New Treatment Options for Multidrug-Resistant Pseudomonas aeruginosaBy: Will Miller, PharmD, MBA; PGY2 Infectious Diseases Pharmacy Resident
Mentor: Tamara Krekel, PharmD, BCPS, BCIDP; Infectious Diseases Clinical Pharmacy Specialist
Program Number: 2021-12-05
Approved Dates: February 1, 2022-August 1, 2022
Approved Contact Hours: One Hour(s) (1) CE(s) per session
Pseudomonas aeruginosa is an aerobic Gram-negative bacillus that is found commonly in the environment and is capable of causing severe infections, particularly in hospitalized patients. As P. aeruginosa thrives in moist environments, it is often associated with pneumonia, catheter-related infections, and surgical site infections. It is capable of extensive colonization and represents a significant challenge in healthcare due to its intrinsic and acquired resistance to many common antibiotics. As a result, the Centers for Disease Control and Prevention (CDC) has described carbapenem-resistant P. aeruginosa as a serious threat, with 32,600 estimated cases and 2,700 estimated deaths in hospitalized patients in 2017.1 Despite not getting the highest level of classification as an urgent threat, the designation as a serious threat indicates that increasing incidence, decreased antimicrobial efficacy, and significant clinical and economic impact are anticipated, thus greater attention and action are needed.
Multidrug-resistant (MDR) P. aeruginosa is defined as nonsusceptibility to at least three classes of antibiotics (penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems) to which susceptibility is generally expected.3 However, some MDR P. aeruginosa isolates are resistant to all of these antibiotics (known as difficult-to-treat resistance “DTR” P. aeruginosa). P. aeruginosa can acquire resistance through a combination of mechanisms including AmpC β-lactamases, carbapenemases, porin loss, and efflux pumps.
AmpC β-lactamases are ubiquitously produced by P. aeruginosa and are responsible for the majority of its antibiotic resistance. These β-lactamases do not typically confer resistance to antipseudomonal penicillins, cephalosporins, or carbapenems; this is accomplished with the addition of a carbapenemase, porin loss mutation, and/or efflux pumps.4 Carbapenemases can include Klebsiella pneumoniae carbapenemases (KPCs), metallo-β-lactamases (MBLs: NDM, IMP, VIM), and OXA-48. These confer resistance to all β-lactams but may be overcome with the addition of a β-lactamase inhibitor such as avibactam (exception: MBLs). Porin loss mutations, specifically OprD, confer resistance to carbapenems by preventing them from entering the periplasmic space of P. aeruginosa. As this is largely specific for carbapenems, antipseudomonal cephalosporins may be unaffected by this mutation.5 Perhaps the most unpredictable resistance mechanisms of P. aeruginosa are efflux pumps. There are a variety of efflux pumps that have unique substrates and cause certain antibiotics to be exported from the cell. Through a combination of one or more of these resistance mechanisms, P. aeruginosa can develop resistance to many or all of the traditionally used antibiotics.
New Treatment Options for MDR Pseudomonas aeruginosa
Prior to 2014, the only available treatment options for DTR P. aeruginosa were polymyxin B/colistin and aminoglycoside-based regimens. As these agents have severe toxicities, there was a need for new antibiotics to combat DTR P. aeruginosa that have fewer toxicities. Since 2014, multiple new agents have been developed to meet this need. These include ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol. Of note, meropenem/vaborbactam has no added activity against P. aeruginosa as compared to meropenem alone and should not be utilized against isolates that are resistant to meropenem.
Ceftolozane/tazobactam is a combination advanced-generation cephalosporin/β-lactamase inhibitor that is known for its potent activity against P. aeruginosa. Ceftolozane/tazobactam is stable in the presence of most extended-spectrum β-lactamases (ESBLs), AmpC cephalosporinases, OprD porin loss mutations, and efflux pumps. It is currently FDA-approved for complicated intra-abdominal infections (cIAI) in combination with metronidazole, complicated urinary tract infections (cUTI) including pyelonephritis, and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).7
Ceftolozane/tazobactam is typically dosed at 1.5 g IV every 8 hours (exception: 3 g IV every 8 hours for treatment of HABP/VABP) and is renally adjusted for patients with CrCl < 50 mL/min.8 Ceftolozane has a half-life of 2-3 hours and is primarily eliminated in the urine as unchanged drug.9 It is generally well-tolerated but may be associated with constipation, headache, and pyrexia.
A retrospective cohort study comparing 200 patients with resistant P. aeruginosa highlighted the potential benefit of ceftolozane/tazobactam over traditional polymyxin or aminoglycoside-based therapy.10 Of the patients included in this analysis, 69% were in the intensive care unit, 63% were mechanically ventilated, and 42% were in severe sepsis or septic shock at enrollment. 65% of patients were treated for HABP/VABP, 14% for cUTI, and 7% of patients for a bloodstream infection. The authors conducted a multivariate logistic regression looking at the impact of ceftolozane/tazobactam on clinical cure (defined as the resolution of the signs and symptoms of infection with the initial study regimen without the need for therapy modification due to clinical failure or toxicity), acute kidney injury (AKI), and in-hospital mortality. They found that ceftolozane/tazobactam was independently associated with clinical cure [adjusted odds ratio (aOR) 2.63; 95% confidence interval (CI) 1.31–5.30] and was protective against AKI (aOR 0.08; 95% CI 0.03–0.22), with no difference in in-hospital mortality. This was associated with a number needed to treat of five for clinical cure with ceftolozane/tazobactam and a number needed to harm of four for AKI with a polymyxin or aminoglycoside-based regimen, indicating substantial benefits of ceftolozane/tazobactam.
Ceftazidime/avibactam is a combination third-generation cephalosporin/β-lactamase inhibitor that is active against many carbapenemases (exception: MBLs) and is not stable to porin loss mutations or efflux pumps. It is currently FDA-approved for cIAI in combination with metronidazole, cUTI including pyelonephritis, and HABP/VABP.11
Ceftazidime/avibactam is typically dosed at 2.5 g IV every 8 hours and is renally adjusted for patients with CrCl < 50 mL/min. It has a half-life of 3-4 hours and is primarily excreted in the urine as unchanged drug. Adverse reactions associated with ceftazidime/avibactam include CNS effects (e.g., seizures, coma, anxiety) and constipation.12
Clinical trial data for ceftazidime/avibactam in the treatment of MDR P. aeruginosa became available in a 2018 pooled data subgroup analysis of the phase III clinical trial data.13 Of the 95 patients that were included, 56 had received ceftazidime/avibactam and 39 had received a carbapenem comparator. The majority of patients were being treated for a cUTI, with fewer patients being treated for HABP/VABP or cIAI. In this analysis, microbiological response was assessed (defined as absence of causative organism or presumed eradication as determined by clinical cure without repeat cultures) and found a 57.1% microbiological response rate with ceftazidime/avibactam and a 53.8% microbiological response rate with carbapenems. Clinical efficacy was assessed as well but was not specifically reported for the cohort of patients with MDR P. aeruginosa infections. Therefore, the authors concluded that ceftazidime/avibactam demonstrated similar clinical and microbiological efficacy to carbapenems against MDR P. aeruginosa.
