New-Generation Cephalosporins

Since their discovery in the 1950s, cephalosporins have become one of the largest classes of antibiotics. The class is divided into generations or subclasses, which are grouped by chemical properties and subsequent generalized microbiologic spectra.

Cephalosporins have been used to treat a variety of infections, from mild to life-threatening; however, like all antibiotics, resistance has been identified in bacteria. This typically occurs when the medications bind to an active site serine that is located on all functional penicillin-binding proteins (PBPs). The resulting inactive enzyme slowly hydrolyzes the antibiotic so that it forms an inactive entity compared with the bacteria.1

To address antibacterial resistance, the Generating Antibiotic Incentives Now provision of the FDA Safety and Innovation Act (FDASIA; Public Law 112-144) created the designation of “qualified infectious disease products” (QIDPs).2 This status is granted to agents that are intended to treat dangerous or life-threatening infections caused by resistant, novel, or emerging pathogens or those listed within the FDASIA. The agents receive an additional 5 years of patent exclusivity and priority and fast-track FDA review. In 2015, ceftolozane/tazobactam (Zerbaxa) became the fourth and ceftazidime/avibactam (Avycaz) became the fifth QIDP to receive FDA approval.3,4 Together, these new cephalosporins have been referred to as fifth-generation cephalosporins, or new-generation cephalosporins (NGCs).

PHARMACOLOGY
Both NGCs are bactericidal agents that bind to PBPs, the essential enzymes involved in the final step of cell wall biosynthesis in both Gram-positive and Gram-negative organisms. 1,3,4 Each is attached to a beta-lactamase inhibitor that does not possess clinically relevant in vitro activity against bacteria but does serve to protect the cephalosporin from degradation. Tazobactam, combined with the novel cephalosporin ceftolozane, is an irreversible inhibitor of class A penicillinases and class C cephalosporinases and forms covalent bonds to some chromosomal and plasma-mediated beta-lactamases. 2,6 Avibactam, a novel beta-lactamase inhibitor combined with ceftazidime, the established third-generation cephalosporin, inhibits class A penicillinases, extended-spectrum beta-lactamases (ESβLs), class C cephalosporinases, class D oxacillinases, and serine carbapenemases.1,5,7

MICROBIOLOGY
Ceftolozane/tazobactam and ceftazidime/avibactam have shown efficacy against a large number of pathogens. Both NGCs demonstrate in vitro activity against enterobacteriaceae in the presence of certain beta-lactamases and ES Ls and are effective against Pseudomonas aeruginosa, including some resistant isolates.6,7 Only ceftazidime/avibactam, however, is effective against Klebsiella pneumoniae carbapenemases. 7 Ceftolozane/tazobactam also has shown efficacy against Streptococcus species and the anaerobic pathogens Bacteroides fragilis and Fusobacterium species.6 Neither NGC is effective against the Enterococcus species and therefore may not provide adequate empiric coverage for all patients with a nitrate-negative urinalysis.

THERAPEUTIC USE
The NGCs are FDA approved for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intraabdominal infections (cIAIs).6,7 cIAIs include intraabdominal abscesses, peritonitis, gastric or duodenal perforation, intestinal perforation, appendicitis, cholecystitis, and diverticulitis. When treating cIAIs, metronidazole must be used with the NGCs to provide coverage against anaerobic organisms. The NGCs should be used only in patients 18 years old or older, when treating infections known or strongly suspected to be caused by susceptible organisms, and reserved for patients with no or limited antibacterial alternatives.

DOSING AND ADMINISTRATION
NGCs are parenteral antibiotics that are administered every 8 hours to adult patients with a creatinine clearance >50 mL/min.6,7 Dosing for each antibiotic is the same for the 2 approved indications. Ceftazidime/avibactam 2.5 g (2 g/0.5 g) should be infused during a 2-hour period, whereas ceftolozane/tazobactam 1.5 g (1 g/0.5 g) only requires a 1-hour infusion. The dose of ceftolozane/tazobactam is reduced with declining kidney function (creatinine clearance ≤50 mL/min), but the 8-hour frequency is unchanged. In contrast, decreased dosing and extended interval frequency are required for ceftazidime/avibactam when the creatinine clearance is ≤50 mL/min.

