130
Views
19
CrossRef citations to date
0
Altmetric
Review

Ceftazidime/avibactam: a novel cephalosporin/nonbeta-lactam beta-lactamase inhibitor for the treatment of complicated urinary tract infections and complicated intra-abdominal infections

, &
Pages 2379-2386 | Published online: 26 Jul 2016

Abstract

There has been greater interest in developing additional antimicrobial agents due to the increasing health care costs and resistance resulting from bacterial pathogens to currently available treatment options. Gram-negative organisms including Enterobacteriaceae and Pseudomonas aeruginosa are some of the most concerning threats due to their resistance mechanisms: extended-spectrum beta-lactamase production and Klebsiella pneumoniae carbapenemase enzymes. Ceftazidime is a third-generation broad-spectrum cephalosporin with activity against P. aeruginosa and avibactam is a novel nonbeta-lactam beta-lactamase inhibitor. Avycaz®, the trade name for this new combination antibiotic, restores the activity of ceftazidime against some of the previously resistant pathogens. Avycaz was approved in 2015 for the treatment of complicated urinary tract infections, including pyelonephritis, and complicated intra-abdominal infections with the addition of metronidazole in patients with little to no other treatment options. This review article assesses the clinical trials and data that led to the approval of this antibiotic, in addition to its spectrum of activity and limitations.

Introduction

Increasing resistance to currently available antimicrobial agents has prompted a renewed interest in developing additional agents. According to the World Health Organization’s (WHO) Global Report on Surveillance, five out of six WHO regions reported >50% resistance of Escherichia coli against third-generation cephalosporins and six out of six WHO regions reported equivocal resistance rates of Klebsiella pneumoniae against third-generation cephalosporins.Citation1 Within the hospital setting, there has been increasing rates of resistance against some of the most common pathogens that cause complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs), which have resulted in longer lengths of stay and increased hospital costs.Citation2

According to the United States Centers for Disease Control, some of the most concerning threats to antibiotic resistance include carbapenem-resistant Enterobacteriaceae, extended-spectrum beta-lactamase-producing Enterobacteriaceae, and multidrug resistant Pseudomonas aeruginosa.Citation3 These gram-negative organisms are responsible for several infections including cIAIs and cUTIs. The mechanism of resistance of Enterobacteriaceae species and P. aeruginosa is primarily caused by their production of extended-spectrum beta-lactamases and K. pneumoniae carbapenemase (KPC) enzymes. The production of these enzymes renders the current beta-lactamase inhibitors ineffective against these resistant gram-negative pathogens.Citation3,Citation4 Before ceftazidime/avibactam, the primary drug of choice for KPC infection was polymyxin, which has been known to have a severe side effect profile.Citation5

Ceftazidime/avibactam (Avycaz®) is a combination cephalosporin and beta-lactamase inhibitor that was approved in February 2015.Citation6 The presently available beta-lactamase inhibitors are ineffective against Ambler Class A carbapenemases and Class C enzymes.Citation7Citation9 Avibactam, formerly known as NXL104, is a nonbeta-lactam beta-lactamase inhibitor that has potent activity against most Ambler Class A enzymes, which include narrow and extended-spectrum beta-lactamases and some carbapenemases, Ambler Class C enzymes, which include extended spectrum cephalosporinases, and some Class D enzymes, which include carbapenemases.Citation10 In this article, the clinical microbiology, pharmacology, and the most recent clinical data on ceftazidime/avibactam (two Phase I, two Phase II, and Phase III trials)Citation11Citation15 are discussed.

Clinical microbiology

Avibactam has activity against extended-spectrum beta-lactamases, including K. pneumoniae-producing carbapenemases, Class A enzymes, and extended-spectrum cephalosporinases that contain the AmpC gene, which are Class C enzymes.Citation16 Avibactam also has some activity against carbapenemases produced from the OXA gene, which are Class D enzymes. Ceftazidime has broad-spectrum activity against gram-negative bacteria including P. aeruginosa. Consequently, the addition of avibactam to ceftazidime increases the spectrum of activity to organisms that produce beta-lactamase enzymes.Citation17 It is important to recognize that the addition of a beta-lactamase inhibitor does not increase activity against anaerobic organisms, in contrast to other combination beta-lactam/beta-lactamase inhibitors.