Imipenem/cilastatin/relebactam is a combination carbapenem/β-lactamase inhibitor that has activity against some carbapenemases (KPCs) and also often retains activity in the presence of efflux pumps. However, it not active against MBLs or in the presence of porin loss mutations. It is currently FDA-approved for cIAI in patients who have limited or no alternative treatment options, cUTI including pyelonephritis in patients who have limited or no treatment options, and HABP/VABP.14
Imipenem/cilastatin/relebactam is typically dosed at 1.25 g IV every 6 hours and is renally adjusted for patients with CrCl < 90 mL/min. It has a half-life of 1 hour and is excreted in the urine as mostly unchanged drug. Adverse reactions associated with imipenem/cilastatin/relebactam include nausea, diarrhea, headache, and CNS reactions including seizures.15
To assess the utility of imipenem/cilastatin/relebactam in treating MDR bacterial infections, investigators conducted the RESTORE-IMI 1 trial, a multicenter, randomized, double-blind trial that compared imipenem/cilastatin/relebactam to colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections.16 Thirty-one hospitalized patients with HABP/VABP, cIAI, or cUTI were assigned 2:1 to imipenem/cilastatin/relebactam versus colistin plus imipenem. 77% of patients had P. aeruginosa as their qualifying pathogen. The primary endpoint of this study was favorable overall response (HABP/VABP, 28-day all-cause mortality; cIAI, day 28 clinical response; cUTI, composite clinical and microbiologic response at the end-of-therapy visit) and secondary endpoints included clinical response, 28-day all-cause mortality, and treatment-emergent toxicity. For the primary endpoint, 71% of patients who received imipenem/cilastatin/relebactam achieved a favorable overall response, compared to 70% of patients who received a combination of colistin and imipenem (90% CI -27.5%-21.4%), indicating no difference between groups. However, imipenem/cilastatin/relebactam was associated with a significantly higher favorable clinical response [71% v. 40% (90% CI 1.3%-51.5%)], numerically lower 28-day all-cause mortality [10% v. 30% (90% CI -46.4%-6.7%)], and significantly less treatment-emergent nephrotoxicity (10% v. 56%, p=0.002). As a result, the authors concluded that imipenem/cilastatin/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections.
Cefiderocol is a novel siderophore cephalosporin with activity against MDR P. aeruginosa, including most isolates with carbapenemases (including KPCs, MBLs, and OXA-48), porin loss mutations, and efflux pumps. Cefiderocol has a unique mechanism in that it binds to free iron and is actively transported into the periplasmic space of Gram-negative bacteria through iron transport channels. Once gaining entry into the cell, it acts like other β-lactams to inhibit bacterial cell wall synthesis.17
Cefiderocol is FDA-approved for the treatment of cUTI, including pyelonephritis, and HABP/VABP. It is typically dosed at 2 g IV every 8 hours and is renally adjusted for patients with CrCl < 60 mL/min. Of note, cefiderocol is also dose-escalated to 2 g IV every 6 hours for patients with CrCl > 120 mL/min. It has a half-life of 2-3 hours and is primarily excreted in the urine as unchanged drug.18 Listed adverse reactions and warnings include neurotoxicity and increased risk of mortality as compared to best available therapy in critically ill patients with carbapenem-resistant Gram-negative bacterial infections.
The CREDIBLE-CR study, a randomized, open-label, phase III study, compared cefiderocol to best available therapy for the treatment of serious carbapenem-resistant Gram-negative infections.19 Of the 118 patients who were included in the analysis, 22 of them had P. aeruginosa as the causative pathogen, 12 of whom were assigned to the cefiderocol arm and 10 of whom were assigned to the best available therapy arm. Best-available therapy was left to the discretion of the provider and most often included combination therapy (71%) and/or colistin-based treatment (66%). Of patients with P. aeruginosa infection, 18% of patients receiving cefiderocol and 18% receiving best-available therapy met the outcome of all-cause mortality at 28 days following the end of therapy.
While the CREDIBLE-CR study included a subgroup of patients with carbapenem-resistant P. aeruginosa infection, the study as a whole included patients with carbapenem-resistant Acinetobacter spp (n=59), Klebsiella pneumoniae (n=43), P. aeruginosa (n=22), Escherichia coli (n=4), or Stenotrophomonas maltophilia (n=3). 59% of patients were treated for nosocomial pneumonia, 31% for bacteremia or sepsis, and 24% for cUTI. The primary endpoint differed by indication (nosocomial pneumonia or bacteremia/sepsis, clinical cure at day 7; cUTI, microbiological eradication at test of cure visit). Overall, 66% of patients receiving cefiderocol achieved clinical cure versus 58% of patients receiving best available therapy. Comparative efficacy was seen within the nosocomial pneumonia population (50% cefiderocol v. 53% best available therapy) and bacteremia/sepsis population (43% in each group), with higher rates of clinical cure with cefiderocol in the cUTI group (53% v. 20%). As such, the study concluded that cefiderocol had similar clinical and microbiological efficacy to best available therapy in infections caused by carbapenem-resistant Gram-negative bacteria.
The CREDIBLE-CR trial also reported other results that may have important clinical implications. First, cefiderocol was associated with substantially higher cure rates as compared to best available therapy in isolates producing MBLs (75% v. 29%), suggesting that cefiderocol may be a good treatment option for organisms known to harbor this resistance mechanism. Second, more patients in the cefiderocol arm died by the end of the study (34% v. 18%), which led to the mortality warning on the package insert of cefiderocol. However, it is important to note that this difference was mostly attributed to patients with Acinetobacter as the causative pathogen (50% v. 18%). With all other included organisms, including P. aeruginosa, there was no difference in mortality.
As part of an effort to identify the place in therapy of each of these new agents and to improve the outcomes of patients with MDR Gram-negative infections, Infectious Diseases Society of America (IDSA) recently published a living guidance document titled ““Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa)”, that includes recommendations for treating DTR P. aeruginosa. These recommendations account for the source of infection and assume that in vitro activity of the antibiotics has been demonstrated.3
Treatment of MDR and DTR P. aeruginosa infections should be guided by susceptibility testing and first-line treatment options should be utilized as appropriate. In isolates that are non-susceptible to all first-line treatment options, utilization of ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, or cefiderocol is appropriate. However, susceptibility of these agents must also be confirmed.
When susceptibility testing indicates the activity of multiple agents against DTR P. aeruginosa, there are several areas to consider when selecting an agent, some of which include antibiotic stewardship, duration of therapy, and presence of a mixed infection. From a stewardship perspective, ceftolozane/tazobactam may be an ideal option as it has increased activity against P. aeruginosa and does not have activity against most other MDR organisms, allowing agents that have this extra activity to be spared for that purpose. Duration of therapy considerations may influence agent selection as it relates to patient tolerability, affordability, and ability to utilize outpatient parenteral antibiotic therapy. Lastly, in patients with mixed infections, agents with broader coverage such as ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol may allow the consolidation of therapy and decreased antibiotic use.
The treatment of P. aeruginosa is increasingly difficult due to the emergence of MDR and DTR isolates. However, newly developed agents including ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol provide new treatment options that may be more effective and better tolerated than previous agents. Therefore, it is imperative that pharmacists have a solid understanding of these agents in order to employ them in appropriate clinical scenarios.
By: Naphtali Eke, PharmD
Mentor: Justinne Guyton, PharmD, BCACP, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis/St. Louis County Department of Public Health
According to the National Diabetes Statistics Report, published by the Centers for Disease Control and Prevention, approximately 34.2 million people (10.5% of the population in the U.S.) have diabetes, with 7.3 million of those people who continue to go undiagnosed.1 Blood glucose monitoring (BGM) allows patients to measure their glucose from a blood drop, commonly through a fingerstick. However, continuous glucose monitoring (CGM) allows patients to measure their glucose in the interstitial fluid, in a continuous manner providing results every 5 minutes. Interstitial glucose levels correlate well with blood glucose levels, although there may be a delay if the glucose levels change quickly.2 Capillary blood glucose measurement via the fingerstick method in comparison to interstitial fluid measurements via CGMs has shown to provide more accuracy during periods of rapidly changing glucose levels such as hypoglycemia or right after a meal or dose of bolus insulin.3 Despite this, use of CGMs provide a wide variety of benefits, such as no fingerstick, alarms during periods of trending hyper or hypoglycemia, 24-hour monitoring, increased quality of life, and the ability to share results with primary care providers and family. However, they do come with a few well known disadvantages such as increased costs, reimbursement from Medicare mainly for insulin-dependent type-1 diabetics, and the inconvenience of having to constantly wear a device for benefit.4 The role of CGMs has been well established in type 1 diabetes, and more recent data from a meta-analysis in patients with type 2 diabetes also found that the use of CGMs compared to BGM resulted in improvement in hemoglobin A1c, improved ability to detect hypoglycemic events and nocturnal hypoglycemia, decreased time spent in hyperglycemia, and improved patient satisfaction.5 The purpose of this review is to compare and contrast the different features of the most common CGM systems on the U.S. market today: Dexcom G6, Freestyle Libre 2, and Medtronic’s Guardian Sensor.
