The course of the patient’s illness illustrates an increasingly relevant problem: serious infections caused by multidrug-resistant bacteria acquired abroad.
Burn wounds are rapidly colonised by bacteria from the patient’s own flora or from the environment. Nevertheless, bacterial growth on wound surfaces does not necessarily mean a wound infection that must be treated. More emphasis must be placed on local signs of inflammation, and particularly on microbes in samples from normally sterile areas, such as the blood, lower respiratory tract or central venous catheter in this case.
Both operations on and care of burn wounds may cause transient bacteriaemia. Figures for the frequency of transient bacteriaemia in connection with the cleaning of large burn wounds have varied from 13 % to 65 % (3, 4).
For the first twenty four hours after arrival at the Burn Centre, the patient was given piperacillin-tazobactam. An overall clinical assessment after the wound surfaces had been thoroughly cleaned did not give grounds for continuing with antibiotics. In retrospect we also know that all Gram-negative isolates from normally sterile areas proved subsequently to be resistant to piperacillin-tazobactam.
The microbiological analyses of the wound samples were very work-intensive because we found up to ten different species of bacteria. Most of the Gram-negative isolates proved to produce plasmid-mediated ESBL types (ESBLA, ESBLM-C, ESBLCARBA). It is probable that the patient’s multidrug-resistant isolates were acquired during her stay in a hospital in Pakistan. Several studies have shown that travel and hospital stays abroad, particularly in the Indian subcontinent, are risk factors for colonisation or infection with multidrug-resistant microbes (5) – (7). Isolation and screening of patients are important for avoiding secondary spreading. Although such isolates are rare in Norway, outbreaks secondary to ESBLCARBA-producing isolates introduced through importation have been described (8).
There has been a steady increase in the use of carbapenems in Norway since 2006 (9). The agents are effective, with a very broad-spectrum antibacterial effect and moderate toxic adverse reactions. Studies show a clear association between liberal use of broad-spectrum antibiotics and the frequency of resistance (10) – (12). A study from the Burn Centre in question in Islamabad is also highly relevant, as it showed that in 2012 24 % of K. pneumoniae isolates and no less than 36 % of P. aeruginosa isolates in burn patients in Islamabad were resistant to imipenem (13).
There are clear Norwegian guidelines for screening for possible MRSA infection/colonisation of patients who have been admitted to hospitals outside the Nordic countries (14). Our experience indicates that the same level of focus must be on determining whether patients transferred from abroad are infected, or colonised, with multidrug-resistant Gram-negative rod bacteria or VRE. New recommendations from the Norwegian Institute of Public Health recommend that all patients who have been in health institutions outside the Nordic countries be tested for ESBL-producing bacteria if they are later admitted to Norwegian hospitals (15).
Rapid microbiological diagnostics and targeted treatment are crucial for effective treatment of serious systemic infections caused by multidrug-resistant bacteria. In the present case, new methods such as mass spectrometry, direct resistance testing and gene technology methods permitted faster results for methicillin-resistant Staphylococcus aureus and suspicion of ESBL-producing Gram-negative bacilli.
The incidence of methicillin-resistant Staphylococcus aureus, linezolid- and/or vancomycin-resistant enterococci and Gram-negative rod bacteria with detected carbapenemases (ESBLCARBA) is monitored through the Norwegian Surveillance System for Communicable Diseases (MSIS) for public health reasons. ESBLCARBA, also called carbapenemases, are β-lactamases that can deactivate carbapenems in addition to other β-lactams (16). Isolates with ESBLCARBA are rare in Norway (9), but rapidly increasing worldwide. The global spread of enteric ESBLCARBA -producing Gram-negative bacteria gives grounds for particular concern because of multidrug-resistance with very few or no effective treatment options.
Several ESBLCARBA-positive isolates were also resistant to aminoglycosides and fluoroquinolones. This combination provides broad-spectrum resistance to the antibiotics groups that are most important in our treatment of severe bacterial infections. The genes that code for these resistance mechanisms are mainly located on mobile DNA elements that can easily be transferred between different species of bacteria. This results in more effective dissemination of resistance in a bacterial population in particular under antibiotic selection.
The choice of antimicrobial therapy under such circumstances is very difficult and experimental. There are currently ongoing but not yet available randomised clinical trials to provide an evidence-based therapy option (16, 17). Summaries from a number of observational studies support the choice of combination therapy rather than monotherapy for multidrug-resistant ESBLCARBA-producing Enterobacteriaceae (17, 18). Meropenem/doripenem and colistin should be included in these therapies. In addition, an aminoglycoside, tigecycline, phosphomycin or rifampicin can be added, depending on resistance patterns. Tängden and Giske (16) recommend a combination of colistin and meropenem if the minimum inhibitory concentration (MIC) for carbapenem is ≤ 4 mg/l. If MIC for carbapenem is > 8 mg/l or for empirical treatment of suspected ESBLCARBA sepsis without known resistance, three agents should be chosen by adding tigecycline to colistin and meropenem. Due to a frequent link between aminoglycoside and carbapenem resistance, aminoglycosides are a doubtful choice as a third agent. Colistin as monotherapy is not recommended because of the high risk of therapy failure (16).
When transferring patients after extensive hospital treatment abroad, routine consultation with infection control personnel is recommended. Patients must be isolated on arrival at a hospital in Norway. It is a matter for discussion whether the isolation routines should be maintained in certain cases even if screening tests for MRSA and other resistant bacteria are negative, particularly because ongoing antibiotic therapy during sampling may result in false-negative test results. This applies particularly if a patient has a wound with secretion, has had intensive care treatment, has been treated for burn injuries or undergone surgery abroad.
More than a year after the patient’s death, we have not re-encountered any of the multidrug-resistant isolates in clinical isolates from patients who have subsequently been treated in the department.