The antimicrobial activity of ceftazidime/avibactam was tested against gram-negative bacilli that were collected from 73 medical centers throughout the US.Citation18 The results of the study confirmed that the combination of ceftazidime/avibactam had potent activity against KPC-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa, both of which are resistant to currently available beta-lactamase inhibitors (clavulanic acid, tazobactam, and sulbactam).Citation18

The in vitro antibacterial activity of ceftazidime/avibactam against a panel of clinically isolated P. aeruginosa strains was evaluated to determine the clinical utility of this combination. The minimum inhibitory concentration (MIC) is a diagnostic laboratory test used to determine the susceptibility of pathogenic microorganisms to antibiotics. The MIC is determined by the minimum concentration of an antibiotic that inhibits visible growth overnight.Citation19 When tested in comparison to other available beta-lactams, the addition of avibactam was effective in lowering the MIC for aztreonam, piperacillin, and imipenem. However, the addition of avibactam to ceftazidime resulted in the largest increase in activity from the 126 P. aeruginosa strains collected between 2006 and 2007. Only 65% of isolates were susceptible to ceftazidime alone, but 94% were susceptible to the combination of ceftazidime/avibactam.Citation16

The activity of ceftazidime/avibactam was also tested against Enterobacteriaceae and P. aeruginosa isolates that expressed beta-lactamase genes. The addition of avibactam to ceftazidime resulted in a fourfold to 512-fold reduction in the MIC of the isolates with beta-lactamase genes, compared to avibactam alone.Citation20 However, there were three isolates that demonstrated no change in MIC upon the addition of avibactam to ceftazidime. The first isolate was from an E. coli strain containing the blaTEM gene, in which the MIC remained unchanged when tested against ceftazidime and ceftazidime/avibactam. The second was a P. aeruginosa isolate containing the blaVIM gene, which is a Class B metallobeta-lactamase to which avibactam had no effect. The third exception was a P. aeruginosa isolate with the blaOXA-23 gene, a member of the Class D carbapenemase-producing class, hence its resistance was unlikely to be caused by beta-lactamase as this class is unable to hydrolyze extended-spectrum cephalosporins, such as ceftazidime.Citation20 One study has determined that ceftazidime/avibactam is effective against P. aeruginosa strains that contain a derepressed AmpC gene, which is intrinsically resistant to ceftazidime.Citation21 These strains were incubated in fixed concentrations of avibactam along with increasing ceftazidime concentrations. The frequency of resistance to ceftazidime/avibactam was low in the three strains that were challenged. Additionally, the authors suggested that the risk of developing spontaneous resistance to the ceftazidime/avibactam combination was low as their findings revealed that the rate of resistance was lower when compared to meropenem or imipenem.Citation21

A previous study has described the extensive microbiology activity of ceftazidime/avibactam, but until recently there have been no KPC-producing K. pneumoniae isolates that have been reported to be resistant to the drug. One case report has been published that documented the first case of resistance to ceftazidime/avibactam in a KPC-3-expressing K. pneumoniae isolate.Citation11 The carbapenem-resistant K. pneumoniae isolate was resistant to aztreonam, tobramycin, carbapenems, ampicillin/sulbactam, extended-spectrum cephalosporins, piperacillin/tazobactam, and ciprofloxacin. The isolate was also resistant to doxycycline, minocycline, chloramphenicol, and tigecycline. The exact mechanism of resistance for this KPC K. pneumoniae isolate to ceftazidime/avibactam is uncertain and is under investigation. Despite the introduction of these enzymes are uncommon, the previous example of resistance warrants increased monitoring and surveillance for these isolates.Citation11

Pharmacokinetics

Ceftazidime/avibactam is available as an intravenous (IV) formulation. The components of ceftazidime/avibactam are formulated in a 4:1 ratio containing 2,000 mg of ceftazidime and 500 mg of avibactam.Citation22 The pharmacokinetics of both ceftazidime and avibactam are similar, in which their individual properties remain unchanged when both are coadministered. Ceftazidime and avibactam follow two-compartment linear kinetics with their maximum plasma concentration (Cmax) and area under the curve increasing linearly with additional and higher doses. Both components of ceftazidime/avibactam are minimally protein bound with <10% plasma protein binding.Citation11 Ceftazidime (80%–90% of the dose) and avibactam are not metabolized and are primarily renally excreted in their unchanged form; the renal clearance for ceftazidime and avibactam is 115 mL/min and 158 mL/min, respectively.Citation6 In patients with normal renal function, the half-life (t1/2) for each component is relatively similar: 2.76 hours and 2.71 hours for ceftazidime and avibactam, respectively.Citation6