The G6 is Dexcom’s latest generation CGM system, the Dexcom G6 is one of the most popular and commonly used devices in the U.S. It consists of a sensor, transmitter, and a display device, which can either be a receiver, compatible smartphone or watch. Compatible with these devices through their “Dexcom G6” and “Dexcom CLARITY” apps, it automatically sends real-time glucose readings every 5 minutes and is considered a real-time CGM (rtCGM). A new sensor is applied to the skin every 10 days. Another feature is that it is factory calibrated, which means the patient does not have to calibrate the device, or obtain a confirmatory blood glucose reading to make clinical decisions, although the option to calibrate is still available if the patient were to need it. The system can be used alone, or in conjunction with the Tandem t:slim X2 or the Tubeless Omnipod insulin pump. It is FDA-approved for ages 2 and up, which is the lowest approved age out of the three. The Dexcom G6 is covered by Medicare for patients with type 1 or 2 diabetes on intensive insulin therapy through approved Durable Medical Equipment (DME) suppliers. Of note, Missouri Medicaid does cover this device for patients with type 1 diabetes based on certain approval criteria.
Freestyle Libre 27
The Freestyle Libre 2 system is one of the latest systems from Abbott, and it consists of a sensor and a reader. It works by holding the reader over the sensor each time a reading is desired, and is considered an intermittent scanned CGM (is-CGM), with readings as frequently as every 1 minute. Patients should scan at least every 8 hours for a full dataset. A new sensor is applied every 14 days and is a much simpler process in comparison to other systems. Just like the Dexcom G6, calibration is not required and the readings can be seen with a phone app rather than the reader. Also similar to Dexcom G6, the Freestyle Libre is covered by Medicare for patients with type 1 or 2 diabetes on intensive insulin therapy through DME suppliers. A great benefit to using this sensor is that despite whether a patient has insurance or not, the cost is priced 70% lower than the list price of other CGM systems. The FDA has approved its use in patients ages 4 and up.
Medtronic Guardian 38
There are many ways to compare these systems. The Medtronic seems to be the least favored due to its need for daily calibration, and lack of Medicare coverage. It also has the shortest sensor lifespan. Changing a sensor may not be bothersome to some patients, but can be an inconvenience to others. The Freestyle Libre 2 has the longest sensor lifespan, the shortest sensor warm-up time, and is the lowest cost option for uninsured patients. The sensor warm-up time is the time it takes for a newly inserted sensor to acclimatize to the body before a patient is able to obtain accurate readings. A couple of disadvantages include no alerts when the glucose levels are trending to abnormal ranges (only notifies when it is already out of range), and no integration with an insulin pump. The patient would have to scan the sensor at least every 8 hours with either the reader or smartphone to obtain the current levels. This can be an inconvenience for patients who would prefer to be more discrete. Lastly, the Dexcom G6 has the benefit of real-time monitoring on an Apple Watch, unique from the others. Another consideration between meters is the potential for drug interactions (e.g. uric acid, galactose, xylose, acetaminophen, L-DOPA, and ascorbic acid) that can affect readings and vary by monitor.2 Patient’s should be instructed to check the device manual when receiving a CGM.
By Meleah Collins, PharmD. Candidate 2022, Xavier University College of Pharmacy
Mentor: Christine Kelso, PharmD, BCPS, AE-C, Barnes-Jewish Hospital, St. Louis
Sodium-glucose-co-transporter-2 (SGLT-2) inhibitors are oral agents that were originally approved to treat type-2 diabetes mellitus (T2DM), working by inhibiting renal glucose absorption. Their integration into clinical practice has continued to rise and approval has been expanded to patients without T2DM due to cardiovascular and renal benefits associated with some of these agents, as well as advantages of weight reduction, low hypoglycemia risk, and decreases in blood pressure. Despite its relative rarity in phase 3 clinical trials, 20 cases of diabetic ketoacidosis (DKA) associated with SGLT-2 inhibitors have been reported in both type 1 and type 2 diabetes, subsequently resulting in the U.S. Food and Drug Administration (FDA) publishing a formal warning regarding this potential complication in May of 20151.
Euglycemic Diabetic Ketoacidosis
Euglycemic DKA (EDKA) is characterized by euglycemia (BG <250 mg/dL) in the presence of severe metabolic acidosis and ketonemia.2 DKA is one of the more severe and life threatening complications of diabetes mellitus, and in the setting of euglycemia, delayed diagnosis may lead to poorer outcomes.3
While EDKA can have many causes, the overall mechanism stems from a state of starvation that is usually a carbohydrate deficit. This results in a decrease in serum insulin and an increase in counter-regulatory hormones.4 As the insulin to glucagon ratio increases, lipolysis and free fatty acids also increase, resulting in ketoacidosis.
SGLT-2 inhibitors enhance excretion and block reabsorption of filtered glucose from the proximal convoluted tubule.5 The loss of urinary glucose can create carbohydrate starvation while this class of agents simultaneously stimulates the direct release of glucagon from the pancreas.5 Additionally, SGLT-2 inhibitors suppress the kidney’s ability to remove beta-hydroxybutyrate and acetoacetate.2 Once an anion gap is present, it triggers respiratory compensation, accompanied by dyspnea, nausea, vomiting, and anorexia, further worsening DKA.
Any condition that involves or mimics being in a fasted state such as anorexia, alcohol use disorder, or being on a ketogenic diet, can put one at risk for EDKA.6 Other triggers include pancreatitis, surgery, infection, cirrhosis, pregnancy, and use of an insulin pump. In addition, there may be evidence that patients with type 1 diabetes mellitus (T1DM) are prone to EDKA following bariatric surgery, with an incidence of over 20%.7
Among patients on SGLT-2 inhibitors, those with low body mass index and decreased glycogen stores are at increased risk; even more so if suffering major illness or trauma, reduced insulin doses, and the conditions previously stated. A common trigger of EDKA seen in practice is when patients who are on SGLT-2 inhibitors and insulin miss doses or decrease their doses of insulin either by too much or too rapidly when they have decreased intake whether because of a gastrointestinal issue such as nausea/vomiting, or otherwise.
Euglycemic DKA presents similarly to hyperglycemic DKA. Patients may present with general malaise, fatigue, lethargy, nausea, vomiting, loss of appetite, abdominal pain, or shortness of breath. Patients may also present with Kussmaul respiration (deep and rapid breathing) which is indicative of respiratory compensation for metabolic acidosis.2 They may have a fruity odor to their breath due to the loss of acetone. In more severe cases, patients may experience hypovolemic shock, respiratory failure, coma, or even death due to extensive dehydration and metabolic changes.2 Unlike with DKA, symptoms less likely to be present in EDKA are polyuria, polydipsia, or severe changes in mental status since patients with EDKA have glucose levels within the normal range. As a result, it can be difficult to detect from a clinical perspective, as well as for patients who are monitoring their glucoses and symptoms at home.
Early Evaluation, Recognition, and Diagnosis
When detected and treated promptly, most patients who experience EDKA will recover. Delays in diagnosis and treatment can lead to persistent symptoms, longer hospitalizations, and poorer outcomes.
Patients presenting with malaise and the accompanying symptoms of EDKA while on SGLT-2 inhibitors should immediately undergo screening of serum pH and ketone testing via blood or urine.3,8 Successful and timely diagnosis is dependent on early screening with serum or urine ketones, even when serum glucose is normal, whenever EDKA is suspected. The initial laboratory evaluation of EDKA includes a basic metabolic panel, calcium, magnesium, serum ketones, beta-hydroxybutyrate, arterial or venous blood gas analysis, lactic acid, chest radiograph, and electrocardiogram.2 If infection is a suspected cause or factor, complete blood count and blood cultures may also be pertinent to obtain. In patients who appear to have acidosis, all other possible causes must be ruled out, such as sepsis or ketoacidosis due to alcohol consumption. Serum levels of beta-hydroxybutyrate greater than 3 mmol/L, blood glucose less than 250 mg/dL, metabolic acidosis, and a total decreased serum bicarbonate are indicative of EDKA. Serum ketones must also be elevated to make the diagnosis of EDKA.2
It is important to educate patients taking SGLT-2 inhibitors about the signs and symptoms, as well as the severity of DKA if left unaddressed. Additionally, it is important to stress the importance of adequate calorie intake, proper blood glucose monitoring, and communication with primary care providers, especially if on insulin so that providers can make adjustments to the regimen as appropriate. Insulin dosing should correlate with patients’ intake in order to avoid exacerbation of a potential carbohydrate deficit. Patients should contact their primary care provider if they have any significant changes to their enteral intake, especially carbohydrates, or if they experience nausea or vomiting. Ketogenic diets, as well as any other diet consisting of low-carbohydrate intake should be avoided if taking an SGLT-2 inhibitor, especially if the patient is insulin dependent.
