Optimal Management of Complicated Infections in the Pediatric Patient: The Role and Utility of Ceftazidime/Avibactam

Figures & data

Table 1 Indication and Usage of CAZ-AVI in Adult and Pediatric Population

Adult Population (18 Years and Older)	Pediatric Population (3 Months and Older)
● cIAI, used in combination with metronidazole ● cUTI, including pyelonephritis ● HAP, VAP ● Infections due to aerobic Gram-negative organisms in adult patients with limited treatment options.	● cIAI, used in combination with metronidazole ● cUTI, including pyelonephritis

Abbreviations: cIAI, complicated intra-abdominal infections; cUTI, complicated urinary tract infections; HAP, hospital-acquired pneumonia; VAP, ventilator-associated pneumonia.

Table 2 Classification of Most Frequent Extended-Spectrum b-Lactamases and Carpapenemase

Molecular Class	Enzymes	Relevant Organisms	Substrates of Hydrolysis
A	ESBL (TEM, SHV, CTX-M, others)	E. coli Klebsiella spp. Proteus mirabilis	Penicillins, cephalosporins (except cefamycins), aztreonam.
A	KPC	E. coli K. pneumoniae K. oxytoca Serratia marcescens Enterobacter spp. Citrobacter freundii	Penicillins, cephalosporins, aztreonam, carbapenems.
B	MBLs (VIM, IMP, NDM, others)	E. coli K. pneumoniae K. oxytoca Serratia marcescens Enterobacter spp. Citrobacter freundii	Penicillins, cephalosporins and carbapenems. Monobactams are susceptible.
C	AmpC	K. pneumoniae E. coli Enterobacter spp. Salmonella enteritidis C. freundii S. marcescens	Cephamycins, 3rd generation cephalosporins
D	OXA (OXA-48, OXA-23, others)	Acinetobacter baumannii P. aeruginosa E. coli K. pneumoniae P. mirabilis C. freundii	Penicillin, aztreonam and carbapenems

Abbreviations: ESBL, extended-spectrum b-lactamases; IMP, imipenmase metallo-beta-lactamase; KPC, Klebsiella pneumoniae carbapenemase; MBLs, metallo-β-lactamases; NDM, New Delhi metallo-beta-lactamase; OXA-48, oxacillinase-48; OXA-23, oxacillinase-23; VIM, Verona integron-encoded metallo-beta-lactamase.

Table 3 Spectrum of Activity of Ceftadizime/Avibactam

ACTIVE in vitro	NOT ACTIVE in vitro
● Aeromonas ● Arcanobacter ● B. cepacia ● Capnocytophaga ● Citrobacter freundii +Citrobacter koseri ● Enterobacter aerogenes + Enterobacter cloacae ● Escherichia coli ● Hemophilus influenzae ● Kingella spp ● Leptospira spp ● Klebsiella oxytoca + Klebsiella pneumoniae ● Mycobacterium avium ● Mycobacterium tuberculosis ° ● Moraxella catarrhalis ● Morganella spp. ● Neisseria meningitides ● Propionibacterium acnes ● Pseudomonas aeruginosa ● Proteus mirabilis + Proteus vulgaris ● Peptostreptococci ● Providencia spp. ● Salmonella spp. ● Serratia spp. ● Shigella spp. ● Streptococcus agalactiae (B) ● Streptococcus anginosus spp ● Streptococcus gp C, F, G ● Streptococcus pneumoniae ● Vibrio parahemolyticus + Vibrio vulnificus	● MRSA ● Anaerobes ● Enterococcus spp. ● Stenotrophomonas maltophilia ● Acinetobacter spp (limited activity)
SUSCEPTIBLE MDR-GN *	NOT SUSCEPTIBLE MDR-GN
● ESBL ● CRE-KPC ● CRE-OXA48 ● MDR Pseudomonas	● NDM ● VIM ● IMP ● Most Class D enzymes

Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum beta-lactamase; IMP, imipenmase; MBLs, metallo-β-lactamases; MDRGN, multidrug-resistant gram-negatives; MRSA, methicillin-resistant Staphylococcus aureus; NDM, New Delhi metallo-β-lactamase; VIM, Verona integron-encoded metallo-β-lactamase ° including MDR strains; *, in vitro sensitive strains.

Table 4 Treatment Options with Ceftazidime-Avibactam and Combo Therapy for MDR-GN Infections. Dose Adjustment Is Recommended Depending on Renal Function and Antimicrobial Susceptibility Tests

Drug	Dosage	Reference
Ceftazidime/avibactam	According to weight and age-Weight <40 kg≥6 months to <18 year: 50 +12.5 mg/kg every 8 hours-Weight >40 kg≥6 years: 2000 + 500 mg/kg every 8 hoursAccording to age≥3 to <6 months: 40 + 10 mg/kg every 8 hours Observations: EI (over 3 h) every 8 hours is recommended	[^Citation44]
Aztreonam	90–120 mg/kg/day divided in 3 dosesIn Cystic fibrosis200 to 300 mg/kg/day divided in 4 doses	[^Citation99,Citation100]
Meropenem	60 mg/kg/day divided in 3 dosesIn Cystic fibrosis or onco/hematological patients120 mg/kg/day divided in 3 dosesObservations: CI every 6 h in 6 hours or EI every 8 hours over 3–6 is recommended	[^Citation101]
Fosfomycin	According to weight and age-Premature neonates, corrected gestational age <40 weeks: 100 mg/kg divided in 2 doses-Neonates, corrected gestational age *40–44 weeks: 200 mg/kg in 3 divided doses*1 to 12 months (up to 10 kg): 200–300 mg/kg in 3 divided doses*1 to 12 years (10 to 40 kg): 200–400 mg/kg in 3 to 4 divided dosesObservations: Always in combination therapy. Contains high sodium concentrations. Caution is recommended in patients with liver cirrhosis or heart failure	[^Citation62,Citation64]
Colistin	Caution required due to very limited safety data-Usual adult dose is: 9.000.000 IU as loading dose and then 4.500.00 IU every 12 hours Possible dosage suggested based on available data:200.000 IU/kg loading dose and then 100.000 every 12 hours Observations: High doses are associated with renal toxicity	[^Citation69^–^Citation75,Citation78]
Tigecycline	According to age8 to 11 years: 1.2 mg/kg (max 50 mg) every 12 hours12 to 17 years: 50 mg every 12 hour	[^Citation77,Citation102]
Amikacin	15–20 mg/kg/day single doseObservations: High doses are associated with renal toxicity	[^Citation83,Citation101]
Gentamicin	7 mg/kg/day single doseObservations: High doses are associated with renal toxicity	[^Citation101]
Rifampicin	20 mg/kg/day single doseObservations: Always in combination therapy	[^Citation61,Citation78,Citation85]

Notes: The loading dose should be administered in all patients including those with renal dysfunction. Antimicrobial susceptibility test: Colistin: MIC ≤ 2 mg/L continue colistin; MIC >2 mg/L consider alternative in vitro active antimicrobial. Tigecycline: MIC ≤1 mg/L consider tigecycline; MIC >1 mg/L consider alternative in vitro active antimicrobial. Fosfomycin: MIC ≤32 mg/L consider fosfomycin; MIC >32 mg/L consider alternative in vitro active antimicrobial. Aminoglycoside: MIC ≤2 mg/L for gentamicin/tobramycin or ≤4 mg/L for amikacin consider aminoglycoside; MIC >2 for gentamicin/tobramycin or >4 mg/L for amikacin consider alternative in vitro active antimicrobial.

Abbreviations: CI, continuous infusion; EI, extended infusion; h, hours.

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