Patients with hematological malignancies are at high risk for acquiring healthcare-associated infections, many of which can be fatal. This is especially for bloodstream infections, for which the rapid diagnosis and the appropriate and timely therapeutic intervention are crucial for patient’s prognosis. Improving the medical intervention requires knowledge regarding patient’s characteristics and the local circulating bacterial strains. We present the case of a 55-year-old female, with multiple myeloma, in chemotherapy and hemodialysis, admitted in an intensive care unit due to a suspicion of bronchopneumonia. In the early hospitalization, she was diagnosed with an invasive listeriosis, which evolved favorably with ampicillin antibiotic treatment and after the removal of the venous hemodialysis catheter. On the nineteenth hospitalization day, Escherichia coli producing extended spectrum betalactamases had caused a severe sepsis. The strain was sensitive only to carbapenems, and its starting point remained unknown.
Pacienţii cu hemopatii maligne au un risc crescut de a contracta infecţii asociate asistenţei medicale, care le pot fi fatale. Acesta este în special cazul infecţiilor sanguine, pentru care diagnosticarea rapidă şi intervenţia medicală adecvată şi promptă sunt cruciale în prognosticul pacientului. Pentru a îmbunătăţi intervenţia medicală sunt necesare cunoştinţe despre caracteristicile pacienţilor şi ale tulpinilor circulante la nivel local. Prezentăm cazul unei femei de 55 de ani, cu mielom multiplu, în chimioterapie şi hemodializă cronică, internată într-o unitate de terapie intensivă pentru suspiciune de bronhopneumonie. La începutul spitalizării a fost diagnosticată cu o formă invazivă de listerioză, care a evoluat favorabil sub tratament cu ampicilină şi după îndepărtarea cateterului venos pentru hemodializă. În ziua a nouăsprezecea de spitalizare, o tulpină de Escherichia coli producătoare de betalactamaze cu spectru extins i-a cauzat un episod de sepsis sever. Tulpina a fost sensibilă numai la carbapeneme, iar originea acesteia a rămas necunoscută.
Nosocomial bloodstream infections are among the most important nosocomial manifestations due to their threat on patients’ lives. Their multiple determinism, implying the healthcare quality, challenges medical teams, who need to conduct rapid and appropriate therapeutic intervention(1-3).
Regarding the patient’s safety, there is a high risk of fatality, which is 25-30% in case of severe sepsis, and 30-70% in the septic shock stage(1,3-5). So far, the only ways to reduce this mortality is the early recognition with a rapid stage diagnosis, followed immediately by the selection and application of proper therapy. The main interventions for sepsis remain such as: the improvement of tissular perfusion by administering intravenous fluids and the control of infection by antibiotics(1,6). These medical measures must be applied in intensive care conditions, where the patient is also monitored mainly for the circulatory function in the first six hours, and are crucial for his prognosis.
The presence of Escherichia coli strains in the circulatory bloodstream triggers the immune response that is accompanied with the release of a great quantity of inflammatory mediators, leading to blood clots, leaky blood vessels and shock(1,3,5,7,8). The Escherichia coli strains involved in systemic infections can have as starting point a urinary tract infection, an infection of abdominal organs, abdominal cavity lining or even a pneumonic or cutaneous process(2,5). These strains are different from those that are causing diarrhea or are commensals, as they have many virulence factors encoded in specialized traits alongside the common genes to all Escherichia coli strains(5). The differentiation from commensal strains can be specifically detected through a comparative genome analysis. As origin, the virulence factors are mainly vertically inherited, but also can be horizontally acquired through transmission by plasmids, transposons, integrons, insertion sequence elements or phage-mediated transduction(5,8). In addition to virulence factors, the resistance to antibiotics facilitates the selection and the circulation of these invasive strains.
Etiologically, at European level, the Escherichia coli invasive strains are among the ten most frequently isolated bacteria from intensive care unit-acquired bloodstream infections(9). In the reports of The European Surveillance System (TESSy) for 2014 and of the European Antimicrobial Resistance Surveillance Network (EARS-Net) for 2002-2009, Romania has no reported cases of Escherichia coli bloodstream infections(9,10). For the medical practice, having information about epidemiological characteristics of Escherichia coli invasive regionally circulating strains is important for the timely and effective interventions for sepsis.
