL for multidrug-resistant 

compared with 8 μg/mL, 4 μg/mL, and 4 μg/mL, respec&shy;tively, for doxycycline.

 The MIC90 of omadacycline was 4 mg/ mL for ESBL-producing 

spp compared with >8 μg/mL for each for doxycycline, and 0.25 μg/mL and 1 μg/mL, respec&shy;tively, for tigecycline.

Omadacycline also demonstrated activity against some strains of 

, although the MIC90 of 8 μg/mL indicates that it will be inef&shy;fective for some strains.

 The approved breakpoints for omad&shy;acycline are 4 μg/mL for Enterobacteriaceae, 0.5 μg/mL for 

In an in vitro environment mimicking the gut microbiome, omadacycline and moxifloxacin were instilled to determine induction of a simulated 

 Moxifloxacin, a fluoroquinolone, was previously observed to induce CDI in an in vitro gut model.

 Fluoroquinolones carry a high risk of CDI, a reason for avoiding their use in some patients. It was observed in this study by Moura and colleagues that the environment in which moxifloxacin was instilled had spore germination and vegetative cell proliferation, while the environment in which omadacycline was instilled had no vege&shy;tative cell proliferation.

 This suggests that omadacycline may provide activity against 

rather than increasing the risk for proliferation and development of CDI such as that seen with the fluoroquinolones.

Omadacycline had been studied in 3 phase 3 trials to date: the OASIS 1 and 2 trials for ABSSSIs, and the OPTIC trial for CABP. The OASIS 1 study compared intravenous to oral omadacycline with linezolid for 7 to 14 days for the treatment of ABSSSIs due to gram-positive pathogens in 627 adults. The number of patients with an abscess was capped at 30%, as the primary treatment for these patients is incision and drainage for source control. The primary endpoint was early clinical response, defined as ≥20% reduction in lesion size without receipt of another antimicrobial for ABSSSIs, at 48 to 72 hours of therapy. Omadacycline demonstrated noninferiority with a success rate of 84.8% compared with 85.5% with linezolid, a difference of —0.7% (95% CI, –6.3% to 4.9%). Omadacycline also demonstrated a clinical success rate, defined as sufficient resolution of infection according to the investigator’s analysis at the posttreatment evalu&shy;ation, of 86.1% compared with 83.6% with linezolid.

The OASIS 2 study mirrored the OASIS 1 design, but compared oral-only omadacycline with linezolid in 720 adults, with up to 25% of randomized patients permitted to receive 1 dose of a short-acting antibiotic prior to the study drug. Omadacycline again demonstrated noninferiority in early clinical response compared with linezolid (87.5% vs. 82.5%) with a difference of 5.0% (95% CI, —0.2% to 10.3%). The clinical success rate at the posttreatment eval&shy;uation was 84.2% with omadacycline versus 80.8% with linezolid.

 Omadacycline received FDA approval for ABSSSIs at an indi&shy;cated dose of 200 mg intravenously (IV) once or 100 mg IV every 12 hours on day 1, followed by a maintenance regimen of 100 mg IV once daily. It may also be dosed as an oral regimen of 450 mg once daily on days 1 and 2, followed by a maintenance regimen of 300 mg once daily.

The OPTIC trial compared omadacycline with moxifloxacin for the treatment of CABP for 7 to 14 days in 774 adults. Patients enrolled required hospitalization for moderate to severe infection that was radiographically confirmed without empyema or abscess and no evidence of septic shock. The primary endpoint was early clinical success, defined as at least 1 level of improvement on a scale of absent, mild, moderate, or severe in at least 2 CABP symptoms (cough, sputum production, pleuritic chest pain, dyspnea) without worsening of any other CABP symptoms, at 72 to 120 hours after the first dose of study drug. Omadacycline demonstrated noninferiority in early clinical success with a rate of 81.1% compared with 82.7% of patients who received moxi&shy;floxacin, a difference of —1.6% (95% CI, –7.1% to 3.8%). At the posttreatment evaluation 5 to 10 days after the last dose of the study drug, the clinical success rate according to the inves&shy;tigator’s analysis was 87.6% with omadacycline compared with 85.1% with moxifloxacin.

 The FDA granted omadacycline approval for CABP at an indicated dose of 200 mg IV once or 100 mg IV every 12 hours on day 1, followed by a maintenance dose of 100 mg IV once daily or 300 mg orally once daily.