Chemical structure

The basic structure of cephalosporins comprises of a four-member β-lactam ring and a six-member dihydrothiazine ring. Different side chain substitutions at the three and seven positions have yielded the manufacture of several antibiotics in the cephalosporin class.Citation23 Ceftazidime contains a pyridinium group at position 3 that increases activity against P. aeruginosa and its water solubility.Citation23,Citation24 At position 7, the aminothiadiazole ring provides activity against gram-negative bacilli, while the carboxypropyl-oxyimino group enhances its activity toward P. aeruginosa and increases its stability against beta-lactamase; however, it also consequently reduces its activity against Enterobacteriaceae.Citation25Citation27 Avibactam is categorized into a new class of nonbeta-lactam beta-lactamase inhibitors, diazabicyclooctanes (DBOs).Citation17

Indications and usage

Current clinical indications for ceftazidime/avibactam include the treatment of patients 18 years or older with cIAIs and cUTIs.Citation6 However, there are ongoing clinical studies that are investigating additional indications for the use of ceftazidime/avibactam. Full results from the Phase III trials and future studies are likely to expand the use of ceftazidime/avibactam to include hospitalized adults with nosocomial and ventilator-associated pneumonia, hospitalized pediatric patients aged 3 months to 18 years with cIAIs, and cystic fibrosis patients with resistant respiratory P. aeruginosa infections.Citation12,Citation28,Citation29

Clinical pharmacology

Ceftazidime/avibactam consists of an antibacterial beta-lactam, ceftazidime, and a beta-lactamase inhibitor, avibactam. Ceftazidime is a beta-lactam that exhibits bactericidal activity by inhibiting cell wall synthesis by binding to penicillin-binding proteins, resulting in bacterial cell death.Citation30,Citation31 Avibactam binds covalently to beta-lactamases at the active site, but this simple mechanism does not involve a rearrangement that other inhibitors with a beta-lactam moiety undergo after the opening of the four-membered beta-lactam ring.Citation17 Avibactam is from a group of beta-lactamase inhibitors called DBOs, which are more potent when compared to the prototypical beta-lactam ring structure. For example, a significant amount of tazobactam and clavulanic acid is required to inhibit one beta-lactamase molecule, compared to only one to five molecules of avibactam.Citation17 The increased efficiency and activity of the DBO molecule are due to the ring opening and being stabilized by residues that are close to the active site, causing polar interactions. In contrast, the opening of the four-ring beta-lactam structure undergoes rearrangement upon the opening of the ring, resulting in destabilization. This mechanism of reaction allows for a more efficient inhibition and broadens the activity against bacteria that would normally degrade ceftazidime.Citation17

Clinical trials

Phase I studies

Two Phase I randomized, double-blinded, placebo-controlled studies were done to evaluate the safety, tolerability, and pharmacokinetics of avibactam both alone and in combination with ceftazidime.Citation22 Subjects were included if they were healthy males aged 18 years to 45 years of age, had a body mass index of 18–27 kg/m2, negative serology for HIV, hepatitis B, hepatitis C, negative urine drug screen, and no history of hypersensitivity to any medications. Additionally, no other medications were allowed beginning 14 days before the first dose until the end of the study; the only exception was 1,000 mg of acetaminophen per day for a headache. Subjects were excluded if there were any electrocardiogram abnormalities, a presence of clinically significant illness 3 months before the beginning of the study, or any condition that would obstruct the absorption, distribution, metabolism, or excretion of any medication.Citation22 Subjects were also excluded if there were any abnormal vital signs such as a diastolic blood pressure >90 mmHg and/or systolic blood pressure >150 mmHg, any history of drug abuse 1 year prior to the study, smoking more than five cigarettes per day in the prior 3 months, consuming any products that contain grapefruit 7 days before the first dose, and blood or blood product donation >500 mL 3 months before the start of the study.

