Combination of aztreonam, colistin and tigecycline in the treatment of neonatal carbapenemase-producing Enterobacteriaceae infection: a case report

Abstract

The increased deployment of carbapenem antibiotics has led to a rise in carbapenem-resistant Enterobacter (CRE) prevalence. Notably, the incidence of CRE-related infections in neonatal intensive care units (NICUs) has surged, presenting significant clinical challenges. This case report emphasizes the treatment of neonatal CRE infections complicated by pneumonia and renal impairment and investigates the safety of tigecycline and polymyxin in pediatric settings. We conducted a retrospective analysis of clinical data from neonates with CRE-related pneumonia and renal impairment treated with a combination of tetracycline, polymyxin, and aztreonam. The case report assessed the risks and benefits of this regimen in managing neonatal infections and optimized the therapeutic protocol accordingly. In cases requiring invasive mechanical ventilation, infants exhibited enhanced respiratory mobility, managed spontaneous breathing, and showed occasional blood oxygen level fluctuations that normalized independently. Pulmonary ultrasound findings indicated a predominance of B-lines. The intervention controlled the infection effectively, leading to the infant's recovery and subsequent hospital discharge without significant adverse events. For neonates with CRE-related pneumonia and renal dysfunction, combining tetracycline and peptide antibiotics with other drugs effective against Escherichia coli, such as aminoglycosides, has shown to lower mortality rates associated with neonatal pneumonia caused by carbapenem-resistant Gram-negative bacteria. Our findings further elucidate CRE drug resistance mechanisms, antimicrobial selection, and pediatric safety for tetracyclines and peptides. Personalized combination therapy enhances treatment efficacy and minimizes adverse effects, particularly in cases involving drug-resistant bacterial infections.

Introduction

Neonatal infection significantly contributes to increased morbidity and mortality among newborns, particularly in preterm infants with underdeveloped immune systems. Despite advancements in medical care have enhanced neonatal survival and altered the disease landscape, neonatal pneumonia continues to be a significant cause of neonatal fatalities [1]. Between 2000 and 2015, of the 5.942 billion children under five years old, 2.681 billion (45.1%) deaths occurred in the neonatal phase, with neonatal pneumonia accounting for a mortality rate of 2.7% [2]. The predominant causative agents of bacterial pneumonia in neonates are group B Streptococcus and Escherichia coli [3].Other bacterial pathogens include Klebsiella, Staphylococcus aureus, and Streptococcus pneumoniae. Severe disease progression can lead to bacteremia, marked by hemodynamic changes and other clinical symptoms. Risk factors for neonatal nosocomial infection in intensive care units include premature birth, low birth weight, prolonged mechanical ventilation, and prior use of third-generation cephalosporins [4]. Nosocomial infections often exacerbate the severity of neonatal pneumonia, potentially leading to death.

In recent years, the widespread use of carbapenem antibiotics has escalated the prevalence of carbapenem-resistant Enterobacteriaceae (CRE). Notably, the incidence of CRE-related infections in neonatal intensive care units (NICU) has risen sharply, presenting significant clinical challenges. The 30-day mortality rate following the initial positive CRE blood culture stands at 21.59% [5]. Due to developmental factors, the basal metabolism of preterm infants may be compromised compared to that of full-term infants. In cases of hepatic or renal impairment, clinicians often face difficulties in selecting anti-infection treatments based on drug sensitivity results, potentially opting for tetracycline and peptide antibiotics. However, the safety, efficacy, and pharmacokinetics of these drugs in pediatric anti-infection treatment, particularly in neonates, remain inadequately defined. This review aims to underscore the challenges in treating CRE infections with concurrent renal injury in children and to assess the safety of tetracyclines in pediatric applications. Developing effective treatment strategies for neonatal CRE-associated septicemia is challenging. This article examines case data on the use of tigecycline and polymyxin combined with aztreonam in treating neonatal CRE-associated septicemia and reviews recent literature on the use of tetracyclines and peptides in pediatric anti-infective treatments, thereby suggesting new approaches for rational pediatric pharmacotherapy.