Following a single 100-mg IV dose, omadacycline achieved a maximum concentration (Cmax) of 1507 ng/mL and an area under the curve (AUC) of 9358 h*ng/mL. The mean steady-state Cmax with intravenous administration is 2120 ng/mL, and AUC is 12,140 h*ng/mL. Omadacycline is 34.5% bioavailable, explaining its oral dosing at 300 mg, which achieved a Cmax of 548 ng/mL and AUC of 9399 h*ng/mL following a single dose. The mean steady-state Cmax with oral administration of 300-mg tablets is 952 ng/mL and AUC is 11,156 h*ng/mL, comparable to the 100-mg intrave&shy;nous dose. There is a significant food effect with oral administra&shy;tion. When administered 2 hours after a high-fat, nondairy meal, Cmax and AUC were reduced by 40% and 59%, respectively. As with other tetracyclines, concur&shy;rent administration with multi&shy;valent cations such as calcium should be avoided with the oral formulation.

The mean volume of distri&shy;bution with intravenous admin&shy;istration is 190 L, and protein binding is estimated to be 20%.12 Omadacycline had a steady-state 24-hour mean epithelial fluid lining concentration of 0.41 mg/L and mean alveolar macrophage concentration of 11.06 mg/L, indicating sufficient lung concentra&shy;tions.13 Omadacycline is not metabolized and does not induce or inhibit CYP450 enzymes. It has a half-life of approximately 15 hours and is eliminated mainly in the feces (81%) unchanged, with 14% renal elimination following oral administration. Dosage adjust&shy;ment is not required for renal or hepatic impairment.

ADVERSE REACTIONS, WARNINGS, AND PRECAUTIONS 

Warnings and precautions associated with omadacycline use are consistent with those reported for older tetracyclines, including tooth discoloration and inhibition of bone growth in children, as well as hypersensitivity. Additionally, omadacycline carries a labeled warning for a mortality imbalance in patients with CABP: 2% with omadacycline versus 1% with moxifloxacin. All deaths occurred in patients over 65 years, most of whom had multiple comorbidi&shy;ties.

 Adverse events most commonly observed in clinical studies were transaminase elevation, headache, and infusion-site reactions.11 Although nausea, vomiting, and diarrhea occurred among patients receiving omadacycline, its structural modification may reduce the incidence of these events compared with that of tigecycline.

Within 1 hour of dosing omadacycline 100 mg IV, a mean increase in heart rate of 17 bpm was observed, although no symptoms or QTc changes were found.

Although omadacycline shows some activity against resistant bacteria, the in vitro and clinical data for multidrug-resistant organisms are limited at this time. Omadacycline presents an alternative agent for patients with multiple antimicrobial allergies that limit thera&shy;peutic options and as an alternative to fluoroquinolones. With its broad-spectrum activity, omadacycline may be particularly useful in treating CABP in such patients where coverage of gram-positive, gram-negative, and atypical organisms is necessary in situations where cultures cannot be obtained.

Dr. Heaney is a PGY2 resident in Infectious Diseases Pharmacy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She completed her PharmD at the University of the Sciences Philadelphia College of Pharmacy and a PGY1 residency at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania.

Nelson ML, Levy SB. The history of the tetracyclines. 

. 2011;1241:17-32. doi: 10.1111/j.1749-6632.2011.06354.x.

Wood WS, Kipnis GP, Spies HW, Dowling HF, Lepper MH, Jackson GG. Tetracycline therapy: clinical and laboratory observations on one hundred eighty-four patients treated with tetracycline. 

Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR. Omadacycline enters the ring: a new antimicrobial contender. 

. 2018;38(12):1194-1204. doi: 10.1002/phar.2185.

Macone AB, Caruso BK, Leahy RG, et al. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. 

. 2014;58(2):1127-1135. doi: 10.1128/AAC.01242-13.

Pfaller MA, Rhomberg PR, Huband MD, Flamm RK. Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014). 

. 2018;91(2):179-183. doi: 10.1016/j.diagmicrobio.2018.01.019.

Pfaller MA, Huband MD, Shortridge D, Flamm RK. Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe as part of the 2016 SENTRY Antimicrobial Surveillance Program. 