The first of these studies (NXL104-1001) was conducted using avibactam as a single ascending dose. Subjects were allotted to one of seven groups that consisted of avibactam doses ranging from 50 mg to 2,000 mg. Each group was made up of ten subjects: two subjects received placebo and eight received avibactam. After a 7-day washout period, subjects from the 250 mg and 500 mg groups received either placebo or a second avibactam dose that contained 1,000 mg or 2,000 mg of ceftazidime.Citation22 The second study (NXL104-1002) was performed in two parts: the first part of the study was a multiple ascending dose study, which was made up of ten subjects in each one of the four dosing groups – avibactam 500 mg, 750 mg, or 1,000 mg, or avibactam 500 mg/ceftazidime 2,000 mg. Two subjects in each dosing group would receive placebo and eight subjects would receive avibactam every 8 hours for 5 days. The group receiving avibactam 500 mg/ceftazidime 2,000 mg received a 30-minute IV infusion every 8 hours for 10 days. The second part of this study included eight subjects from a separate cohort who received avibactam 500 mg IV or orally.Citation22 There were no serious adverse events reported in either study.Citation22 There were eleven treatment-emergent adverse effects (TEAEs), all of which were mild-to-moderate intensity, and all resolved spontaneously except one which was a moderate hematoma located at the injection site. No significant abnormalities in vital signs, hematology, electrocardiogram, biochemistry, and urinalysis were reported. Avibactam, when administered alone or in combination with ceftazidime, was well tolerated in the study dosages which ranged from 50 mg to 2,000 mg. The two Phase I trials illustrate that the pharmacokinetic and safety profile of avibactam are not affected when given in combination with ceftazidime.

Phase II studies

Ceftazidime/avibactam was studied in two Phase II, randomized, double-blinded clinical trials.Citation13,Citation14 One study was conducted in patients with cIAIs, and the other study was performed in patients with cUTIs. Each study was designed to test the safety and efficacy of ceftazidime/avibactam when compared with a carbapenem. The similarities and differences between the two Phase II trials upon which ceftazidime/avibactam gained its Food and Drug Administration approval are illustrated in .

Table 1 Comparison of safety and efficacy data of Phase II cUTI and Phase II cIAI trials

In one Phase II randomized, double-blinded, active-controlled trial, the safety and efficacy of ceftazidime/avibactam plus metronidazole compared to meropenem was evaluated in 203 hospitalized patients with cIAIs.Citation29 Patients with a confirmed diagnosis of cIAI that required surgical intervention and antibiotics were enrolled and randomized in a 1:1 ratio. Patients received either a combination dose of ceftazidime 2,000 mg plus avibactam 500 mg administered IV over 30 minutes every 8 hours plus a separate infusion of metronidazole 500 mg administered over 1 hour every 8 hours, or meropenem 1,000 mg every 8 hours plus an infusion of placebo over 1 hour (). The primary end point of the study was clinical response at the test of cure (TOC) visit, 5 days to 14 days after treatment. Patients were eligible to participate if they were aged 18 years to 90 years with a cIAI requiring surgical intervention and antibiotics. The diagnoses that were accepted included diverticular disease with perforation or abscess, secondary peritonitis, intra-abdominal abscess with intraperitoneal involvement, cholecystitis with gangrenous rupture, or acute gastric or duodenal perforation. Patients were excluded if they had small bowel obstruction or ischemic bowel without perforation, abdominal wall abscess, or other coexisting infections that would interfere with the analysis of the study. Patients were also excluded if they had previously received antibiotic therapy within 72 hours of study therapy, abnormal liver function defined as aspartate transaminase greater than three times the upper limit of normal, or an infection caused by a pathogen with resistance to the study medication. Further exclusion criteria included patients with infections of the female genitalia or perinephric infections, survival anticipated to be less than the study period, sepsis with shock not responsive to IV fluids, APACHE II score >25, or renal dysfunction defined as creatinine clearance (CrCl) <50 mL/min. Continued exclusion criteria included hematological or metastatic malignancy requiring chemotherapy, chronic cirrhosis or hepatitis, body mass index >45 kg/m2, absolute neutrophil count <1,500 cell/mm3 (unless associated with infection), or immunocompromised status defined as HIV with AIDS or CD4+ T-lymphocyte count <2,000 cells/mm3. The final exclusion criteria included patients with a hemoglobin level <10 g/dL, platelet count <100,000 cells/mm3, splenectomy or chronic corticosteroid therapy defined as >20 mg of prednisone daily, patients who required additional systemic antibiotic therapy, and patients with 5 days to 14 days of therapy that were deemed unlikely to respond to treatment.