In this paper we present the multidimensional aspects of a hospital-acquired sepsis with Escherichia coli in a patient with immune impairment caused by hematological malignancy and antineoplastic therapy.
The patient was a 55-year-old female pensioner (due to sickness), resident in urban area, who was admitted in the intensive care unit for a suspicion of bronchopneumonia. She was having a history of 2-3 days of muco-purulent expectoration, chills, fever, vertigo, laboratory investigated thrombocytopenia, inflammatory syndrome, increased azotemia, and bronchopneumonic lesions (determined by radiological images). At the admission, the patient presented low blood pressure (93/57 mmHg), a heart rate of 66 beat per minute, oliguria (100 ml/24 hours), petechial, purpura skin lesions on abdomen and left costal area of the chest, mouth sores and reactive arthritis in both knees.
She was overweight, with 29.4 kg/m2 body mass index (80 kg weight, 165 cm height), never a smoker and not an excessively alcohol consumer.
Personal pathological antecedents included: a deep vein thrombosis (nineteen months earlier), bilateral fracture of humerus, and fracture by compaction of the vertebral bodies between the twelfth dorsal vertebra and the first lumbar vertebra of the spine, corrected in the previous year with vertebroplasty.
She presented associated diseases too, as following: high blood pressure in stage III, chronic kidney disease in stage G5 KDIGO, on hemodialysis (started three months earlier for four hours each session, for three session per week), and multiple myeloma with lambda chain in chemotherapy with the third treatment session of bortezomib-dexamethasone (Vel-Dex).
In the first hospitalization day the hypotension persisted, the arterial partial pressure of carbon dioxide was 29 mmHg, and she presented neutrophilia (87.4%), anemia (erythrocytes 3.47*106/µl, hemoglobin 10 g/dl, hematocrit 28.6%) thrombocytopenia (10,000/µl) and high level of C reactive protein (CRP: 5.63 mg/dl). Listeria monocitogenes, sensitive to all antibiotics tested (penicillin, erythromycin, ampicillin, meropenem, trimethoprim-sulfamethoxazole) was identified in the hemoculture from blood collected from the right jugular catheter which was used for hemodialysis. In dynamics, in the third day, the white blood cells (WBC) count elevated to 13,480/µl, the CRP to 9.53 mg/dl and the anemia (2.93*106/µl erythrocytes, 8.5 g/dl hemoglobin, 24.9% hematocrit) aggravated (Figure 1). Based on these data, the diagnosis of sepsis with Listeria monocitogenes was established. Leukocytes and CRP significantly decreased after initiating the treatment with ampicillin and mainly after the removal of the central venous catheter (CVC) in the fifth day.
During hospitalization, hemodynamic instability was always present, and it was constantly countered with low doses of noradrenaline through continuous infusion. The oxygen therapy was administered also continuously, through nasal cannula and starting from the nineteenth day, by intubation and mechanical ventilation. For the support of renal function, two sessions of hemodiafiltration were conducted (in the ninth and twentieth days). The administered blood (iso-group, iso-Rh: B III, Rh negative), five units of erythrocyte mass and two of thrombocyte mass were transfused as an attempt to correct the secondary anemia and the massive thrombocytopenia. For the exclusion of meningoencephalitis, the lumbar puncture was done in the nineteenth day, and in the prelevated cerebrospinal fluid, only an isolated cyto-albumin dissociation was identified.
As in the intensive care, the devices that were implanted to the patient were: a CVC in the left jugular vein, changed two times in the eighth and nineteenth days, a bladder catheter was also present at the admission and then removed on the fifth day of anuria, and the catheter of oro-tracheal intubation installed in the nineteenth day.
On the nineteenth day, in the context of a 38.1°C fever and the inflammatory parameters partially modified (particularly 91.4% neutrophilia), an Escherichia coli extended spectrum betalactamases (ESBL+) producing strain was identified in the hemoculture. This strain was not the same as the strain from sputum, for which the culture was made for the purpose of the etiological diagnosis of the suspected respiratory infection (Table 1). The invasive Escherichia coli strain was sensitive only to carbapenems and sulfonamides, and intermediate sensitive to amikacin.