The duration of therapy differs between the 2 agents and by indication. A cUTI should be treated for at least 7 dayswith either NGC, although it may require up to 14 days with ceftazidime/avibactam.6,7 Patients with a cIAI should receive ceftolozane/tazobactam for 4 to 14 days or ceftazidime/ avibactam for 5 to 14 days. When used to treat cIAI, intravenous metronidazole 500 mg every 8 hours also should be administered.

COMPARATIVE EFFICACY
To the author’s knowledge, no head-to-head studies between the 2 NGCs have been conducted. The approvals of both NGCs for cIAIs were based on the results of similar large clinical trials of hospitalized patients in which the NGC plus metronidazole was compared with meropenem.6,7

Ceftolozane/tazobactam was evaluated in a multinational noninferiority study of 979 patients that assessed clinical response, defined as complete resolution or significant improvement in signs and symptoms of the infection 24 to 32 days after the first dose of the study drug.6 Ceftolozane/ tazobactam plus metronidazole was shown to be noninferior to meropenem in clinical response (83% vs 87.3%; observed difference, −4.3% [95% CI, −9.2% to 0.7%]). A subanalysis of Escherichia coli and K pneumoniae isolates used genotypic testing to identify ESβL groups in 9% of isolates, with clinical cure rates being similar between the groups.

Ceftazidime/avibactam also was evaluated in a multinational noninferiority study in combination with metronidazole compared with meropenem alone.7 The study enrolled 1058 patients to evaluate clinical cure, which had the same definition as previously noted for clinical response, but was evaluated at 28 to 35 days after enrollment. Ceftazidime/avibactam plus metronidazole also was shown to be noninferior to meropenem alone (81.6% vs 85.1%; observed difference, −3.5% [95% CI, −8.6% to 1.6%]). A subanalysis of genotypic testing for ESβLs also was conducted, with cure rates continuing to be similar between the 2 groups.

Ceftolozane/tazobactam was approved by the FDA for the treatment of cUTIs based on a multinational study of 1068 patients that compared cephalosporin with levofloxacin for 7 days.8 The primary endpoint was complete resolution or marked improvement of clinical symptoms and microbiological eradication at 7 days after the last dose of the medication. Ceftolozane/tazobactam was shown to have better efficacy compared with levofloxacin (76.9% vs 68.4%; observed difference, 8.5% [95% CI, 2.3%-14.6%]), but 26.5% of patients had isolates that were resistant to levofloxacin. Among the patients with levofloxacin-sensitive organisms, efficacy was similar between the 2 antibiotics (82.6% vs 79.7%; no 95% CI provided).

The approval of ceftazidime/avibactam for cUTIs was granted predominantly based on the results of previous studies on the efficacy and safety of ceftazidime alone forcUTIs7; the contribution of avibactam to the efficacy of the medication was supported by in vitro and animal studies.7 Ceftazidime/avibactam was compared with imipenem-cilastatin in a phase 2 randomized multicenter study of hospitalized patients with cUTIs caused by Gram-negative organisms. 9 The cure’s effectiveness was evaluated in 62 patients who were microbiologically evaluable 5 to 9 days after therapy, with a favorable microbiologic response similar between the groups (70.4% vs 71.4%; observed difference, −1.1% [95% CI, −27.2% to 25%]).

Ceftazidime/avibactam also was compared with doripenem in a postapproval phase 3 noninferiority study for 10 days (up to 14 days, if bacteremia was detected) in 1033 patients with cUTIs.10 Ceftazidime/avibactam was shown to be noninferior to doripenem in patient-reported symptomatic resolution at day 5 (70.2% vs 66.2%; observed difference, 4% [95% CI, −2.39% to 10.42%]) and combined symptomatic resolution and microbiological eradication at test of cure (71.2% vs 64.5%; observed difference, 6.7% [95% CI, 0.3%-13.12%]).

ADVERSE EFFECTS
Adverse effects (AEs) with NGCs typically are mild, but there are several common and serious AEs worth noting. Both agents cause nausea and diarrhea in ≥5% of patients.6-10 Ceftazidime/avibactam also may cause constipation, diarrhea, abdominal pain, dizziness, or anxiety.7 Ceftazidime alone has been associated with more serious central nervous system (CNS) AEs, including seizures, encephalopathy, and coma.7 AEs with ceftolozane/tazobactam include headache and pyrexia.6

DRUG–DRUG INTERACTIONS
Minimal drug–drug interactions have been observed with the NGCs. Both tazobactam and avibactam are substrates of organic anion transporter 1 (OAT1) and OAT3 kidney transporters.6,7 Probenecid, an inhibitor of these transporters, can prolong the half-life of the beta-lactamase inhibitors, and coadministration is not recommended. Cytochrome activity is not affected at clinically relevant blood concentrations, but at supratherapeutic blood concentrations, tazobactam may inhibit cytochrome P450 1A2 (CYP1A2), CYP2D6, and CYP3A4, and avibactam may induce CYP2E1.