A total of 87 patients in the ceftazidime/avibactam plus metronidazole group and 90 patients in the meropenem group were clinically evaluable (CE). There were 68 and 76 patients who were microbiologically evaluable (ME), with a median duration treatment time of 6 days and 6.5 days in the ceftazidime/avibactam plus metronidazole and meropenem groups, respectively.Citation13 In the ceftazidime/avibactam plus metronidazole and meropenem groups, a clinical response was seen in 92% and 94.4%, respectively, in the CE subgroup and 91.2% and 93.4%, respectively, in the ME subgroup at TOC. The authors of the study concluded that there was no relationship between APACHE II scores at baseline and treatment outcome. However, it should be noted that the number of patients with an APACHE II score >10 was limited to 12 and eleven patients in the ceftazidime/avibactam plus metronidazole and meropenem group, respectively. Furthermore, response rates appeared to be similar between the two groups, independent of whether the infection was monomicrobial or polymicrobial in nature.Citation13

A small prospective, randomized, investigator-blinded, Phase II trial compared the efficacy, safety, and tolerability of ceftazidime/avibactam and imipenem/cilastatin in adults who were hospitalized with a severe cUTI resulting from a gram-negative pathogen.Citation14 This trial recruited patients from 26 different centers located throughout five countries. Patients in the study were randomized to receive either ceftazidime 500 mg plus avibactam 125 mg infused IV over 30 minutes every 8 hours or cilastatin/imipenem 500 mg infused IV over 30 minutes every 6 hours. The median duration of therapy was 5 days in the ceftazidime/avibactam group and 6 days in the cilastatin/imipenem group. The primary end point of the study was a positive microbiological response in the ME patients at the TOC visit, which was 5 days to 9 days after the last dose of therapy. The secondary end point of the study was a microbiological response in the ME patients at the end of IV therapy and late follow-up visit (LFU), 4 weeks to 6 weeks after therapy. Patients were included if they were between the ages of 18 years and 90 years and were diagnosed with acute pyelonephritis or cUTI caused by a gram-negative pathogen that was deemed to be a serious infection requiring parenteral therapy. Acute pyelonephritis was defined to include patients who were febrile (oral body temperature >37.8°C) with the presence of chills beginning 12 hours into the study, pyuria, flank pain, and positive urine culture with ≥105 CFU/mL caused by a pathogen with a known susceptibility to the study drugs. Patients with cUTIs were defined by having signs and symptoms that were consistent with a UTI. This included an oral body temperature >37.8°C, suprapubic pain, nausea/vomiting, dysuria, frequency, urgency, incontinence, costovertebral angle tenderness, and a positive urine culture with ≥105 CFU/mL caused by a pathogen with known or considered susceptibility to the study drugs. Patients were excluded if they had previously received at least one dose of another systemic antibiotic 48 hours before the admission urine culture, if the cUTI was caused by a pathogen with known resistance to any of the study drugs, full obstruction of the urinary tract, fungal UTI, presence of vesicoureteral reflux or ileal loops, pregnant or breast-feeding women, patients with a known history of hypersensitivity to the study medications, patients with permanent indwelling catheter, and patients believed unlikely to survive the study trial period.

The CE population had a favorable clinical response in all patients at the end of IV therapy. A favorable clinical response among the CE population at the TOC visit was observed in 24/28 (85.7%) of the ceftazidime/avibactam group and 29/36 (80.6%) in the imipenem/cilastatin arm. Results for these positive clinical outcomes are presented in . In the ME population, there was a 70.4% and 71.4% positive clinical response at TOC visit, 96.2% and 100% positive clinical response at the end of IV therapy, and a 57.7% and 60% positive response at the LFU visit in the ceftazidime/avibactam and imipenem/cilastatin groups, respectively. Comprehensively in the ME population, there was a positive microbiological and clinical response in 66.7% and 60% of patients at the TOC visit and 53.8% and 60% at the LFU visit in the ceftazidime/avibactam and imipenem/cilastatin groups, respectively. The authors of the study noted that despite the small sample size, six of seven patients (85.7%) and nine of eleven patients (81.8%) in the ME group who had a ceftazidime-resistant pathogen at the TOC visit showed a positive microbiological response with ceftazidime/avibactam and imipenem/cilastatin, respectively.Citation14