US Food and Drug Administration. Omadacycline injection and oral products FDA identified breakpoints. FDA website. www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm622612.htm. Updated October 5, 2018. Accessed January 4, 2019.

Moura IB, Buckley AM, Ewin D, et al. Omadacycline gut microbiome exposure does not induce 

 proliferation or toxin production in a model that simulates the proximal, medial and distal human colon [published online November 19, 2018]. 

Omadacycline p-toluenesulfonate tablets and injection for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) briefing document for: Antimicrobial Drugs Advisory Committee (AMDAC). FDA website. www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm615849.pdf. Accessed December 21, 2018.

Omadacycline [package insert]. Boston, MA: Paratek Pharmaceuticals Inc.; 2018. www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf. Accessed January 4, 2019.

Gotfried MH, Horn K, Garrity-Ryan L, et al. Comparison of omadacycline and tigecycline pharmacokinetics in the plasma, epithelial lining fluid, and alveolar cells of healthy adult subjects. 

Villano S, Tanaka SK. Omadacycilne, an aminomethylcycline antibiotic, has no effect on QT/QTc intervals in healthy subjects. Poster presented at: 26th European Congress of Clinical Microbiology and Infectious Diseases; April 9-12, 2016; Amsterdam, Netherlands. Omadacycilne, an aminomethylcycline antibiotic, has no effect on QT/QTc intervals in healthy subjects.

An oral alternative for patients requiring broad-spectrum therapy in this era of resistance. 

Omadacycline: A New Player for Team Tetracycline

Aminoglycosides date back to the 1940s, with the intro&shy;duction of streptomycin. Streptomycin was the first antibiotic available for the effective treatment of tuber&shy;culosis, netting its discoverer, Selman Waksman, a Nobel Prize. During the golden age of antibiotic development in the 1940s through 1960s, aminoglycosides continued to advance, along with many novel classes of antibiotics. Because of their potent activity against gram-negative organisms, aminoglycosides became mainstays of infectious diseases pharmaco-therapy, before eventually being displaced by broad-spectrum β-lactams, which became widely available in the 1980s and 1990s.

Inevitably, organisms developed resistance mechanisms to aminoglycosides. In Enterobacteriaceae, resistance is commonly due to plasmid-encoded aminoglycoside-modifying enzymes (AMEs). These enzymes cause a change in the chemical structure of the aminoglycoside compound, resulting in lower binding affinity for the bacterial ribosome and high-level resistance to the class. Plazomicin, which was approved by the US Food and Drug Administration (FDA) on June 25, 2018, for the treatment of complicated urinary tract infections (cUTIs), was developed with structural modifications to protect it from AMEs.

 On August 3, 2018, the Centers for Medicare & Medicaid Services granted plazomicin a new technology add-on payment for inpatient use.

Plazomicin is active against all aminoglycoside-modifying enzymes that confer resistance to older aminoglycosides, except N-acetyltransferase exhibited in 

 Compared with older aminoglycosides, it has more potent activity against extended-spectrum β-lactamase—producing and carbapenem-resistant Enterobacteriaceae (CRE).

 In an in-vitro comparison with CRE, plazomicin had a minimum inhibitory concentration for 90% of the isolates (MIC90) of 2 mg/mL compared with gentamicin (MIC90 64 mg/mL), tobramycin (MIC90 32 mg/mL), and amikacin (MIC90 32 mg/mL).

 The approved breakpoint for plazomicin is 2 mg/mL.

. The EPIC trial compared plazomicin with meropenem for the treatment of cUTIs, including acute pyelonephritis (AP), in 388 adults. Plazomicin demonstrated noninferiority in composite cure, defined as achieving micro&shy;biologic eradication and clinical cure, at the test-of-cure visit with a success rate of 81.7% compared with 70.1% with meropenem, a difference of 11.6% (95% CI, 2.7 to 20.3).

Interestingly, patients in the plazomicin arm also experienced a significantly lower rate of clinical relapse at late follow-up compared with those in the meropenem arm (1.8% vs 7.9%).

 The FDA granted plazomicin approval for the treatment of cUTI including AP in adults 18 years and older with limited or no available treatment options. The indicated dose is 15 mg/kg intravenously every 24 hours.