SAFETY ISSUES

Ceftolozane/tazobactam and ceftazidime/avibactam are less effective in patients with a baseline creatinine clearance of 30 to ≤50 mL/min.6,7 Creatinine clearance should be monitored daily in patients receiving these antibiotics, and alternative agents, if available, against the target organism should be considered in patients whose kidney function fallsconsistently within these parameters. Studies of both NGCs reported more AEs in geriatric patients.6,7 Clostridium difficile- associated diarrhea has been reported with both agents, with severity ranging from mild to fatal.6,7 Caution should be exercised when determining whether to use either antibiotic in a patient with a penicillin or other beta-lactamase allergy because of the risk of cross-reactivity.

Serious CNS reactions are known to occur with ceftazidime, especially in patients with decreased kidney function.7 Reactions include seizures, encephalopathy, coma, asterixis, myoclonia, and neuromuscular excitability. Ceftazidime/ avibactam should be avoided in patients with other risk factors for these CNS effects whenever possible. However, if the combination must be used in patients with a creatinine clearance ≤50 mL/min, then the dosage should be adjusted to lessen the risk of CNS reactions.7

Both NGCs should be protected from exposure to light.6,7 Ceftazidime/avibactam can be stored at a controlled roomtemperature (77°F, with excursions 59°-86°F permitted).7 Once mixed in fluid, it is stable for 12 hours at temperatures ranging from 68° to 77°F and for 24 hours if refrigerated. Ceftolozane/tazobactam should be refrigerated until it is reconstituted. After dilution, ceftolozane/tazobactam can be stored at room temperature for a maximum of 24 hours or in the refrigerator for up to 7 days.6

References

Bush K, Bradford PA. β-lactams and β-lactamase Inhibitors: an overview. Cold Spring Harb Perspect Med. 2016;6(8). doi: 10.1101/cshperspect.a025247.
Frey P. FDA Safety and Innovation Act. Paper presented at: FDA Small Business Regulatory Education for Industry conference; June 19, 2016;
FDA approves new antibacterial drug Zerbaxa. Arlington, VA: Infectious Diseases Society of America; December 19, 2014. idsociety.org/FDA_20141222/. Accessed June 7, 2017.
FDA approves new antibacterial drug Avycaz. Silver Spring, MD: FDA; February 26, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435629.htm. Accessed August 26, 2016.
Wang DY, Abboud MI, Markoulides MS, Brem J, Schofield CJ. The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam. Future Med Chem. 2016;8(10):1063-1084. doi: 10.4155/fmc-2016-0078.
Zerbaxa [prescribing information]. Whitehouse Station, NJ: Merck & Co; 2015.
Avycaz [prescribing information]. Cincinnati, OH: Forest Pharmaceuticals; 2.016
Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind phase 3 trial (ASPECT-cUTI). Lancet. 2015;385(9981):1949-1956. doi: 10.1016/S0140-6736(14)62220-0.
Vasquez JA, González Patzán L, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective investigator-blinded, randomized study. Curr Med Res Opin. 2012;28(12):1921-1931. doi: 10.1185/03007995.2012.748653.

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ጤናአዳም (Rue)

Species Name፡   Ruta chalepensis

Family Name፡   Rutaceae

Synonym   Ruta bracteosa

Amharic Name፡   Tenadam; Tena Adam

Amharic Name፡ (Ge’ez)