Phase III studies

Results from two new Phase III trials, RECLAIM-1 and RECLAIM-2, were only available in abstract form. The two studies were analyzed as one dataset and were conducted in patients with cIAIs that compared ceftazidime/avibactam plus metronidazole to meropenem.Citation15,Citation32 Both studies used the randomization of ceftazidime 2,000 mg plus avibactam 500 mg every 8 hours and metronidazole 500 mg every 8 hours or meropenem 1,000 mg every 8 hours. However, the ceftazidime/avibactam infusion was changed to 2 hours compared to the 30 minutes that was conducted in the Phase II trial.Citation14 The primary efficacy end point of the RECLAIM study was clinical response at the TOC visit, which was assessed at 28 days to 35 days after randomization. The study randomized a total of 1,066 patients, and the subjects were followed after a period of 2 years. The overall cure rate was achieved in 82% patients receiving ceftazidime/avibactam and 85% for meropenem (−3.5; 95% CI: −8.6 to 1.6), showing noninferiority between the two treatments.Citation15,Citation32 Results from this Phase III cIAI trial showed meropenem had decreased mortality compared with ceftazidime/avibactam plus metronidazole (1.5% versus 2.5%, respectively).Citation6 Clinical cure rates were reduced in patients with moderate renal impairment (CrCl 30–50 mL/min) who received ceftazidime/avibactam compared to those patients who received meropenem, 45% and 74%, respectively. Within this group of patients with a CrCl 30–50 mL/min, death occurred in 25.8% of participants who received ceftazidime/avibactam plus metronidazole compared with 8.6% of participants who received meropenem, which may be attributed to participants receiving a 33% lower daily dose than is recommended.Citation6,Citation32 This difference in clinical cure rates was not seen in patients with a normal renal function or mild renal impairment (CrCl >50 mL/min), suggesting insufficient dosing may have caused the lower cure rates.Citation15

Adverse drug reactions

Based on Phase I and Phase II trials, ceftazidime/avibactam is generally well tolerated. All subjects completed the study with no patients requiring discontinuation from the study due to adverse effects (AEs). There were six TEAEs reported in four subjects in the single ascending dose arm of the study. Only one AE was considered moderate in intensity and it resolved spontaneously while the others were considered only mild in intensity. The TEAEs that were considered related to the therapy included: postural dizziness, anxiety, abdominal pain, somnolence, and sense of oppression. In the multiple ascending dose arm, the only TEAE observed was a moderate hematoma at the injection site.Citation22 The AEs reported from the two Phase II trials also indicated that ceftazidime/avibactam was well tolerated when compared with meropenem and imipenem/cilastatin for cIAI and cUTI.Citation13,Citation14 Observations of AEs were reported in 64.4% of patients who received ceftazidime/avibactam plus metronidazole, compared to 57.8% of patients who received meropenem. The most common TEAEs reported were an increased frequency of vomiting (13.9%), nausea (9.9%), pyrexia (8.9%), and abdominal pain (7.9%) in the ceftazidime/avibactam plus metronidazole group. However, most of the AEs were mild to moderate in intensity. In a separate Phase II study, 67.6% of patients in the ceftazidime/avibactam group and 76.1% of patients in the imipenem/cilastatin group reported AEs. Based on 68 subjects in the group receiving ceftazidime/avibactam, the most common TEAE included a headache (19.1%), abdominal pain (14.7%), constipation (10.3%), anxiety (10.3%), and diarrhea (8.8%).Citation14

Drug interactions

Ceftazidime/avibactam retains its clinical efficacy when exposed to levels of pulmonary surfactant that would otherwise inhibit the bactericidal effects of daptomycin. As well, there have been no known antagonistic effects of ceftazidime/avibactam when used in conjunction with other antibiotics for the treatment of nosocomial-associated pneumonias.Citation5,Citation33 However, avibactam, in vitro, is a substrate of OAT1 and OAT3 transporters. The coadministration of probenecid with avibactam resulted in the inhibition of ~56% to 70% of the uptake of avibactam. Therefore, the coadministration of ceftazidime/avibactam and probenecid is not recommended.Citation6,Citation34 Furthermore, administration with oral contraceptive pills is not recommended due to decreased intestinal uptake of estrogen causing subtherapeutic levels of estrogen.Citation5,Citation35

Contraindications

Contraindications for the use of ceftazidime/avibactam include known severe hypersensitivity reactions to Avycaz, ceftazidime, avibactam, or other members of the cephalosporin class.Citation6

