Gram-negative meningitis and the significance of SPICE organisms

CASE 1

A 6-week-old term female infant born via emergency Caesarean section for fetal bradycardia was admitted to exclude meningitis. She was febrile, anorexic, and irritable with a bulging anterior fontanelle. Empiric treatment with vancomycin and cefotaxime was started. Blood and cerebrospinal fluid (CSF) cultures showed no growth. MRI head confirmed the presence of a large abscess. The abscess was drained and cultures grew Citrobacter sp. Antibiotics were changed to meropenem and later ceftriaxone once the bacteria was further identified as Citrobacter koseri. Serial MRI monitoring directed two further abscess aspirations. The course was complicated by increasing hydrocephalus, requiring placement of an external ventricular drain, and as well by focal tonic clonic seizures. The latter were treated with phenobarbital followed by levetiracetam. After over 2 weeks, she was discharged home to complete parenteral therapy as an outpatient. At 12 weeks, MRI showed improvement but there was new and progressing high T2 signal in the left temporal white matter. She was developing neutropenia (absolute neutrophils 0.4) from prolonged ceftriaxone use. Outpatient antibiotics were changed to ceftazidime. Antibiotics were discontinued after a follow-up MRI showed improvement in the abscess compared to initial imaging.

CASE 2

A 2-week-old term male infant presented to the emergency department with fever, irritability and two episodes of ‘shivering’ without eye deviation or tonic posturing. His mother had received intrapartum antibiotic prophylaxis for Group B Streptococcus. Upon admission, a full septic workup was completed. IV ampicillin and cefotaxime were started empirically. Head ultrasound and MRI head were normal. CSF findings were as follows: WBCs 3361 × 10⁶/L (67% segmented neutrophils), RBCs < 1,000 × 10⁶/L, protein 2.07 g/L, glucose 1.7. CSF and blood cultures grew C. koseri (resistant to ampicillin, sensitive to meropenem and ceftriaxone). Antibiotics were switched to ceftriaxone and continued for 21 days.

DISCUSSION

Citrobacter species are opportunistic Gram-negative bacilli that can be found in gut flora. They can cause nosocomial and community-acquired infections, particularly in neonates, infants and immunocompromised adults. Citrobacter infection occurs in the urinary tract in about 50% of cases. Other common sites of infection include the respiratory and gastrointestinal tracts, the central nervous system (CNS), blood, bone, and endocardium. Most infections are caused by Citrobacter koseri (formerly known as C. diversus). This species has been associated with neonatal meningitis outbreaks due to fecal colonization in infant guts and nosocomial transmission. Citrobacter infection (particularly C. koseri) confers an especially high risk of abscess formation requiring neurosurgical intervention (1). Therefore, all infants with Citrobacter infections of the CNS should have head imaging.

Citrobacter is a SPICE organism (Serratia, Providencia, indole-positive Proteus, Citrobacter, Enterobacter, and some other less common pathogens) (2). This group is unique because of its tendency to develop resistance to beta-lactam antibiotics. The genomes of SPICE organisms encode AmpC, an inducible beta-lactamase. The expression of this gene increases upon exposure to beta-lactam antibiotics, so organisms may initially appear susceptible and become resistant to beta-lactams within days or weeks. After stopping treatment, AmpC gene expression returns to baseline levels. Importantly, beta-lactamase inhibitors like clavulanic acid and tazobactam do not effectively inhibit AmpC beta-lactamases (2,3). Due to the development of beta-lactam resistance, carbapenems are the appropriate choice of antibiotics if initial culture results show the presence of Citrobacter sp.

Citrobacter koseri, however, is not a classic SPICE organism. Its genome does not contain AmpC, so it does not develop beta-lactam resistance through this mechanism. Thus, C. koseri infections usually respond to cephalosporins and can be treated with ceftriaxone. Importantly, Citrobacter infections should be treated with carbapenems and it is only safe to switch to a cephalosporin once the species has been identified as C. koseri. In such cases, it is essential to consult with infectious disease specialists when considering changes to antibiotic therapy.

Informed Consent: Informed consent was obtained from the parents of both infants whose cases are described in this manuscript.

Funding: There are no funders to report for this submission.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.