Patients should hold SGLT-2 inhibitors in the setting of surgery (at least 3 days prior, and up to 5 days prior if performing bariatric surgery).9 Postoperatively, volume status, caloric intake, and glucose levels should be monitored, and the SGLT-2 inhibitor should be discontinued if T2DM is in remission.9 In patients who will continue therapy post-procedure, ensure all risk factors for EDKA have resolved prior to reinitiating. Although the SGLT-2 inhibitors have been shown to have extra benefits on cardiovascular and kidney health, they are not recommended to be used in the management of patients with T1DM because of the high risk of DKA.10-12
Pharmacists play a pivotal role in both the education and prevention of EDKA. Pharmacists can assist in patient education surrounding self-monitoring and communication, particularly in the outpatient setting. Both inpatient and outpatient, providers and other healthcare professionals can look to pharmacists for appropriate interventions and education on drug interactions or agents that may contribute to EDKA.
Overall, working together as a healthcare team to properly weigh the risks and benefits of SGLT-2 inhibitor use, encourage proactive patient self-monitoring, and implement early surveillance and recognition of potential EDKA can ensure positive patient outcomes.
Author: Hyoeun Ashley Kang, PharmD Candidate 2022, UMKC School of Pharmacy
Mentor: Annie Ungerman, PharmD, BCPS; Clinical Lead Pharmacist, Rheumatology Truman Medical Centers
Romosozumab subcutaneous injection was approved by the U.S. Food and Drug Administration (FDA) in April 2019 for osteoporosis in postmenopausal women who are at high risk of fracture.Osteoporosis is a common disease state in women and affects more than 10 million individuals in the United States.1 Among multiple risk factors for developing osteoporosis, glucocorticoid (GC)-induced osteoporosis is the most common cause of secondary osteoporosis. Long-term use of GC therapy reduces bone formation and can trigger significant bone loss. In rheumatology clinics, GC medications are frequently prescribed for the treatment of rheumatoid arthritis (RA).2 Lee et al. showed that the incidence of osteoporosis is 1.9 times higher in patients with RA than without.3 Romosozumab is not mentioned in the American College of Rheumatology (ACR) Glucocorticoid-induced Osteoporosis guideline as it was last updated in 2017.
Risk of Glucocorticoid-induced Osteoporosis
Mechanism of Action
Romosozumab is an agent that has a different mechanism of action to stimulate bone formation than other osteoporosis treatments. Romosozumab is a monoclonal antibody that inhibits the action of sclerostin protein, which is a regulatory factor to block bone formation.Romosozumab is the first agent with a dual effect that increases bone formation (osteoblastic activity) and decreases bone resorption (osteoclastic activity).1,7
Dosage and Administration
The recommended dose of romosozumab is 210 mg by subcutaneous injection every four weeks for a total of 12 months. A healthcare professional should administer it as two separate injections of a 105 mg/1.7 mL syringe on the same day. The recommended injection sites of administration are abdomen, thigh, or upper arm. Additionally, patients should be on daily calcium and vitamin D supplements while taking romosozumab. If a dose is missed it is recommended to administer as soon as possible and reschedule subsequent doses from the date of the last dose.Use after 12 months is not advised as the effect of bone formation wanes after 12 doses.1,7
The most common side effects of romosozumab are arthralgia (8% to 13%), hypersensitivity reaction (7%), and headache (5% to 7%).10 Romosozumab has a black boxed warning that it can increase the risk of stroke, myocardial infarction (MI), and cardiovascular death. Thus, romosozumab should not be used in patients who previously have had an MI or stroke within the past year.7,10 The data for the Major Adverse Cardiac Events (MACE) from the ARCH trial (2017) are analyzed in Table 3.
Romosozumabis the first monoclonal antibody agent designed to target sclerostin protein. The ARCH trial and STRUCTURE trial demonstrated the efficacy and safety of romosozumab versus active comparator agents. This novel pathway of romosozumab provides an important treatment option for osteoporosis in postmenopausal women who are at high risk of fracture.
De-Sema-nating the Best Semaglutide Formulation for Your Patient
By Kelly Williams, PharmD Candidate Class of 2023, UMKC School of Pharmacy and Jordan Rowe, PharmD, BCACP, BC-ADM, UMKC School of Pharmacy
Semaglutide, a glucagon-like peptide (GLP-1) receptor agonist, works by mimicking the effects of human GLP-1 to induce insulin secretion and augment the metabolism of blood sugar. Current American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) guidelines recommend GLP-1 agonists as a possible second-line therapy following first-line metformin for most patients, and the recent ADA 2022 update recommends that GLP-1 agonists may be appropriate initial therapy for those with certain risk or disease factors.1, 2 Semaglutide has been used on label for the last four years in the treatment of type 2 diabetes (T2DM) and off-label for weight management through its favorable glycemic profile, A1c-lowering, weight-reducing effects. Further data has shown additional benefits in secondary atherosclerotic cardiovascular disease (ASCVD) prevention. With the U.S. Food and Drug Administration’s (FDA) approval of Novo Nordisk’s third semaglutide formulation, Wegovy™, for weight management in early 2021, a clear, concise clinical decision support tool would be beneficial for providers who may be scratching their heads at the different forms of semaglutide and their appropriate uses. This article aims to describe the similarities and differences between three formulations of semaglutide (Ozempic®, Rybelsus®, and Wegovy™) and provide an overview given patient-specific factors.
The first formulation of semaglutide approved was Ozempic®. On December 5th, 2017, Novo Nordisk approved Ozempic®, a once weekly 0.5 mg or 1 mg injection, as adjunctive therapy with diet and exercise for the treatment of T2DM in patients with or without cardiovascular complications.3 The results of the SUSTAIN trials skyrocketed Ozempic® to the public eye by demonstrating several eye-catching attributes, including significant weight loss, A1c lowering, and secondary ASCVD risk reduction.3 Ozempic® was studied as a once weekly injection, yielding another advantage over several other currently available once or multiple daily GLP-1 injections. Although the associated weight reduction is a particularly attractive feature of Ozempic® given the benefits of achieving a healthy weight in those with T2DM, the formulation is not FDA-approved for obesity or weight management. Consequently, Ozempic® would not be ideal in patients only seeking weight management or patients who do not feel comfortable with injection therapy. Analogous to all currently available semaglutide formulations, Ozempic® is not available as a generic and thus carries a significant price tag. Although patient assistance programs and coupons for Ozempic® are available, cost may direct prescribers away from semaglutide formulations and towards more cost-effective alternatives as Ozempic® average wholesale price (AWP) costs over $1000 for a one-month supply.4
Next came Rybelsus®, a once-daily oral alternative to Ozempic®. On September 20th, 2019, less than two years after the release of Ozempic®, Novo Nordisk announced Rybelsus® was FDA-approved as 7 mg or 14 mg tablets for the treatment of T2DM.5 A pioneer in its class, Rybelsus® was the first oral GLP-1 agonist, providing an option to patients unable or unwilling to use injections. The PIONEER trials showed that Rybelsus® had similar favorable A1c lowering and weight lowering effects to Ozempic®, although it failed to demonstrate superiority in secondary ASCVD risk reduction.6 Although current literature has not fully elucidated why Rybelsus® did not show a similar secondary ASCVD benefit profile like Ozempic®, some theories about the mechanism by which GLP-1 agonists reduce risk as well as the discrepancy between agents have been described. Proposed theories include differing kinetic concentration profiles between the oral and subcutaneous formulations are the root of the difference, or perhaps that there is no difference, and the duration of the PIONEER trials was simply not long enough to identify cardiovascular benefits.6 Comparable to Ozempic®, Rybelsus® is not advantageous for those only seeking weight reduction or weight management as the only FDA-indication for Rybelsus® is for the treatment of T2DM. Cost should also be considered with Rybelsus®, as similar to Ozempic®, the drug also has an AWP cost of over $1000 per month.4 It is noteworthy that both Ozempic® and Rybelsus® would likely have a lower price tag for insured patients compared to Wegovy™ as most insurance companies have relatively robust coverage for agents treating T2DM, while many plans have limited to no coverage for medications with indications for weight management alone.