Case presentation

A neonate, 20 min postpartum, weighing 0.8 kg, was admitted to a local hospital due to respiratory distress observed 10 min post-delivery. The patient, born prematurely at 25 weeks and 5 days of gestational age via cesarean section, exhibited cyanosis and progressively developed dyspnea accompanied by inspiratory subcostal retractions. The mother, a gravida 1 para 2 (G1P2) woman, experienced premature rupture of membranes 6 days prior to delivery. Although the amniotic fluid was clear during labor, the mother had been prenatally diagnosed with suspected chorioamnionitis. The neonate also has a twin sister, who was admitted to the NICU.

Upon admission, the physical examination revealed the following: body temperature at 36℃, pulse rate at 128 bpm, respiratory rate at 59 beats/min, blood pressure at 48/29 mmHg, and oxygen saturation at 95% with trachea cannula. The patient exhibited inspiratory retractions, diminished breath sounds in both lungs without audible rales,a body length of 31 cm, alertness, coherent mental responses, ruddy complexion, robust heart sounds, and reduced muscle tone. Laboratory results indicated a white blood cell (WBC) count of 36 × 10⁹/L, neutrophil percentage (N%) of 81.4%, hemoglobin level of 138g/L, platelet (PLT) count of 153 × 10⁹/L, hs-CRP at 10.3mg/L, PCT count of 53.31ng/mL. Ureaplasma urealyticum DNA tested qualitatively positive. Bedside chest X-ray suggested a pneumonia-like pattern in the newborn. Initial diagnoses included neonatal sepsis, severe pneumonia, neonatal respiratory distress syndrome, respiratory failure, and Ureaplasma urealyticum infection.

Upon admission, the patient received invasive respiratory support, thermoregulation, intravenous and nasal nutrition, and anti-infection therapy. On the first day, cefotaxime and ampicillin, each at a dosage of 0.039g (50 mg/kg), were administered bi-daily for one to seven days. Additionally, a daily oral dose of azithromycin dry suspension at 7.8mg(10 mg/kg/time) was given for seven days. By the eighth day, the WBC was 31.57 × 10⁹/L, N% was 58.8%, and hs-CRP level was 2mg/L. Blood culture tests showed no bacterial growth over five days, yet the patient exhibited increased respiratory secretions and yellow mucous sputum, indicating suboptimal infection control. The patient's dyspnea was pronounced, and chest X-rays indicated disease progression. Consequently, treatment with cefotaxime and ampicillin was ceased, and cefoperazone sodium with sulbactam sodium at 0.039g (50 mg/kg) was initiated every eight hours.On the 11th day, the endotracheal tube cultured a small amount of Escherichia coli with CRE-resistant phenotype for the first time, but laboratory tests showed that WBC 23.93 × 10⁹/L,N% 56.7% 4.2mg/L, hs-CRP 4.2mg/L, which was better than before. We considered that the anti-infective effect was effective and thought that the bacteria might be colonized and continue the previous anti-infective program. On day 14, despite the adjusted treatment, the patient still showed severe respiratory symptoms, copious sputum production, and no improvement in inflammatory markers. Ureaplasma Urealyticum was negative at this time.Treatment with cefoperazone sulbactam sodium was halted, and meropenem at 0.035g(20 mg/kg) was administered every 6 h. By the 16th day of hospitalization, chest digital radiography(DR) revealed progressive bilateral lung lesions. The sputum cultures identified Escherichia coli with a CRE-resistant phenotype in a medium amount of quantity. This isolate was sensitive to aztreonam yet showed resistance to meropenem (MIC ≥ 16);the results are displayed in Table 1, and the creatinine level was 48.2 μmol/L, Consequently, meropenem was discontinued, and from day 16 to 24, the treatment included amikacin at 15 mg/kg once daily and aztreonam at 30 mg every 8 h. The peak plasma concentration of amikacin was aimed to be between 56–64 μg/ml, with a trough concentration of less than 1ug/ml. Initially, the peak and trough levels of amikacin were 64.44 μmol/L and 15.96 μmol/L, respectively. The dosage was subsequently reduced to 7.5 mg/kg once daily. On day 24, sputum cultures again isolated Escherichia coli with a large number CRE-resistant phenotype, and creatinine was measured at 69.7 μmol/L. On day 24, the patient exhibited high respiratory effort, mild fever, and reliance on invasive mechanical ventilation. Lung ultrasound indicated C2 (consolidation).According to the treatment plan, chest DR findings showed progressive pulmonary lesions, excessive respiratory secretions, and an elevated creatinine level, leading to adjustments in ventilator parameters. Based on all relevant data, the CRE isolated from sputum culture was identified as a potential pathogen despite ongoing antibiotic therapy.Treatment with amikacin was discontinued and, following parental consent (documented via signed informed consent), aztreonam (0.026g, 30 mg/kg, ivvp, q12h) and an initial double dose of tigecycline (1.2mg/kg, ivvp, q12h) were administered, along with colistin (1.8mg, nebulized, q12h) and fluconazole (0.01g, 12mg/kg, ivvp, q48h).After 17 days of combined anti-infection therapy, the patient exhibited a slight increase in respiratory effort while on invasive ventilator support,with acceptable spontaneous breathing and transient fluctuations in blood oxygen,which gradually normalized. The patient remained afebrile and tolerated feeding well. Laboratory results showed a WBC of 9.26X10⁹/L, N% of 18%, hs-CRP of 5.5mg/L, and creatinine of 38.8 μmol/L. The sputum cultures were negative, no fungal hyphae or spores were observed in sputum fungal smears, and lung ultrasound indicated a predominance of B1 lines.