Warnings and precautions

Hypersensitivity and skin reactions, Clostridium difficile-associated diarrhea, and central nervous system adverse reactions that were more prevalent in renally impaired patients, are concerns with ceftazidime/avibactam. Possible development of drug-resistant bacteria should also be recognized with use of ceftazidime/avibactam.Citation6,Citation35 In the Phase III cIAI trial, patients with a baseline CrCl of 30 mL/min to 50 mL/min demonstrated a lower clinical response to ceftazidime/avibactam. CrCl should be monitored, and the dose should be adjusted accordingly in patients with changing renal function.Citation6,Citation15

Special populations

This formulation has not been studied and is not currently approved for patients younger than 18 years of age. The dose and/or interval of ceftazidime/avibactam should be adjusted in patients with renal impairment (CrCl <50 mL/min based on the Cockcroft and Gault formula). Cephalosporins as a class are considered pregnancy risk category B and ceftazidime is excreted in breast milk. It is unknown if avibactam is excreted in breast milk.Citation6

Conclusion

Clinicians have fewer antibiotic options to treat patients as drug-resistant gram-negative pathogens continue to rise. The introduction of avibactam, a nonbeta-lactam beta-lactamase inhibitor, acts differently than other beta-lactamase inhibitors and broadens the activity against bacteria that would normally degrade ceftazidime such as Amp C beta-lactamases, carbapenemase-producing Entera bacteria gene, and multidrug resistant Pseudomonas aeruginosa.Citation5,Citation10 Ceftazidime/avibactam is currently only indicated for use in patients with cIAIs (in combination with metronidazole) and cUTIs, including pyelonephritis, and should be reserved for patients who have no alternate treatment options because of antibiotic resistance. Judicious use of antibiotic stewardship should be used when using this medication to prevent the incidence of drug resistance. Ceftazidime/avibactam has been shown to be well tolerated in several clinical trials, with only mild-to-moderate intensity AEs reported. Future indications and resistance mechanisms remain to be seen. However, the broad spectrum of activity that ceftazidime/avibactam provides is an important advancement in the treatment of patients with cUTIs and cIAIs with limited treatment options.

Acknowledgments

Celeste M Vinluan is currently affiliated with West Coast University at the time of publication.

Disclosure

The authors report no conflicts of interest in this work.