English Name፡   Rue

To Ethiopia፡   Indigenous

Description

Ruta is an old Latin name for the rue plant. It means bitterness, unpleasantness, which may refer to the strong smell and taste of rue. In ancient Greece and Egypt, rue has been used for medicinal purposes. Ruta chalepensis L. (Syn: Ruta bracteosa). (Rutaceae). Tenadam, Tena Adam, Tienadam, Teinadam (Amh). Herb of Grace, Rue (Eng). This is the common rue found in Ethiopia. This spice plant is widely cultivated as a culinary herb to flavor milk, cottage cheese, coffee and tea and a local beverage, called Kuti. It is also used in the preparation of Berbere. The Amharic name “Tena Adam” means “Health for Adam”. A decoction of plant parts, mixed with tea, is drunk against headache, cold, heart-pain, earache and intestinal disorders. The root extract of Ruta chalepensis yields the alkaloids chaloridone, skimmianine, kokusaginine and graveoline with the coumarins rutalpinin, chalepin and chalepensin. More uses of Ruta chalepensis and Ruta graveolens in Ethiopia: for treating taeninsis, ascariasis, diarrhea, anthelminthic (Source: Fekadu Fullas, 2006, Interaction of Ethiopian Herbal Medicine and Spices with Conventional Drugs).

10 Black Box Warnings Every Pharmacist Should Know

Black box warnings are the strictest labeling requirements that the FDA can mandate for prescription drugs.

First implemented in 1979, black box warnings highlight serious and sometimes life-threatening adverse drug reactions within the labeling of prescription drug products. These safety concerns are generally identified through the FDA’s Adverse Event Reporting System and Office of Surveillance and Epidemiology, which evaluates postmarket safety data. Sometimes, however, a black box warning is handed down right at the time when a new drug is approved.

How often are drugs with black box warnings prescribed? One study found that within a 30-month period, more than 40% of patients within an ambulatory care setting received at least 1 medication that carried a black box warning for a serious adverse drug reaction that could potentially affect them.1

Although black box warnings are not necessarily absolute contraindications, pharmacists should be aware of these safety concerns when counseling patients and making recommendations to physicians. Every pharmacist should be familiar with the following black box warnings.

  1. Brilinta Raises Bleeding Risk

Ticagrelor (Brilinta) received FDA approval in 2011 to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction.

Like other antiplatelet agents, Brilinta has a black box warning for causing significant and sometimes fatal bleeding. The package labeling states that Brilinta should be avoided in patients with active pathological bleeding or a history of intracranial hemorrhage.

Brilinta’s labeling also states that concomitant maintenance doses of aspirin should not exceed 100 mg. During a pivotal trial, maintenance doses of aspirin greater than 100 mg were shown to decrease the effectiveness of Brilinta.

  1. Linzess Should Not Be Used in Children

Linaclotide (Linzess) is a guanylate cyclase C (GC-C) agonist indicated for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

According to the prescribing information, Linzess is contraindicated in pediatric patients younger than 6 years and should be avoided in those aged 6 through 17 years.

In nonclinical studies, administration of a single adult dose of Linzess in young juvenile mice caused increased fluid secretion and more deaths from dehydration as a result of GC-C agonism. Because of increased intestinal expression of GC-C, children younger than 6 years may be more likely to develop significant diarrhea than older children and adults.

  1. Tygacil Increases All-Cause Mortality

Tigecycline (Tygacil) is an injectable tetracycline antibiotic that was approved by the FDA in 2005. The drug carries a black box warning for increasing all-cause mortality, as it was higher in patients treated with Tygacil than comparators in a meta-analysis of phase 3 and 4 clinical trials.

Although the cause of the 0.6% difference in mortality risk (95% CI 0.1, 1.2) has not been established, the deaths generally resulted from worsening infection, complications of infection, or underlying comorbidities. As a result, Tygacil’s labeling states it should be reserved for use in situations when alternative treatments are not suitable.

  1. Lamictal Causes Serious Skin Reactions

Lamotrigine (Lamictal) is an antiepileptic drug indicated for the treatment of epilepsy and bipolar disorder.

Lamictal has a black box warning for causing cases of life-threatening serious rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death. The rate of serious rash has been greater in pediatric patients than adults.

Additional factors that may increase the risk of rash include coadministration with valproate and exceeding the recommended initial dose or dose escalation of Lamictal.

Although Lamictal may also cause benign rashes, the prescribing information states that it is not possible to predict which rashes will prove to be serious or life-threatening. Therefore, the medication should be discontinued at the first sign of rash, unless it is clearly not drug-related.

  1. Cigarette Smoking Raises Risk of Serious Cardiovascular Events from Combination Oral Contraceptives

Combination oral contraceptives such as Alesse, Beyaz, Loestrin, Ocella, Yaz, and Zarah include an estrogen and a progestin to prevent pregnancy.

Because cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use, the package labeling warns women older than 35 years who smoke to avoid the products. Of note, this risk increases with age and the number of cigarettes smoked.