Table 1.

Antibiotics susceptibility tests for Escherichia coli

Antibiotics	MIC (mg/L): susceptibility interpretation
	Hospital day 10; source: sputum	Hospital day 16; source: sputum	Hospital day 21; source: sputum
Ceftriaxone sodium	≥ 64:Resistant	≥ 64:Resistant	≥ 64:Resistant
Amoxicillin/clavulanic acid	≥ 32:Resistant	≥ 32:Resistant	≥ 32:Resistant
Imipenem	≥ 16:Resistant	≥ 16:Resistant	≥ 16:Resistant
Meropenem	≥ 16:Resistant	≥ 16:Resistant	≥ 16:Resistant
Tetracycline	≥ 16:Resistant	≥ 16:Resistant	≥ 16:Resistant
Ceftazidime	≥ 64:Resistant	≥ 64:Resistant	≥ 64:Resistant
Amikacin	≤ 2:Susceptible	≤ 2:Susceptible	≤ 2:Susceptible
Piperacillin/tazobactam	≥ 128:Resistant	≥ 128:Resistant	≥ 128:Resistant
Tigecycline	≤ 0.5:Susceptible	≤ 0.5:Susceptible	≤ 0.5:Susceptible
Moxifloxacin	1:Susceptible	1:Susceptible	1:Susceptible
Aztreonam	≤ 1:Susceptible	≤ 1:Susceptible	≤ 1:Susceptible
Cefoperazone/sulbactam	9 mm:Resistant(K-B)	8 mm:Resistant(K-B)	8 mm:Resistant(K-B)

The patient exhibited no adverse drug events during hospitalization. The clinician will monitor the patient for common and potential adverse events, including tooth discoloration and metabolic issues affecting renal function.

Figure 1 presents the timeline of drug treatment. Parental consent was obtained to publish this case report, including all associated results and images, in academic journals. All procedures involving human participants adhered to the ethical standards of the relevant institutional and national research committees and conformed to the 2013 revision of the Helsinki Declaration.

Fig. 1.

Timeline of drug treatment

Discussion

Drug resistance mechanism of CRE

Global studies estimate the annual incidences of neonatal sepsis to be between 1.3 and 3.9 million neonatal sepsis cases,with 400,000 to 700,000 neonatal deaths annually [6]. Recent meta-analyses indicate a global neonatal sepsis incidence of 2,824 per 100,000 live births [7]. Notably, microbial cultures identifying gram-negative bacteria, such as Escherichia coli, often reveal the presence of extended-spectrum β-lactamase resistance genes, including blaTEM, blaSHV and blaCTX-M-15, as well as carbapenemase resistance genes such as blaOXA-23-like, blaOXA-48-like, and blaNDM, These genes impart resistance to a broad spectrum of beta-lactam antibiotics. Carbapenemases are categorized into three classes: Class A (serine carbapenemases),which includes blaKPC, blaSME, blaIMI, blaNMC, and blaGES; Class B (metalloβ-lactamases),which includes blaNDM, blaIMP, blaVIM, blaGIM, and blaSPM; and Class D, which comprises blaOXA-181 and blaOXA-232, categorized as OXA-48 serine carbapenemases.