References

  • World Health Organization [webpage on the Internet]Antimicrobial Resistance: Global Report on Surveillance, 20142014 Available from: http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1Accessed March 20, 2016
  • CosgroveSEThe relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costsClin Infect Dis200642suppl 2S82S8916355321
  • Centers for Disease Control and Prevention [webpage on the Internet]Antibiotic Resistance Threats in the United States, 20132013 Available from: http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdfAccessed February 3, 2016
  • ChenJShangXHuFBeta-lactamase inhibitors: an updateMini Rev Med Chem201313131846186123895190
  • SharmaRParkTEMoySCeftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination for the treatment of resistant gram-negative organismsClin Ther201638343144426948862
  • Avycaz (Ceftazidime-Avibactam) [package insert]Cincinnati, OHForest Pharmaceuticals2015
  • CastanheiraMFarrellSEWangerARolstonKVJonesRNMendesRERapid expansion of KPC-2-producing Klebsiella pneumoniae isolates in two Texas hospitals due to clonal spread of ST258 and ST307 lineagesMicrob Drug Resist201319429529723530541
  • TzouvelekisLSMarkogiannakisAPsichogiouMTassiosPTDaikosGLCarbapenemases in Klebsiella pneumoniae and other enterobacteriaceae: an evolving crisis of global dimensionsClin Microbiol Rev201225468270723034326
  • WoodfordNTurtonJFLivermoreDMMultiresistant gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistanceFEMS Microbiol Rev201135573675521303394
  • AktaşZKayacanCOnculOIn vitro activity of avibactam (NXL104) in combination with β-lactams against gram-negative bacteria, including OXA-48 β-lactamase-producing Klebsiella pneumoniaeInt J Antimicrob Agents2012391868922041508
  • HumphriesRMYangSHemarajataPFirst report of ceftazidime-avibactam resistance in a KPC-3-expressing Klebsiella pneumoniae isolateAntimicrob Agents Chemother201559106605660726195508
  • AstraZeneca; PRA Health Sciences [webpage on the Internet]Evaluation of Safety, Pharmacokinetics and Efficacy of CAZ-AVI with Metronidazole in Children Aged 3 Months to 18 Years Old with Complicated Intra-abdominal Infections (cIAIs)ClinicalTrials gov [Internet]Bethesda, MDNational Library of Medicine (US)2000 [cited March 24, 2016]. Available from: http://clinicaltrials.gov/show/NCT02475733
  • LucastiCPopescuIRameshMLipkaJSableCComparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trialJ Antimicrob Chemother20136851183119223391714
  • VazquezJGonzález PatzánLStricklinDEfficacy 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 studyCurr Med Res Opin201228121921193123145859
  • MazuskiJEGasnikLAmstrongJEfficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection-results from a Phase III program (Abstract O191)25th European Congress of Clinical Microbiology and Infectious Disease (ECCMID)Copenhagen2015
  • LevasseurPGirardAMClaudonMIn vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolatesAntimicrob Agents Chemother20125631606160822214778
  • ColemanKDiazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitorsCurr Opin Microbiol201114555055521840248
  • SaderHCastanheiraMFlammRFarrellDJJonesRNAntimicrobial activity of ceftazidime-avibactam against gram-negative organisms collected from U.S. medical centers in 2012Antimicrob Agents Chemother20135831684169224379201
  • AndrewsJMDetermination of minimum inhibitory concentrationsJ Antimicrob Chemother200148suppl 151611420333
  • KeepersTRGomezMCeleriCNicholsWWKrauseKMBactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against β-lactamase-producing enterobacteriaceae and Pseudomonas aeruginosaAntimicrob Agents Chemother20145895297530524957838
  • LahiriSDWalkupGKWhiteakerJDSelection and molecular characterization of ceftazidime/avibactam-resistant mutants in Pseudomonas aeruginosa strains containing derepressed AmpCJ Antimicrob Chemother20157061650165825645206
  • MerdjanHRangarajuMTarralASafety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studiesClin Drug Investig2015355307317
  • BealeJAntibacterial antibioticsBealeJBlockJWilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry12th edBaltimoreLippincott Williams & Wilkins2011258329
  • CaprileKThe cephalosporin antimicrobial agents: a comprehensive reviewJ Vet Pharmacol Ther19881111323288766
  • DunnGCeftizoxime and other third-generation cephalosporins: structure-activity relationshipsJ Antimicrob Chemother198210suppl C1106295993
  • NeuHβ-Lactamase stability of cefoxitin in comparison with other β-lactam compoundsDiagn Microbiol Infect Dis1983143133166321094
  • NeuHβ-lactam antibiotics: structural relationships affecting in vitro activity and pharmacologic propertiesClin Infect Dis19868suppl 3S237S259
  • AstraZeneca [webpage on the Internet]A Study Comparing Ceftazidime-Avibactam versus Meropenem in Hospitalized Adults with Nosocomial PneumoniaClinicalTrialsgov [Internet]Bethesda, MDNational Library of Medicine (US)2000 [cited March 24, 2016]. Available from: http://clinicaltrials.gov/show/NCT01808092Accessed June 10, 2016
  • University of Southern California [webpage on the Internet]Steady-State Pharmacokinetics of Ceftazidime/Avibactam in Cystic FibrosisClinicalTrials.gov [Internet]Bethesda, MDNational Library of Medicine (US)2000 [cited March 24, 2016]. Available from: http://clinicaltrials.gov/show/NCT02504827Accessed June 10, 2016
  • VollmerWBlanotDDe PedroMPeptidoglycan structure and architectureFEMS Microbiol Rev200832214916718194336
  • SauvageEKerffFTerrakMAyalaJACharlierPThe penicillin-binding proteins: structure and role in peptidoglycan biosynthesisFEMS Microbiol Rev200832223425818266856
  • MawalYCritchleyIARiccobeneTATalleyAKCeftazidime–avibactam for the treatment of complicated urinary tract infections and complicated intra-abdominal infectionsExpert Rev Clin Pharmacol20158669170726420166
  • DallowJOttersonLGHubandMDKrauseKMNicholsWWMicrobiological interaction studies between ceftazidime-avibactam and pulmonary surfactant and between ceftazidime-avibactam and antibacterial agents of other classesInt J Antimicrob Agents201444655255625293578
  • VishwanathanKMairSGuptaAAssessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potentialDrug Metab Dispos201442593294224616266
  • Fortaz [package insert]Schaumburg, IllinoisSagent Pharmaceuticals Inc2014