Combination Therapy for OXA-48 Carbapenemase-Producing Klebsiella Pneumoniae Bloodstream Infections in Premature Infant: A Case Report and Literature Review

Figures & data

Figure 1 Changes in temperature and CRP of the patient during hospitalization and the changes of antimicrobial agents.

Abbreviations: SAM, ampicillin-sulbactam; MEM, meropenem; SCF, cefoperazone-sulbactam; MTR, metronidazole; Van, vancomycin; FOF, fosfomycin; AMK, amikacin; ATM, aztreonam; CAZ-AVI, ceftazidime-avibactam.

Table 1 Antimicrobial Susceptibility of Multidrug-Resistant Klebsiella Pneumoniae

Antibiotics	MIC (mg/mL)	KB (mm)	Interpretation
Levofloxacin	≥8.0		R
Tigecycline	2.0		S
ESBL	Pos		Pos
Cefazolin	≥64.0		R
Ceftriaxone	≥64.0		R
Amoxicillin-clavulanate	≥32.0		R
Piperacillin-tazobactam	≥128.0		R
Cefepime		15	R
Aztreonam	16.0		R
Ertapenem	≥8.0		R
Imipenem	4.0		R
Amikacin	<=2.0		S
Gentamicin	<=1.0		S
Tobramycin	<=1.0		S
Ciprofloxacin	≥4.0		R
TMP-SMZ	≥320.0		R
Cefuroxime		6	R
Cefoperazone-sulbactam		16	I
Meropenem		15	R

Abbreviations: MIC, minimum inhibitory concentration; KB, Kirby-Bauer disc diffusion method; mm, millimeter; R, resistance; S, susceptibility; Pos, positive; TMP-SMZ, Trimethoprim-sulfamethoxazole; I, intermediate susceptibility.

Figure 2 Aetiological examination of multidrug-resistant Klebsiella pneumoniae: (A) colonies; (B) Gram stain.

Figure 3 Rapid enzyme type detection (A) and combination susceptibility test in vitro (B and C).

Abbreviations: ATM, aztreonam; AK, amikacin; CZA, ceftazidime-avibactam; MEM, meropenem; SCF, cefoperazone-sulbactam; CRO, ceftriaxone; FEP, cefepime.

Table 2 mNGS Results of Blood Culture

Name of Pathogen	Reads Per Ten Million	Genus Name	Relative Abundance (%)	Resistance Gene Name
Klebsiella pneumoniae	120,540	Klebsiella	81.2	blaOXA-48

Figure 4 mNGS Results of blood culture.