KPC and NDM carbapenemases are predominantly produced by CRE strains isolated clinically in China, with OXA-48, IMP, and VIM types also detected in a limited number of strains. Among these, Klebsiella pneumoniae and Escherichia coli are the most frequently isolated CRE strains. Escherichia coli primarily produces NDM metalloenzymes [8]. In pediatric cases, carbapenem-resistant Klebsiella pneumoniae strains typically produce KPC, NDM, and OXA-48 carbapenemases, whereas strains isolated from adults predominantly produce KPC carbapenemases. Both pediatric and adult isolates of carbapenem-resistant Escherichia coli mainly produce NDM metallo-β-lactamase [5].

Selection of antimicrobial agents for CRE children with poor renal function

Combining at least two antimicrobials is necessary for treating CRE, although the optimal antibiotic combination remains undetermined. The rationale for combination therapy includes a higher mortality rate associated with severe CRE infections, evidence suggesting that combination therapy reduces mortality, and concerns regarding resistance with monotherapy [9–11]. Notably, 31% of neonatal deaths annually are linked to septicemia, with Enterobacteriaceae constituting 80% of the gram-negative pathogens responsible for neonatal septicemia. A particularly alarming trend is the rise of carbapenem-resistant strains in gram-negative neonatal infections, limiting treatment options for CRE infections [12, 13]. In vitro drug sensitivity testing indicated that amikacin, moxifloxacin, aztreonam, and tigecycline are preferable. Based on these tests, a regimen of amikacin combined with aztreonam was administered; however, nine days post-treatment, patient sputum cultures still yielded Escherichia coli with a CRE drug resistance phenotype at a medium dose.

CRE typically exhibit high sensitivity to tigecycline, colistin, and new β-lactamase inhibitors such as ceftazidime-avibactam. Conversely, these organisms are highly resistant to most β-lactam antibiotics, including carbapenems,and quinolones, and are generally resistant to aminoglycosides [8]. Guidelines recommend ceftazidime-avibactam in combination with aztreonam or cefiderocol as the preferred treatment for infections involving NDM and other metallo-β-lactamase infections [14]. Meta-analyses suggest that the combination of ceftazidime-avibactam and aztreonam is superior due to fewer side effects and reduced adverse clinical outcomes in patients with metallo- β-lactamase infections [15]. Additionally, guidelines indicate that evidence supporting the use of ceftazidime-avibactam and aztreonam as a first-line treatment for CRE infections that produce metallo-β-lactamases is extremely limited. It is advisable to identify the specific carbapenemase type produced by CRE strains before initiating treatment with ceftazidime-avibactam [16].

This report discusses a very premature infant diagnosed with neonatal septicemia and severe pneumonia. On day 16 of hospitalization, due to the unavailability of ceftazidime-avibactam in our hospital formulary and the patient’s ongoing clinical progression, we initiated treatment with amikacin and aztreonam based on antimicrobial susceptibility testing results. On the second day of therapy, the measured peak and trough plasma concentrations of amikacin were 64.44 μmol/L and 15.96 μmol/L, respectively–both above the target range–prompting a 50% reduction. By hospital day 21, the patient’s serum creatinine had risen to 69.7 μmol/L, indicating impaired renal function and necessitating a reevaluation of the treatment regimen. According to IDSA guidelines [17], a combination of ceftazidime-avibactam and aztreonam is recommended as first-line therapy for metallo-β-lactamase-producing infections. However, ceftazidime demonstrates relatively low distribution into bronchial epithelial lining fluid and plasma [18], and is primarily eliminated via renal excretion, leading to a significantly prolonged serum half-life in patients with renal impairment. Considering these factors, we decided not to use ceftazidime.

The apparent distribution volume of tegacycline is large. Studies have indicated that the AUC of tegacycline in alveolar cells is higher than in plasma, and the AUC in the mucosal layer of epithelial cells exceeds that in serum. The primary excretion pathway for tegacycline is biliary, with renal excretion being secondary [19]. Although polymyxin nephrotoxicity is significant, intravenous antibiotics combined with nebulized colistin inhalation are recommended for patients with hospital-acquired pneumonia or ventilator-associated pneumonia caused by multi-drug-resistant enterobacteria [9, 20]. Due to the lower incidence of nephrotoxicity associated with nebulization, and the higher likelihood of airway complications from polymyxin B, colistin is the preferred form of inhaled colistin.