Lastly, on June 4th, 2021, Novo Nordisk announced Wegovy™ as a new semaglutide product to be FDA-approved for the exclusive indication of chronic weight management (in addition to diet and exercise) as a once-weekly 2.4 mg injection.7 Candidates for Wegovy should have a BMI of ≥30 kg/m2 or have one weight-related comorbidity (i.e. high blood pressure, high cholesterol, type 2 diabetes) with a BMI of ≥27 kg/m2.8 The STEP trials demonstrated that Wegovy™ showed significant weight loss and improved physical function.8 These trials did not show A1c-lowering effects in the general population, which is likely due to the trials excluding patients living with T2DM in all but the STEP 2 trial. In this instance, cost concerns are most dramatically at the forefront of clinical decision-making, as many insurance companies have limited to no coverage in medications indicated for weight management. Thus, Wegovy™ may incur the largest out-of-pocket expense by the patient of all semaglutide formulations with a price tag starting over $1600 per month AWP, regardless of strength.4
Given the similarity of Wegovy™ to its semaglutide predecessor, Ozempic®, the injectable dosage form of 2.4 mg once weekly begs the question whether two separate formulations are even necessary, as all semaglutide formulations are exclusively manufactured by Novo Nordisk. The SUSTAIN FORTE trial compared weekly Ozempic® 1 mg to Ozempic® 2 mg (not currently commercially available) for the purposes of assessing A1c lowering in patients with T2DM.9 The trial showed statistical superiority of the 2 mg dosage over 1 mg of Ozempic® in A1c reduction, although the absolute difference of 0.3% between the two dosages may or may not be considered clinically significant.9 The most substantial difference in study arms was in mean bodyweight change, mirroring results in the STEP trials.8, 9 This suggests that while the weight loss potential with semaglutide increases with escalating doses, the glycemic management benefits seem to plateau. It will be intriguing to see if the cardiovascular risk reduction will also be mirrored between the two injectable formulations, but the results of the SELECT trial, investigating secondary ASCVD risk reduction in patients using Wegovy™ for weight management, are not anticipated for several years.10
Reviewing Best Practices in the Treatment of Acute Agitation
Author: Tyler Frieda, PharmD, PGY-1 Pharmacy Resident, Mercy Hospital Springfield
Mentors: Hannah Norris, PharmD, BCPS; Amanda Troup, PharmD, BCPS, PGY-1 Pharmacy Residency Program Director
Program Number: 2021-12-06
Approved Dates: February 1, 2022-August 1, 2022
Approved Contact Hours: One Hour(s) (1) CE(s) per session
Acute agitation is a symptom that can result from a variety of several different medical and psychiatric conditions. Agitation, especially if severe, can result in harm to the patient themselves, those trying to provide care, or both if not appropriately managed.1 Several studies consistently show high rates of violence experienced by healthcare workers even in areas other than the emergency department. In a survey study by Li et al of 196 emergency medicine residents, 91% of residents reported experiencing some form of abuse, ranging from verbal abuse to physical attacks.2 Similarly, a prospective study of 272 emergency medicine residents and attending physicians by Behnam et al found 78% of study respondents reported at least one act of violence in the last year,3 and a study of 101 emergency medicine physicians by Al-Sahwali et al reported 86% experiencing violence in the workplace with 7% experiencing physical assaults likely to have caused serious harm.4 These trends extend beyond the emergency room with 73% of psychiatry residents reported having been threatened with 36% having been physically assaulted based on a study by Schartz and Park,5 and a study of 364 workers at public infectious disease clinics by Schulte et al reported 38% experiencing a violent incident.6 Workplace violence is not only experienced by physicians as Kansagra et al study of 65 emergency departments found that nurses were least likely to report feeling safe among the healthcare workers interviewed.7 While these statistics are not strictly due to cases of agitation, they emphasize the prevalence of violence among healthcare workers, and highlight the importance of taking actions to prevent or minimize situations that place workers in harm. Appropriately managing agitation is one such action in which pharmacists can play an important role.
As a pharmacist, it is important to understand the role these non-pharmacological treatment measures have in the treatment of acute agitation. The American Association for Emergency Psychiatry Project BETA expert consensus guidelines on the best practices in the treatment of agitation outline these approaches.1,10,11 Historically, non-pharmacological approaches have included restraint and seclusion.11 While these approaches are appropriate in select cases after other treatments have failed, de-escalation is regarded as the key approach to calming patients while maintaining the safety of coworkers.1,10,11 Utilization of de-escalation strategies have been found to enhance a positive clinician-patient relationship, decrease the likelihood of restraints, seclusion, and hospital admissions, and decrease length of stay.10 Meanwhile, the use of restraints is associated with increased lengths of stay, increased likelihood of psychiatric hospitalization, increased likelihood to cause severe distress to patients harming the clinician-patient relationship, and more likely to result in harm to both patients and healthcare workers.11 De-escalation contains key domains outlined by the Project BETA guidelines that were developed by a workgroup of emergency psychiatry practitioners experienced in behavioral emergencies. The key domains include: respect personal space, be concise and clear, listen to the patient, avoid further provocation, identify wants and needs, explain expectations and limits, establish verbal contact, agree or agree to disagree, offer choices and optimism, and debrief the patient and staff.10 The Project BETA workgroup consisted of emergency psychiatry practitioners experienced in behavioral emergencies who established these domains based on their collective experience and available evidence.10 For those interested in learning more about de-escalation, the website partnersincalm.com offers materials and updates for the treatment agitation including de-escalation.12
When to Use Medications and Best Practices
Medication therapy may be used in moderate to severe forms of agitation after de-escalation has failed.1,8 The goal of medication administration in agitation is to calm the patient without over sedation.1,8 In patients who partially respond to de-escalation, oral medications may still be offered but parenteral medication should be reserved only for patients posing an immediate threat to themselves or others.8 Even if de-escalation failed to sufficiently calm the patient, it may encourage the patient to be more cooperative to medication if it is offered as a choice to the patient.8,10 Oral medications should be offered over parenteral medications in patients that are cooperative as the use of oral medications has been shown to be just as effective as parenteral medications in acute agitation.8,13,14 Two prospective studies comparing oral and parenteral administration found no difference in the level of agitation at all the time points measured.13,14 Administration of parenteral medications without consent harm the clinician-patient relationship as it can be viewed as punishment rather than treatment by the patient and can potentially cause distress to the patient.8 Parenteral medications without patient consent should only be used if the patient displays a clear risk of harm to themselves or others due to their agitation.8 In most patients, one dose of medication is effective in calming the patient. In the event that a single dose is insufficient, subsequent doses should be administered after enough time has been given for the prior dose to take effect. This length of time varies by the agent and route of administration used as shown in Table 3. Along with this, these medications have a maximum recommended 24-hour dose. Exceeding these increases the risk for adverse effects, particularly oversedation.
