Title:Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Novel Therapy for Multidrug Resistant Gram Negative Infections in Children
VOLUME: 14
Author(s):David P Nicolau*, Brittany A Rodrigueza and Jennifer E Girottoa
Affiliation:Center for Anti-Infective Research and Development, Connecticut Children’s Medical Center, Connecticut Children’s Medical Center
Keywords:beta-lactam/beta-lactamase inhibitor, ceftazidime/avibactam,
ceftolozane/tazobactam, children, Enterobacteriaceae, multidrug resistance
Abstract:The rise in multidrug-resistant (MDR) infections has become a significant problem in
both the developing countries and in the United States (U.S.). Specifically, MDR gram-negative
infections are emerging, affecting not only adults but children as well. The specific gram-negative
organisms that have been most concerning within the pediatric population include MDR P.
aeruginosa, Enterobacteriaceae, and Acinetobacter spp.
The increase in antimicrobial resistance rates is associated with various mechanisms with one of the
most common being the production of beta-lactamases. Both ceftazidime/avibactam (CZA) and
ceftolozane/tazobactam (C/T) are two recently approved antibiotics in the U.S. While both of these
agents are inhibitors of beta-lactamase enzymes, there are differences between them that are important
to understand. At this time, the data in children for these agents are extremely limited. The aim
of this review is to describe the characteristics of these agents and their potential uses in pediatric
patients. Case Presentation: A 16-year-old, 60 kg, previously healthy male was admitted with a
one-day history of emesis, abdominal pain, and right lower quadrant tenderness. Upon presentation,
imaging and inflammatory markers were unremarkable with C-reactive protein (CRP) and white
blood cell (WBC) counts of 0.35 mg/dL and 15 Thous/μL, respectively. Over the next 5 days, the
patient continued to progress with peak temperatures of 39.4ºC and CRP of 28 mg/dL. At that time,
a computerized tomography scan revealed perforated appendicitis that required laparoscopic surgery
and drainage. The patient was started on intravenous (IV) metronidazole 1,500 mg every 24
hours and ciprofloxacin 400 mg every 12 hours. The drained fluid obtained at the time of the procedure
grew an extended spectrum β-lactamase (ESBL) producing Escherichia coli that was sensitive
to cefepime, ertapenem, imipenem, meropenem, gentamicin, and tobramycin. Based upon the
culture and sensitivity data, ertapenem 1000 mg IV every 24 hours was begun. The patient’s fever
continued to elevate with a max of 41.2ºC while receiving ertapenem for 7 days. Repeat imaging
revealed a new intra-abdominal abscess which, when drained, grew a Klebsiella pneumoniae carbapenemase
(KPC) producing E. coli confirmed by PCR. At that time, the patient was transitioned
to ceftazidime/avibactam (CZA) 2000 mg/500 mg IV every 8 hours as a 3-hour infusionμ and metronidazole
500 mg IV every 8 hours. The KPC E. coli was determined to be resistant to ceftazidime
(MIC > 256 μg/mL), ceftriaxone (MIC > 128 μg/mL), meropenem (MIC 4 μg/mL), ciprofloxacin
(MIC > 32 μg/mL), levofloxacin (MIC > 32 μg/mL), tetracycline (MIC > 256 μg/mL), and colistin
(MIC > 32 μg/mL). The organism was sensitive to CZA, gentamicin, tobramycin, and tigecycline
(MIC 0.5 μg/mL). Initially with the change of antibiotics, the patient began to improve; however,
his progress again plateaued. Gentamicin 150 mg IV every 8 hours (7.5 mg/kg/day) was added but
there was still no improvement. A repeat CT scan was performed revealing a residual abscess that
was drained. His antimicrobial coverage expanded to include tigecycline 50 mg IV every 12 hours
(discontinuing gentamicin), and the patient was a clinical cure.
