Clinical and Microbiological Profile of Patients with Bloodstream Infections Caused by Burkholderia cepacia Complex

Introduction

Burkholderia cepacia complex (BCC) is ubiquitous in nature, present in water, soil, and plants. BCC is comprised of gram-negative non-lactose-fermenting bacteria. Burkholderia cepacia has emerged as an opportunistic nosocomial pathogen since the 1980s, particularly in patients with debilitating diseases. Based on molecular analysis, Pseudomonas cepacia has been separated from Pseudomonas and renamed as B. cepaci. BCC is a cluster of at least ten closely related genomic species, which includes B. cepacia, B. multivorans, B. cenocepacia, and others that can be differentiated by molecular and biochemical methods.^[1] It can cause fatal necrotizing pneumonia and bacteremia, especially in patients with cystic fibrosis or chronic granulomatous diseases.^[2-4] Pneumonia, meningitis, urinary tract infections, and bloodstream infections (BSIs) are caused by BCC in noncystic fibrosis patients. BCC is a new pathogen that is causing significant morbidity and mortality in hospitalized patients, owing to its high intrinsic antibiotic resistance.^[5] It has always been a tedious task for a routine microbiological laboratory to identify the nonfermenting gram-negative bacilli (NFGNBs), and poor laboratory proficiency in the identification of BCC prevails worldwide, including our own country. For this reason, reports of disease due to this organism are rare in India.^[6-10] Differentiation of BCC from P. aeruginosa is important as BCC is intrinsically resistant to aminoglycosides, first- and second-generation cephalosporins, and traditional antipseudomonal penicillins. Worldwide, among pathogenic NFGNB, BCC is the fourth most common after P. aeruginosa, Acinetobacter calcoaceticus-baumannii complex, and Stenotrophomonas maltophilia.^[5] In India, there is a dearth of data on BSIs caused by BCC; therefore, in this observational study, we aimed to advance our understanding of BSIs due to BCC, by analyzing the clinical epidemiology and antibiotic susceptibility pattern of these BCC isolates in our patient population.

Materials and Methods

Results

BCC was isolated from 30 BSI patients over a 2-year period. The age of the patient population ranged from 5 to 84 years, with a mean age of 38 (standard deviation: 11.5) years. The number of males and females enrolled in the study was 21 and 9, respectively, with a M:F ratio of 2.3:1. The incidence of nosocomial B. cepacia infections was very low in our hospital (0.32 per 1,000 admissions). The majority of patients in the study had hematological malignancy (17/30; 56%) and were mostly on chemotherapy. Other patients had coronary artery disease (5/30; 17%), solid organ malignancy (3/30; 10%), end-stage renal disease requiring dialysis (2/30; 7%), pancreatitis (2/30; 7%), and acute encephalitis (1/30; 3%).

The majority of Burkholderia complex species involved in clinical infections of the study were B. cepacia (19/30, 64%) and B. cenocepacia (9/30, 30%), but there was one isolate each of B. vietnamiensis and B. contaminans. The most common predisposing factors present in the study population were use of steroids, immunosuppressive drugs, and chemotherapy (93.3%) (►Table 1). Out of 30 patients, five patients suffered from coronavirus disease 2019 (COVID-19) pneumonia and had had bacterial coinfection with BCC. The identifications of these isolates were B. cepacia, B. cenocepacia, and B. vietnamiensis recovered from 3, 1, and 1 patients, respectively.

All 30 isolates showed 100% sensitivity to minocycline. Ceftazidime and meropenem were found to be sensitive in 73.3% and 70%, respectively, of the isolates. However, the sensitivities of levofloxacin, trimethoprim sulfamethoxazole, and piperacillin-tazobactam were 66.7, 60, and 53.3%, respectively. Only 16.7% of isolates were sensitive to ticarcillin–clavulanate (►Fig. 1).

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Fig. 1

Results of antimicrobial susceptibility testing of isolates of Burkholderia cepacia complex causing bloodstream infection.