Data for treatment of acute agitation in pediatric populations is poor with mostly retrospective studies. Diphenhydramine is commonly for its well-established safety profile and familiarity despite having poor data in pediatric agitation. It also has the potential to cause a paradoxical reaction by worsening agitation. Lorazepam has more evidence but also caries the same risk for paradoxical reaction. Risperidone, olanzapine, chlorpromazine and ziprasidone have some evidence in pediatric populations as well. In general, diphenhydramine (PO/IM), lorazepam (PO/IM), risperidone (PO) or olanzapine (PO) can be used for moderate agitation. Avoid diphenhydramine and lorazepam if the child has a history of paradoxical reactions or diagnosis of autism or developmental disability. For severe agitation, chlorpromazine (PO/IM), olanzapine (IM) and ziprasidone (IM) can be added to the available agents, but diphenhydramine is not recommended in severe agitation due to its poor efficacy data compared to other agents. Dosing can be found in Table 3.
These patients should be treated depending on the cause in a similar manner to adult patients with a few key differences. Doses should be decreased as these patients tend to have slower metabolisms and increased risk for adverse effects. Benzodiazepines should be avoided in most cases unless they are specifically indicated (alcohol withdrawal). Similarly, anticholinergics should be avoided especially in delirium. Patients with Parkinson’s disease or Lewy Body dementia, antipsychotics should be avoided with the exception of low dose quetiapine. Benzodiazepines may be used in these patients at reduced doses if indicated.
Benzodiazepines are associated with cleft lip/palate in the first trimester, and low birth weight/muscle tone and premature births when used in the third trimester. However, these are from studies with long term use. Effects of single doses is not yet fully understood. Antipsychotics used in agitation are not associated with any teratogenic effects but long-term use may cause neonatal withdrawal. Short term use or single doses of antipsychotics can be used safely in acutely agitation pregnant patients
Follow PADIS guidelines to treat ICU specific causes of agitation (pain, delirium, etc.). For acute agitation, one-time doses of antipsychotics can be used. However, in cases of delirium, routine use of antipsychotics does not improve delirium symptoms or duration and may lead to unnecessary prescriptions for antipsychotics at discharge. Dexmedetomidine can be used in mechanically ventilated patients weaning off ventilation.
Adhering to appropriate treatment for acute agitation is an area that in which pharmacists can make an impact. As displayed by the statistics discussed earlier, violence in healthcare work is widespread and appropriately managing agitation can potentially help.1-7 As such, de-escalation should always be performed first prior to medication or restraints/seclusion.10 Unless the patient is severely agitated, an attempt to offer oral medication should be made. If the patient is severely agitated and posing a risk to themselves or others, then parenteral medications can be administered. Restraint and seclusion should be used only as a last resort and for the shortest duration possible11 The medication used should be directed towards the suspected contributing condition and population being treated while keeping safety parameters in mind such as maximum dosing and dosing intervals.1,8 These recommendations are based on the Project BETA guidelines, and these guidelines should be used as a reference when treating acute agitation.1
The MSHP R&E Foundation continues to offer both our Resident Ground Rounds series and our Preceptor Development Series.
Information for the Resident Ground Rounds Series can be found here:
This series is expected to run routinely (approximately every other week) for the next several months. We are excited to bring this offering forward to provide a vehicle for residents within the state to continue to hone their presentations skills as well as share new information with other pharmacy practitioners (pharmacists, technicians, and students) throughout the state. These sessions are available for CE through the Missouri State Board of Pharmacy.
Our next session of our Preceptor Development Series will occur on February 24th and will be titled Enhancing Layered Learning Experiences for Preceptors and Learners. Registration and additional details will be shared in the near future.
R&E Foundation award nominations and poster submissions were due January 14th, 2022. We are busy evaluating these submissions and look forward to contacting the award winners and poster presenters over the next few weeks in preparation for our annual Spring Meeting.
Regarding the Spring Meeting if you, your organization, or other colleagues want to assist in the R&E Foundation fundraising efforts, we will once again be hosting a virtual auction. Of course, if you cannot sponsor a basket, we encourage you to bid on the baskets throughout the meeting later in the year!
Tony Huke, Pharm.D., BCPSMSHP R&E Executive Director
Farah Alhalabi, 2022, PharmD Candidate
Heather Erwin, PharmD, MHA, BCPS
Pneumococcal disease, caused by Streptococcus pneumoniae, can cause many types of illnesses. Most of these are mild, but some are considered invasive and can be fatal, such as meningitis, bacteremia, and pneumonia.1 While pneumococcal disease is very common in children, certain adults can also be at a very high risk. In fact, one in every four to five patients who are 65 years and older die after contracting pneumococcal disease.2 There are two types of vaccines that help prevent pneumococcal disease: pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23).3
PCV13 helps protect against thirteen types of pneumococcal bacteria and is recommended for both children and some adults.3 Regardless of age, patients with immunocompromising conditions or treatment, (such as human immunodeficiency virus, malignancy, or organ transplant), cochlear implant, anatomic or functional asplenia, and sickle cell disease should receive the PCV13 vaccine. In addition, patients with certain higher risk chronic medical conditions, such as chronic renal failure, nephropathy, or cerebral spinal fluid leak, are eligible for the PCV13 vaccine.4
The recommendations for PCV13 in patients without immunocompromising conditions are less specific. In 2014, the Advisory Committee on Immunization Practices (ACIP) recommended routine administration of PCV13 in addition to PPSV23 for all patients 65 years of age or older.5 However, in 2019, ACIP changed its recommendation for patient eligibility in the 65 years of age or older group for PCV13 to a shared decision-making process between patients and healthcare providers. This was largely due to increased pediatric uptake of PCV13 leading to decreased population-based burden and transmission. As a result, providers may be faced with a challenge in determining the best candidates for this vaccination among their patients without immunocompromising conditions.
Per ACIP, herd immunity protecting older individuals is likely impacted by decreasing childhood immunization rates, inadequate access to care in certain communities, or lack of a childhood PCV13 program. Thus, a shared clinical decision is based on individual rather than population level benefits.4 Risk of exposure to PCV13 serotypes and underlying disease(s) that a patient has are important factors to consider when determining the benefit of PCV13 for that individual. The vaccine is indicated for adults 65 years of age or older with medical conditions that can make PCV13 type disease burden higher in this age group. These include chronic medical conditions, such as heart disease, liver disease, and lung disease; diabetes mellitus; and inflammatory bowel disease. In addition, the vaccine is recommended for patients who smoke regularly and drink excessive amounts of alcohol. Moreover, patients who are homeless, those who have had a prior pneumonia, or people living in areas where the risk is much higher (e.g., nursing homes, shelters, and jails) should receive the PCV13 vaccine per ACIP.4 In addition, certain types of medications, such as proton pump inhibitors, antipsychotics, opioids, and sedatives may increase a patient’s risk of contracting pneumonia, so individuals on one or more of these medications may also be candidates to receive the PCV13 vaccine if deemed desirable after a discussion between the clinician and the patient. Lastly, groups at a higher risk of contracting pneumococcal infection, such as frail patients, African Americans, Alaska natives, and American Indians, could also benefit from PCV13 vaccine.4
The CDC recommends that PCV13 be administered first when a patient is eligible. The timing of PPSV23 administration following PCV13 vaccination is age- and indication-dependent and detailed in Table 1. If a patient has received a dose of PPSV23 before and is due for another PPSV23 immunization, they should wait five years until receiving that subsequent dose.2 More guidance on PPSV23 eligibility and administration is available on the CDC website.
Because the changes to eligibility and dosing schedules of PCV13 can be complicated and providers may not always find the time to effectively review the benefits of PCV13 with every patient, pharmacists play a vital role in educating patients and providers about pneumococcal vaccines. Pharmacists can help in identifying patients who are candidates for PCV13, especially patients who are immunocompromised or have chronic health conditions that put them at a greater risk of getting pneumococcal disease. The CDC offers excellent resources for patients and healthcare providers to help guide them toward safe and appropriate vaccination decision-making. Pharmacists and healthcare providers should also involve the patients in making this decision by explaining the benefits of PCV13 based on their conditions or risk factors while taking into consideration values, preferences, and views toward vaccinations.