Safety of polypeptide drugs in children

Since the early 1960 s, adverse reactions to colistin, primarily reported in adult studies, have shown an incidence of up to 50%. These reactions include nephrotoxicity and, less commonly, neurotoxicity. Recently, data from the FDA adverse reaction reporting system indicated that colistin carries the highest risk of acute kidney injury among antimicrobial therapies [21]. Currently, evidence regarding colistin inhalation in pediatric populations is limited to small-scale retrospective studies, with most infants receiving inhaled colistin alongside systemic antimicrobials [22]. Colistin monotherapy was successful in 17 newborns with ventilator-associated pneumonia caused by Acinetobacter baumannii [23, 24]. A retrospective comparative study demonstrated that colistin has good pulmonary permeability and may serve as an adjuvant or alternative therapy for ventilator-associated pneumonia due to colistin-sensitive multidrug-resistant Gram-negative bacteria in neonates. Moreover, colistin-related nephrotoxicity and neurotoxicity were less frequently observed in newborns treated with colistin [25].

Safety of tetracyclines in children

Doxycycline and minocycline are commonly used tetracycline antibiotics, with the subsequent development of glycylcycline derivatives led to the introduction of tigecycline, the first of its class. According to FDA guidelines, tigecycline is not approved for use in children and should only be considered in pediatric patients when no alternative antimicrobials are available [26]. As a tetracycline derivative, tigecycline carries a risk of permanent tooth discoloration in children under 8 years of age, particularly with repeated courses of treatment [27]. Nevertheless, when the potential benefits outweigh the risks to tooth development, tigecycline may be employed in the rescue treatment of severe infections in young children. In a retrospective study involving 110 children, including 46 patients with multidrug-resistant Acinetobacter baumannii infections (totaling 51 strains), tigecycline was administered for an average of 10 days, resulting in a clinical improvement rate of 47.27%. In the Acinetobacter baumannii infection subgroup, the clinical improvement rate was 50%, with a microbial eradication rate of 50.98%. Only one 9-year-old boy with hematological disease developed tooth discoloration, and no other adverse events were reported [28]. Another retrospective study in 101 children under 8 years old receiving tigecycline found a moderate incidence of permanent tooth yellowing [29]. A multicenter prospective study reported that tigecycline has a safety profile in children comparable to that in adults, with the most common adverse reactions being nausea and vomiting, and no significant association between drug exposure and these symptoms.

In this report, the patient received tegacycline at a dosage of 1.2 mg/kg, ivgtt, q12h for 17 days, resulting in symptom relief. As the patient was a newborn, tooth discoloration could not be assessed at the time. Post-discharge, long-term follow-up is required to monitor prognosis, including regular dental examinations, and to detect any yellow staining of permanent teeth.

Conclusions

Clinical pharmacists, by participating in the adjustment and the dose recommendation of antibiotics for neonatal septicemia, advise that the combination of sensitive antibiotics be selected based on evidence-based results for the treatment of multidrug-resistant Escherichia coli pneumonia in children. This approach can reduce mortality and prevent the development of drug resistance associated with monotherapy. In this case report, aztreonam combined with tigecycline and colistin was used to manage and alleviate neonatal pneumonia. The duration of tigecycline treatment should not be prolonged, typically limited to about two weeks. During treatment, it is crucial to evaluate both the therapeutic efficacy and the occurrence of adverse drug reactions, with long-term follow-up and dynamic adjustment of the drug regimen based on therapeutic outcomes and any adverse events. Supportive care, including adequate oxygenation, prevention of hypoglycemia, effective sedation, and nutritional support, is equally important. Additionally, stringent management of nosocomial infections, such as timely nursing care, hand hygiene, contact isolation, and environmental cleaning, should be emphasized.

Authors’ contributions

Han Wang and Yangyang Tan contributed to the conception and the collection of the clinical information. Han Wang searched and reviewed relative literature. Yangyang Tan helped to review the article. All authors read and approved the final manuscript.

Funding

This work was supported by the Chengdu Municipal Health Commission (Grant Number: 2023001).

Data availability

Data on patient and case details are available from the author on reasonable request.

Declarations

Ethics approval and consent to participate

This retrospective case report was approved by the Ethics Committee of the Chengdu Women's and Children's Central Hospital, with the approval number: Scientific Research Ethics Approval 2022 (No. 65).

Consent for publication

Written informed consent was obtained from the patient’s parents for publication of this case report.

Competing interests

The authors declare no competing interests.