Table 3 Reports of CRKP Infections in Premature Infants

Publication	Age, Sex	Gestational Age (W), Weight at Birth (g)	Diagnosis	Culture	Notes	Susceptible Drug	Ineffective Antimicrobial Therapy	Definitive Antimicrobial Therapy	Outcome
Current case	After delivery, M	32, 1370	Premature infant, VLBW infant, and neonatal respiratory distress syndrome; neonatal sepsis and septic shock; NEC	Blood	OXA-48, ESBL	TGC, AMK, GEN and tobramycin; intermediate susceptibility to cefoperazone-sulbactam	MEM; cefoperazone-sulbactam + AMK; CAZ-AVI + AMK + Van	CAZ-AVI (62.5mg/kg q8h), ATM (30mg/kg q6h) and FOF (33mg/kg q8h), for 15 days.	Cured
Sameer Bawankule et al 2023^Citation22	Referred to our hospital at day 9, M	27, 1040	Complications of hyaline membrane disease, PDA, and suspected NEC	NR	MBL (NDM) and OXA-48-like	CST	CST + MEM; polymyxin B + CAZ-AVI + ATM	cefiderocol, polymyxin B, CAZ-AVI, and ATM, for 14 days.	Cured
Caterina Monari et al 2023^Citation21	After delivery, F	31+1, 1100	BSI	Blood	MBL (VIM)	Cefiderocol; intermediate susceptibility to IPM	SAM + netilmicin (intolerance); Van + netilmicin; MEM	Cefiderocol (60mg/kg loading dose, followed by 40mg/kg q8h), for 9 days.	Cured
Weicong Pu et al 2023^Citation19	7-hour-old, F	34+4, 2400	Osteoarthritis	Blood	CRKP	Polymyxin, CHL and TGC, after treatment with polymyxin for 4 weeks, indicated resistance to polymyxin	MEM; polymyxin	CAZ-AVI (50mg/kg q8h), for 2 weeks.	Cured
Weicong Pu et al 2023^Citation19	45-day-old, M	32+4, 1270	Right hip arthritis and femoral osteomyelitis	Puncture fluid	CRKP	TET, minocycline, TGC, compound TMP–SMZ, CHL, polymyxin and CAZ-AVI	MEM + Van	CAZ-AVI (50mg/kg q8h), for 4 weeks.	Cured
Andrea Marino et al 2023^Citation17	After delivery, M	25+3940	Klebsiella pneumoniae bacteremia	Blood	KPC	CST, TGC, FOF, TMP–SMZ, CAZ-AVI, ceftolozane-tazobactam	Specific drugs were not reported	CAZ-AVI (50mg/kg q8h) along with FOF or AMK (not report clear), for 15 days.	Cured
Allan da S. Nascimento et al 2022^Citation20	After delivery, NR	29, 830	BSI	Blood	CPKP, ESBL	AMK, CST, and CAZ-AVI	N	CAZ-AVI (50mg/kg q8h for 2 days; next two days adjusted to peritoneal dialysis to 23.75mg/kg q48h; followed by 50mg/kg q8h), totally for 2 weeks.	Cured
Suzan S. Asfour et al 2022^Citation23	After delivery, F	27, 920	Bacteraemia and meningitis	Blood and CSF	CRKP	Blood culture showed sensitive to CST, GEN, TGC. The CSF culture was sensitive to CST.	MEM + Van; CST + GEN	CAZ-AVI (62.5mg/kg q8h) and FOF, for 2 weeks.	Cured
Suzan S. Asfour et al 2022^Citation23	After delivery, F	28, 925	Bacteraemia	Blood	CRKP, ESBL	Initially, sensitive to MEM and AMK. After 15 days sensitive to CAZ-AVI and AMK	cefepime + AMK; MEM + AMK	CAZ-AVI (62.5mg/kg q8h for 4 days and 62.5mg/kg qd for 1 day) and AMK, totally for 5 days.	Died
Yesim Coskun et al 2020^Citation26	After delivery, NR	27, 1000	UTI	Urine	CRKP	TGC	MEM + AMK; MEM + CST	CAZ-AVI (50mg/kg q8h), for 10 days.	Cured
Elias Iosifidis et al 2019^Citation27	Median age 51 days, range from 13 days to 134 days, 3M, 2F	25–32, median weight 1260g, range from 900g to 2030g	NEC, EOS, LOS and other diagnoses	Blood or rectal swab	CRKP	All patients were susceptible to CAZ-AVI, most (4/5) susceptibility to CST, 1 patient were intermediate susceptible to AMK	All patients received other antibiotics prior to CAZ-AVI.	Other antibiotics and CAZ-AVI (62.5mg/kg q8h. In one case of febrile UTI due to renal insufficiency and CVVH, the dose was given at 50% of the recommended dose q8h.)	Cured
Bowen Weng et al 2021^Citation24	At 1 hour postnatally, M	28+1, 970	Sepsis	TI, sputum, and blood	CRKP	CAZ-AVI, polymyxin B, TMP-SMZ and TGC	Van	TMP–SMZ (20mg/kg, bid), for 10 days.	Cured
Yue-E Wu et al 2020^Citation25	After delivery, NR	27, 972	Neonatal sepsis, neonatal meningitis	Blood	CRKP	Levofloxacin and AMK	N	MEM 20mg/kg q12h for 4 days, then 40mg/kg q12h for 3 days.	Cured
Matilde Ciccia et al 2018^Citation28	After delivery, F	25+1, 750	Severe VAP with concomitant bacteraemia	Blood and BAL	MBL (VIM)	TGC and CST	oxacillin + GEN; TZP + GEN	MEM (60mg/kg, qid), GEN and aerosolised GEN (0.6 mg in 2 mL of normal saline qid), for 10 days.	Cured
Paolo Bonfanti et al 2017^Citation29	After delivery, NR	23, 540	Sepsis	Blood and BA	KPC-3	GEN and CST	N	MEM (20mg/kg q8h) and CST (2.5mg/kg bid), for 10 day.	Cured
Javier Antonio Escobar Pérez et al 2013^Citation30	Median age 11.5 days, range from 9 days to 23 days, 2M, 2F	29–32, median weight 1375g, range from 1000g to 1660g	Placenta abruptio, severe perinatal asphyxia, enterocolitis, and other diagnoses.	Blood, catheter tip, feces and peritoneal fluid.	MBL (NDM-1)	ATM, CIP, TET, TGC, and CST	AMP + AMK; AMP + TZP; TZP+ GEN	MEM + rifampin; IPM + CIP	3 cured and 1 died
Debasmita Dubey et al 2013^Citation31	7-day-old, NR	31, 1250	Neonatal septicemia	Blood	MBL, ESBL	N (resistant to 17 antibiotics)	TZP + GEN	N	Died

Abbreviations: F, female; NR, not report; M, male; W, week; VLBW, very low birth weight; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; BSI, Bloodstream infection; UTI, urinary tract infection; EOS, early onset sepsis; LOS, late-onset sepsis; CSF, cerebrospinal fluid; TI, tracheal intubation; BAL, bronchoalveolar lavage; BA, bronchial aspirate; ESBL, extended-spectrum beta-lactamases; MBL, metallo-beta-lactamases; CRKP, carbapenem-resistant Klebsiella pneumoniae; CPKP, carbapenemase-producing Klebsiella pneumoniae; TGC, tigecycline; AMK, amikacin; GEN, gentamicin; CST, colistin; CAZ-AVI, ceftazidime-avibactam; TMP–SMZ, trimethoprim-sulfamethoxazole; IPM, imipenem; CHL, chloramphenicol; TET, tetracycline; FOF, fosfomycin; MEM, meropenem; ATM, aztreonam; CIP, ciprofloxacin; Van, vancomycin; SAM, ampicillin-sulbactam; TZP, piperacillin-tazobactam; AMP, ampicillin; CVVH, continuous venous-venous hemofiltration.

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