Authors: Lauren Busch, Pharm.D. Candidate 2022, Michelle Tulchinskaya, Pharm.D. Candidate 2022, and Yvonne Burnett, Pharm.D., BCIDP
Sexually transmitted infections (STIs) or sexually transmitted diseases (STDs) in the U.S. are on the rise with an all-time high reached for the sixth consecutive year. According to the most recent STI surveillance report by the Center for Disease Control and Prevention (CDC), more than 2.5 million cases of chlamydia, gonorrhea, and syphilis were reported in 2019.1 Chlamydia and gonorrhea testing reached its lowest point in early April 2020, which is associated with the rise of the COVID-19 pandemic, with 27,659 chlamydia and 5,577 gonorrhea cases potentially missed.2 Stigma still remains as a major barrier to treatment as well. Knowledge and understanding of STIs help identify the issues and controversies contributing to the stigma created by STI diagnosis and treatment.3 The CDC’s STI treatment guidelines have been updated in July of 2021 with several new recommendations regarding gonorrhea, chlamydia, pelvic inflammatory disease, trichomoniasis, and Mycoplasma genitalium treatment.4 In addition, the CDC provides a thorough discussion of STIs that allow the healthcare team to gain the necessary understanding of the underlying factors surrounding STI stigma.3 As the guidelines had not been previously updated since 2015, it is important for clinicians to be aware of the several new recommendations in order to best serve their patients.
CDC guidelines have previously recommended ceftriaxone 250 mg intramuscularly (IM) plus azithromycin 1 g orally for the treatment of uncomplicated gonococcal infections of the cervix, urethra, and rectum due to high rates of chlamydia co-infection and in order to delay resistance of Neisseria gonorrhoeae to cephalosporins.5 However, the new CDC guidelines recommend ceftriaxone monotherapy as a single 500 mg IM dose (1 g if patient ≥ 150 kg). If chlamydia coinfection has not been ruled out, then doxycycline 100 mg orally twice daily for 7 days should be added. The removal of azithromycin from the treatment regimen is due to increasing concern for growing rates of resistance to azithromycin by N. gonorrhoeae as well as M. genitalium, Shigella, and Campylobacter. Azithromycin is also no longer equally recommended as the preferred treatment for chlamydia alongside doxycycline as discussed below. The increased dose of ceftriaxone is thought to be necessary for N. gonorrhoeae isolates with elevated minimum inhibitory concentrations (MICs). Data shows that even though 250 mg of ceftriaxone is >99% effective in curing anogenital gonorrhea, a higher dose is needed for strains with a higher MIC.4 Ceftriaxone also needs to have a concentration above the MIC for a longer amount of time when treating pharyngeal gonorrhea compared to urogenital gonorrhea, and a 500 mg dose of ceftriaxone allows for about 50 hours above an MIC of >0.03 mcg/mL.6-8
Though other single-dose injectable cephalosporin regimens have been shown to be effective against uncomplicated urogenital and anorectal gonococcal infections in the past, the pharmacokinetics of these regimens have not been evaluated and are at a disadvantage when compared to ceftriaxone 500 mg. Cefixime is still a single oral dose alternative regimen in the new guidelines; however, it is now recommended without azithromycin and the recommended dose has increased to 800 mg.4 From 2006-2011, the minimum concentrations of cefixime needed to inhibit in vitro growth of the N. gonorrhoeae strains circulating increased, demonstrating that cefixime effectiveness may be decreasing.9 Therefore, cefixime should only be used as an alternative if ceftriaxone is not available. Additionally, an alternative regimen for patients allergic to cephalosporins is gentamicin 240 mg IM plus azithromycin 2 g orally as a single dose.4
The preferred treatment regimen for chlamydia among adolescents and adults is now doxycycline 100 mg orally twice daily for 7 days.4 Azithromycin 1 g orally in a single dose, previously a recommended regimen, is now only recommended as an alternative regimen for pregnant patients.4,5 This change is due to concern regarding the efficacy of azithromycin in treating rectal chlamydia infections.4 The presence of rectal chlamydia cannot be predicted based on sexual practices. Inadequately treated rectal Chlamydia trachomatis infection can increase the risk for transmission and put women at risk for repeat urogenital C. trachomatis infection through autoinoculation from the anorectal site. Treatment failure among men was higher for azithromycin than doxycycline, and other studies found that for rectal chlamydia infection among men who have sex with men (MSM) reported microbiologic cure of 100% with doxycycline vs. 74% with azithromycin.10-15 Azithromycin may be used when non-adherence to doxycycline is a concern, but might require post-treatment evaluation and testing due to lower effectiveness in treating rectal infection. Erythromycin is also no longer recommended as an alternative agent due to the frequency of gastrointestinal adverse effects that can result in non-adherence.4
Pelvic Inflammatory Disease
The recommended treatment of pelvic inflammatory disease (PID) was updated to include metronidazole, while previously it was optional.4,5 Metronidazole has been shown to more effectively eradicate anaerobic organisms in the upper genital tract, which helps prevent long-term side effects such as infertility and ectopic pregnancies.16 A new recommended parenteral regimen consists of ceftriaxone 1 g intravenously (IV) every 24 hours plus doxycycline 100 mg orally or IV every 12 hours plus metronidazole 500 mg orally or IV every 12 hours.4 Cefotetan plus doxycycline and cefoxitin plus doxycycline are still recommended parenteral regimens; however, clindamycin plus gentamicin is now only recommended as an alternative parenteral regimen along with ampicillin/sulbactam and doxycycline.4,5 The guidelines recommend transitioning to oral therapy, after 24-48 hours of clinical improvement with parenteral therapy, with a single dose of ceftriaxone 500 mg IM plus doxycycline 100 mg PO BID and metronidazole 500 mg PO BID for a total treatment duration of 14 days.4 The updated guidelines recommend doxycycline with the addition of metronidazole as these regimens have demonstrated improved prevention of long-term complications associated with PID.4,5
Recommendations for the treatment of trichomoniasis have also changed between the 2015 and 2021 guidelines. Previously, metronidazole 2 g orally or tinidazole 2 g orally as a single dose was preferred, with metronidazole 500 mg orally twice daily for 7 days as an alternative regimen.5 Now, the guidelines recommend metronidazole 500 mg PO BID for 7 days for women and metronidazole 2 g PO as a single dose only for men with tinidazole 2 g PO as a single dose as the alternative for both men and women.4 The change in recommendations comes from new data that demonstrates multi-dose metronidazole is more effective than the 2 g-single dose in women.17 There is currently no data comparing the different dosing regimens of metronidazole in men, so the 2 g-single dose is still preferred in this population.4
The treatment ofMycoplasma genitalium was only addressed in the setting of urethritis, cervicitis, and PID in the previous guidelines. The 2015 guidelines stated azithromycin 1 g PO was preferred over the 7-day PO doxycycline course; however, azithromycin resistance was identified to be on the rise. Moxifloxacin 400 mg daily PO for 7 days was also mentioned as a treatment with a few cases of success, but was not yet tested in clinical trials.5 The current CDC guidelines give the first official recommendations for the treatment of Mycoplasma genitalium. The guidelines recommend against the use of a single dose of 1 g azithromycin due to high rates of macrolide resistance with treatment failures. Treatment should use macrolide resistance-guided therapy. If macrolide sensitive, doxycycline 100 mg PO BID for 7 days, followed by a 1 g PO dose of azithromycin, then azithromycin 500 mg PO daily for 3 more days is recommended. If the strain is resistant to macrolides, doxycycline 100 mg PO BID for 7 days followed by moxifloxacin 400 mg PO daily for 7 days is recommended. If resistance testing is not available (currently not available in the U.S.), it is recommended to treat as if the M. genitalium is macrolide resistant. Doxycycline is included in treatment regimens because it is thought to reduce the organism load and help with clearance of the organism. The new guidelines state that PID treatment regimens are not effective against M. genitalium; therefore, after initial treatment of PID with doxycycline 100 mg PO BID for 14 days, if M. genitalium is detected, moxifloxacin 400 mg PO daily for 14 more days is recommended. The guidelines also updated to recommend a newly FDA-cleared nucleic acid amplification test (NAAT) to test for M. genitalium in men with recurrent non-gonococcal urethritis, women with recurrent cervicitis, and to be considered for women with PID.4
Overall, the 2021 CDC STI treatment guidelines contain several updates regarding not only treatment recommendations, but also diagnostic and screening recommendations.4 Clinicians must be aware of these new updates to best treat their patients due to evolving resistance patterns and new evidence since 2015. The updated guidelines also emphasize the importance of primary prevention of STIs through assessing behavior risk and biologic risk and routinely asking about sexual histories using effective counseling skills.4 With the COVID-19 pandemic potentially hindering patients’ access to screening and treatment, clinicians must be prepared with the knowledge of new treatment recommendations and with effective counseling strategies for when patients are able to seek care.