Plazomicin was also studied in the CARE trial, a prospec&shy;tive, randomized study of patients with CRE infections. Investigators compared plazomicin with colistin in 37 adult patients with bloodstream infections (BSIs), hospital-acquired pneumonia, and ventilator-associated pneumonia caused by CRE. Patients in the plazomicin arm had a 26.5% lower all-cause mortality or disease-related complication rate compared with those in the colistin arm (23.5% vs 50.0%; 95% CI, —0.7 to 51.2). Patients treated with plazomicin for a BSI demonstrated a survival benefit with a hazard ratio for death of 0.37 (90% CI, 0.15 to 0.91).

 In addition, patients with a BSI had a microbiologic response rate of 92.9% when treated with plazomicin compared with 53.3% for those treated with colistin.

Following a single 15-mg/kg intravenous (IV) dose, plazo&shy;micin achieved a maximum concentration of 73.7 mg/mL, a minimum concentration of 0.3 mg/mL, and an area under the curve of 257 mg/mL. The mean volume of distribution is 17.9 L, and protein binding is estimated to be 20%. Plazomicin has a half-life of 3.5 hours in patients with normal renal function and is primarily excreted renally unchanged. Therapeutic drug monitoring can be performed, with a goal trough level of less than 3 mg/mL prior to the second dose to minimize toxicity.

 Plazomicin lung penetration was measured at 13% after a single dose in healthy volunteers.

Warnings and precautions associated with plazomicin use are consistent with those reported for older aminoglycosides. Black box warnings include nephrotoxicity, ototoxicity, neuro&shy;muscular blockade, and teratogenicity. Adverse events most commonly observed in clinical studies include acute kidney injury, diarrhea, headache, nausea, vomiting, and hypertension or hypotension.

 In the EPIC trial, 3.7% of patients treated with plazomicin had a serum creatinine level increase of ≥0.5 mg/dL while on IV therapy compared with 3.0% of patients treated with meropenem.

 In the CARE trial, 11.1% of patients who received plazomicin had serum creatinine level increases compared with 38.1% of those who received colistin.

With its activity against multidrug-resistant Enterobacteriaceae, plazomicin offers an alternative for patients at high risk for, or with a history of, infection caused by organisms such as CRE. Although plazomicin is indicated by the FDA to treat cUTI, there are limited prospective data supporting its use as a treatment for other infections caused by CRE, particularly BSIs. As such, plazomicin may be particularly useful in urosepsis, though its use should be reserved for instances including carbapenem resistance or elevated MICs to older aminoglycosides.

Dr. Heaney is a PGY2 resident in infectious diseases pharmacy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She completed her PharmD at the University of the Sciences Philadelphia College of Pharmacy and a PGY1 residency at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania.

Dr. Gallagher is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia, Pennsylvania. He also is the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple.

Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM. Aminoglycosides: activity and resistance. 

Zhanel GG, Lawson CD, Zelenitsky S, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. 

Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P. Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. 

Haidar G, Alkroud A, Cheng S, et al. Association between the presence of aminoglycoside-modifying enzymes and in vitro activity of gentamicin, tobramycin, amikacin, and plazomicin against Klebsiella pneumoniae carbapenemase- and extended-spectrum-β-lactamase-producing Enterobacter species. 

Cloutier D, Miller L, Komirenko A, et al. Evaluating once-daily plazomicin versus meropenem for the treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP): Results from a phase 3 study (EPIC). Presented at: ASM Microbe 2017; June 4, 2017; New Orleans, LA.

Plazomicin [package insert]. San Francisco, CA: Achaogen, Inc.; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303Orig1s000lbl.pdf. Accessed 18 July 2018.

Daikos G, Connolly L, Jubb A, et al. Plazomicin (PLZ) associated with improved survival and safety compared to colistin in serious carbapenem-resistant Enterobacteriaceae (CRE) infections: Results of the CARE study. Presented at: ASM Microbe 2017; June 5, 2017; New Orleans, LA.

Cass R, Kostrub CF, Gotfried M, Rodvold K, Tack KJ, Bruss J. A double-blind, randomized, placebo-controlled study to assess the safety, tolerability, plasma pharmacokinetics and lung penetration of intravenous plazomicin in healthy subjects. Poster presented at: 23

 European Congress of Clinical Microbiology and Infectious Diseases; May 1, 2013; Berlin, Germany.

The drug presents a new option for patients at high risk of infections caused by organisms, such as carbapenem-resistant Enterobacteriaceae.

Maria Heaney, PharmD

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