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Discussion

The majority of data on nosocomial BCC infections in the literature are limited to epidemics,^[4] whereas our data show no epidemics and only sporadic cases of BCC infections. Ku et al studied BCC bacteremia and found BCC infection to be commoner in male patients (66.7%).^[14] Similarly our study also had a male preponderance with 70% of infected patients being male. The most common species of Burkholderia complex isolated in the study were B. cepacia and B. cenocepacia, which is similar to other studies.^[15,16] The most frequent risk factors in the study population were use of steroids, immunosuppressive drugs, and chemotherapy, which could be because most of the patients in the study had malignancy, which itself is an immunocompromised state. Besides, these patients received chemotherapy as well as lots of immunosuppressive drugs that cause low immunity in the patients. Hence, they were vulnerable to opportunistic infections such as Burkholderia, which is itself nonharmful to healthy people. Five patients suffered from COVID-19 pneumonia and had had bacterial coinfection with BCC. Long-term use of steroids also causes an increase in the rate of infections due to deranged cellular immunity, which could be cause of such infections in both cancer and COVID-19-positive patients. Other risk factors revealed in these patients were invasive procedures, mostly central line insertions like chemo ports as well as peripherally inserted central catheters. As central lines are essential in malignancy patients for long-term chemotherapy infusions, infection of central lines might happen during the insertion procedure as well as during the maintenance period. Biofilm formation in the central lines might cause bacteria to harbor and cause infections in the central lines associated with BSIs. Blood products through central lines might help in the formation of biofilms that might cause infections in central lines in these cases. Neutropenia will be caused by chemotherapy due to myelosuppression during the treatment. Diabetes itself causes an infection due to the deranged blood sugar level in patients. All the above predisposing factors that have been reported in earlier studies^[14,17] were also found to be present in our cases that might have resulted in Burkholderia infections.

BCC is intrinsically resistant to many antibiotics. It has been well documented that it has intrinsic resistance to aminoglycosides, first- and second-generation cephalosporins, and traditional antipseudomonal penicillins. The multidrug resistance of B. cepacia has been credited to an impermeable selective outer membrane, an efflux pump mechanism, and/or the production of an inducible chromosomal β-lactamase.^[18-20] In the current study, antibiotic susceptibility tests revealed that minocycline was the most effective antibiotics against BCC with susceptibility percentage (100%), followed by ceftazidime (73.3%), meropenem (70%), levofloxacin (66.7%), and trimethoprim sulfamethoxazole (60%). They exhibited moderate sensitivity to piperacillin–tazobactam (53.3%), while BCC isolates showed high resistance to ticarcillin–clavulanic acid (83.3%). The study done by Kady et al reported B. cepacia isolates to be 100% susceptible to meropenem, ceftazidime, and piperacillin-tazobactam, followed by cefepime (87.5%), cotrimoxazole, and minocycline (50%). All strains (100%) were resistant to both ciprofloxacin and ticarcillin–clavulanate.^[21] Omar et al in their study found that B. cepacia isolates were 88.5% susceptible to meropenem and 60% to ceftazidime. All are 100% resistant to both co-trimoxazole and ciprofloxacin.^[22]

Comparing the results of this study most of the isolates were sensitive to minocycline meropenem and ceftazidime as suggested by the CLSI guidelines, with varying sensitivity to other antimicrobials tested. On the other hand, this study showed high resistance (83.3%) to ticarcillin–clavulanic acid, which was almost similar to Kady et al (100%). From various studies finally, we could conclude that there were variations in the results of drug susceptibility that may be because of various antibiotic policies followed in different hospitals. So, there is need to properly isolate and do antibiotic sensitivity testing for each strain for better patient management.

Conclusion

As BCC is intrinsically resistant to many antibiotics, laboratory diagnosis with identification of these bacteria becomes mandatory. Moreover, due to the lack of advanced diagnostic facilities to confirm the etiological agent, they are reported as NFGNB or simply as Pseudomonas species. Thus, to facilitate diagnosis and appropriate antibiotic treatment, all NFGNB grown in clinical specimens should be speciated. Our study highlights BCC as an emerging pathogen causing BSIs, especially in malignancy patients. Minocycline can be a good choice for these bacteria.