Authors: Kitana Caesar, PharmD Candidate 2022 and Gabrielle Gibson, PharmD, BCPS, BCCCP
Open fractures are injuries frequently seen in emergency departments or trauma centers. Typically, the skin barrier has been compromised, exposing the sterile bone to environmental debris and soft tissue damage. Exposure to the ambient environment places these wounds at an increased risk of infection.1 The Gustilo-Anderson classification system is utilized to grade the severity of open fractures, and to determine appropriate antibiotic prophylaxis (Table 1). The infection rates for grade I/II fractures range from 0 to 7% whereas the grade III fracture infection rate ranges from 5 to 50% without antibiotic prophylaxis.3 Ineffective prophylaxis may lead to complications such as nonunion of bones and osteomyelitis.2 In fact, 19% of osteomyelitis cases are secondary to traumatic injury. As such, the use of antibiotic prophylaxis to decrease the rate of infective complications after open fractures has been considered standard of care for over 30 years.
As with many historic practices, the justifications for the use of antibiotics have become obscured over time. Recent studies have been based on the standards established by a few key papers with no re-evaluation of the application of those principles in the setting of modern open fracture management nor today’s antibiotic and bacterial resistance patterns. As a result, open fracture antibiotic prophylaxis is currently defined and instituted variably, and evaluation of recommended approaches has been slowed by reluctance to challenge familiar practice patterns. Further complicating standardization is the lack of recommendations for a specific antibiotic and dose combination in open fracture guidelines.1,4 Therefore, this review will aim to analyze antibiotic prophylaxis regimens as well as suggested durations of therapy.
The most common pathogens involved in grade I/II fractures include Gram-positive bacteria (e.g.: Streptococcus spp. and Staphylococcus spp.).1 Patients presenting with grade III fractures and exposure to certain environmental factors are predisposed to infections involving Gram-negative bacteria (e.g.: Enterobacter cloacae and Pseudomonas aeruginosa).1 Increased presence of methicillin resistant Staphylococcus aureus (MRSA) occurs in patients with prior MRSA infection, prior MRSA nasal carriage, wounds present on admission, nursing home residents, recent prolonged health system exposure, and comorbidities, including diabetes or heart failure.5 Prophylactic antibiotic regimens should therefore be tailored to the severity of the fracture and the environment in which the fracture took place. The Eastern Association for the Surgery of Trauma (EAST) guidelines recommend that antibiotic coverage be directed at Gram-positive organisms and additional Gram-negative coverage be added for grade III fractures.1 The Surgical Infection Society (SIS) guidelines recommend first-generation cephalosporins be initiated as soon as possible but make no recommendations for gram-negative or clostridial coverage (Table 2).4
The aforementioned antibiotic recommendations largely originated from a study by Patzakis and colleagues published in 1974.6 This randomized, placebo-controlled trial was the first to examine infection rates in open fractures in relation to antibiotic use and as such, it continues to impact practice today. This study included 310 patients with open fractures (not graded for severity) over a one year period. Patients were randomized to three groups: no antibiotics, penicillin and streptomycin (aminoglycoside), or cephalothin (first-generation cephalosporin with a spectrum of activity similar to cefazolin) for 10–14 days. The study found that patients receiving cephalothin had a lower incidence of infection (2.4%) than the penicillin/streptomycin group (9.8%) and the control group (13.9%), with statistical significance between placebo and cephalothin groups only.6 These data provided strong evidence for the efficacy of first-generation cephalosporins in managing open fractures. In the same study, the investigators described the bacteria that caused the fractures to become infected. In the placebo group, the isolated organisms included Gram-positive, Gram-negative, and rarely Clostridium spp. The penicillin/streptomycin group developed infections with Staphylococcus aureus and Enterobacterales including Pseudomonas spp., whereas the cephalothin group demonstrated infections with gram-negative species.6 These findings led the authors to suggest that combination streptomycin and a cephalosporin would reduce infection rates further. However, this hypothesis was never tested and remains an extrapolation unsupported by the data. Nonetheless, conclusions from this study have been cited for over 30 years.
Therefore, the current recommended antibiotic for all fracture grades is a cephalosporin (including first-, second-, and third-generation). Expanded Gram-negative coverage is recommended for grade III fractures if a first- or second-generation cephalosporin is selected, and additional anaerobic coverage is needed if the fracture is contaminated with soil or fecal matter. Guidelines do not recommend a specific Gram-negative agent, but aminoglycosides are widely used for prophylaxis in open fractures. Recently, the use of aminoglycosides has fallen out of favor due to nephrotoxicity and ototoxicity. A study by Bankhead-Kendall and colleagues evaluated 126 grade III fractures at their institution over a 5-year period.7 Antibiotic prophylaxis was based on the treating surgeon’s preferences, and roughly half (52%) were treated with a first-generation cephalosporin, while the other half (48%) were treated with the addition of an aminoglycoside. No difference was observed in surgical site infection, but there was a statistically significant increase in acute kidney injury in those treated with an aminoglycoside.7 Currently, there is insufficient evidence to support routine gram-negative coverage in prophylaxis for all open fractures.4 Additionally, in the event of a true allergy to cephalosporins, clindamycin and aztreonam may be considered for gram-positive and gram-negative coverage.1 Vancomycin is reasonable to add if patients have risk factors for a MRSA infection (Table 2).
A study by Rodriguez and colleagues evaluated a new protocol that was implemented at their institution. This pre- and post-protocol implementation analyzed 174 patients (101 pre-protocol and 73 post-protocol) with open fracture and stratified groups according to Gustilo-Anderson fracture grade, fracture site, and persistence of resistant organisms. Patients with grade I/II fractures received cefazolin while patients with grade III fractures received ceftriaxone for 48 hours. Aminoglycosides, penicillin, and vancomycin were removed from the post-protocol. There was no difference in skin or soft tissue infection rate per fracture before or after protocol implementation (20.8% vs 24.7%, p=0.58). The authors concluded that implementation of an evidence-based, narrow spectrum antimicrobial prophylaxis protocol resulted in similar infection rates.3 This was one of the first trials to challenge the use of broad-spectrum antibiotics and aminoglycosides when potentially less toxic and narrower agents could be considered.
The duration of antibiotic prophylaxis is a crucial aspect in the management of open fractures. The SIS and EAST guidelines recommend starting antibiotics immediately following injury in all fracture types.1,4 Antibiotics are continued for 24-72 hours depending on the severity of the open fracture and the time soft tissue coverage occurs. For grade III fractures, the EAST guidelines suggest continuing antibiotics for 72 hours after injury but not greater than 24 hours from the time soft tissue coverage is achieved.1 Chang et al demonstrated through a meta-analysis that infection rates between longer durations (3-5 days) and shorter duration (1 day) of antibiotics were no different. However, there was significant risk of bias present considering the included publications were largely provider-reported reviews of practice recommendations whose focus was not antibiotics.8 The SIS guidelines suggest that 48 hours of therapy may be appropriate in grade II fractures, but longer courses of antibiotics do not reduce the risk of infection and can lead to the development of drug resistant organisms and increased adverse effects.4,9 Accordingly, a duration of 24 hours for all fracture types is considered adequate prophylaxis, with special consideration for longer durations (up to 72 hours) in higher grade fractures.
Open fractures of all grades have a risk of infection, and patients benefit from antibiotic prophylaxis. Differences in the recommended antibiotic regimen and durations persist and understandably, optimal prophylactic antibiotic therapy may be dependent on the context of the injury. Although there are limited data supporting the efficacy of narrow-spectrum antibiotics for shorter durations of therapy, developing a unified approach regarding optimal therapy and duration for open fracture antibiotic prophylaxis will require a large, randomized trial.