  1. Fluoroquinolones Increase Risk of Tendon Rupture

Fluoroquinolones such as levofloxacin and ciprofloxacin are associated with an increased risk of tendinitis and tendon rupture in patients of all ages.

This adverse reaction most frequently involves the Achilles tendon, which may require surgical repair. Tendinitis and tendon rupture in the rotator cuff, hand, biceps, thumb, and other tendon sites have also been reported.

This risk is further increased in patients older than 60 years, those taking corticosteroid drugs, and patients who have undergone kidney, heart, or lung transplants. Tendon rupture can occur during or after completion of therapy, as cases occurring up to several months after completion of therapy have been reported.

According to the package labeling, fluoroquinolones should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and then contact their health care provider about potentially switching to a different antimicrobial drug class.

  1. Methadone Raises Risk of Respiratory Depression and QT Interval Prolongation

Methadone is a synthetic opioid analgesic indicated for the treatment of moderate to severe pain, as well as the detoxification or maintenance treatment of opioid addiction.

The drug has a black box warning for increasing the risk of respiratory depression and QT interval prolongation. The package labeling states that cardiac and respiratory death has been reported during methadone initiation and conversion from other opioid agonists.

Respiratory depression is the chief hazard associated with methadone administration. The drug’s peak respiratory depressant effects typically occur after administration and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of drug overdose, particularly during treatment initiation and dose titration.

In addition, cases of QT interval prolongation and serious arrhythmia have been observed during methadone treatment. Most cases involve patients who were treated for pain with large, multiple daily doses of methadone, although cases have also been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.

The prescribing information states that methadone for analgesic therapy in patients with acute or chronic pain should only be initiated if the drug’s potential analgesic or palliative care benefit outweighs the risks.

  1. Actos and Avandia Cause or Exacerbate Congestive Heart Failure

Pioglitazone (Actos) and rosiglitazone (Avandia) are thiazolidinediones indicated for the treatment of type 2 diabetes mellitus. Both medications have been shown to cause or exacerbate congestive heart failure in some patients due to dose-related fluid retention.

The drugs’ package labeling recommends monitoring patients for signs and symptoms of heart failure after initiation and dose increases. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the medications must be considered.

  1. Atypical Antipsychotics Increase Risk of Death in Elderly Patients with Dementia-Related Psychosis

In 2005, the FDA issued a black box warning for atypical antipsychotics, including quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone

(Risperdal), stating that elderly patients with dementia-related psychosis who are treated with these drugs face an increased risk of death.

Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed that drug-treated patients had between 1.6 to 1.7 times the risk of death of placebo-treated patients. Although the causes of death varied, most appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature.

Observational studies have suggested that treatment with conventional antipsychotic drugs may also increase mortality. However, the package inserts acknowledge that the extent to which these findings may be attributed to the antipsychotic as opposed to patient characteristics is not clear.

  1. Antidepressants Raise Suicidality Risk2

In 2004, the FDA issued a black box warning for all antidepressants indicating an association with an increased risk of suicidal thinking, feeling, and behavior in young individuals.

This decision stemmed from a series of meta-analyses of 372 randomized clinical trials involving nearly 100,000 participants, which showed that the rate of suicidal thinking or suicidal behavior was 4% among patients assigned to receive an antidepressant, compared with 2% among those assigned to receive placebo. Subsequent age-stratified analyses showed that this increased risk was significant only among children and adolescents younger than 18 years, as there was no evidence of increased risk among adults older than 24 years, including those older than 65 years.

According to the package labeling for antidepressants, patients of all ages who are started on antidepressant therapy should be monitored closely for emergence and worsening of suicidal thoughts and behaviors. Additionally, families and caregivers should be advised of the need for close observation and communication with the prescriber.

The FDA’s decision to implement this black box warning was controversial. Many members of the medical community worried that it would do more harm than good by discouraging patients from seeking help and discouraging physicians from prescribing antidepressants when clinically indicated.

References

Wagner AK, Chan KA, Dashevsky I, et al. FDA drug prescribing warnings: is the black box half empty or half full? Pharmacoepidemiol Drug Saf. 2006 Jun;15(6):369-86.

Friedman R. Antidepressants’ Black-Box Warning – 10 Years Later. N Engl J Med. 2014; 371:1666-1668October 30, 2014DOI: 10.1056/NEJMp1408480.