While looking for the starting point of the Escherichia coli strain, it was observed that the peripheral hemoculture contained a strain of Staphylococcus cohnii, from the tip of the CVC, a strain of Staphylococcusepidermidis (over 15 colonies on the plaque) was identified, and from the tracheal aspirate, panresistant strains of Klebsiella pneumoniae and another of Acinetobacter baumannii were also identified. The positive hemoculture, and the increasing parameters of inflammation evolving to the depletion of leukocytes support the diagnosis of Escherichia coli of unknown origin sepsis, acquired in the intensive care unit (Figure 1).
The medical treatments for hydroelectrolytic and acido-basic rebalancing (physiological serum, Ringer solution, bicarbonate), inotropic, vasoactive and heart rate correction (noradrenaline, lidocaine, metoprolol), anticoagulant (enoxaparin), and analgesic (tramadol) were combined with the antibiotics administration for etiological treatment of listeriosis with ampicillin (2 grams daily for 14 days) and then for Escherichia coli sepsis with ertapenem (1 gram daily, from the twenty-third day to the end of hospitalization).
Clinically, during hospitalization the patient developed an erythematous rash on legs, abdomen and left arm (in the fifteenth day), edema on the legs (in the fourteenth day) which then spread even more (twenty-sixth day), and ecchymosis on abdomen and breasts on the tenth hospitalization day. The mouth sores evolved causing severe dysphagia (the patient was unable to eat). The initial petechial skin lesions have turned into pustular lesions in the fourth week of clinical evolution. On the eighteenth day the patient became comatose with an aggravated evolution of symptoms and died in the twenty-ninth hospitalization day. The anatomo-pathological examination was not performed.
This case report presented a patient with immunodeficiency caused by multiple myeloma, Vel-Dex cure of chemotherapy and chronic hemodialysis. This category of patients is at high risk to develop infections with fatal consequences. Due to the multiple myeloma’s complications presented by the patient such as bone fractures, deep vein thrombosis, kidney failure in hemodialysis, she required many medical interventions in ambulatory, hospital or at emergency, which increased the risk for healthcare‑associated infections. On the other hand, the patient expressed, by both clinically and laboratory parameters, a severe and uncontrollable thrombocytopenia during its entire evolution, and in the last two days of life, a massive decline of WBC count, and specifically of neutrophils, occurred. These particularities of the hematological disease, alongside to those linked to the individual’s, make the diagnosis and the treatment of infections more difficult than those for immunocompetent persons.
The invasive form of listeriosis was an episode of hemodialysis CVC associated bloodstream infection, having a positive hemoculture and the net amelioration of the manifestations (clinical and the inflammatory syndrome) within 48 hours after the removal of CVC(11). Listeriosis is known as a disease affecting immunocompromised patients, especially those with blood malignancies and chemotherapy, also pregnant women, infants and elderly. In the last years, at the European level, it was observed an increasing trend in the listeriosis frequency(12). The question that remains, through our observation, is how the contamination of the venous hemodialysis catheter had taken place, and what measures should have been taken to avoid it.
The second bloodstream infection with Escherichia coli was associated neither with venous catheters, nor with tracheal intubation or respiratory infection, due to the fact that different strains were identified and there was no sign of Escherichia coli. The strain of Staphylococcus cohnii in hemoculture and of Staphylococcusepidermidis in the tip of CVC reflected a transient bacteraemia and the colonization of the vascular catheter. Also, in the tracheal aspirate, the presence of Klebsiella pneumoniae and Acinetobacter baumannii was a colonization of the tracheal mucosa’s secretions. The sepsis was not polymicrobial because no other germs were identified when the bacteriological examination was repeated from different samples of the same biological fluid. The colonization, mainly by its prolonged duration due to ineffectiveness of nonspecific immune defense mechanisms, represents the first step in the occurrence of an infection with opportunistic germs(2). In this context, patients with hematological malignancies, who have a deficiency in all types of WBC, are at a high risk of infection due to hospital germs. In these circumstances, and in addition to treatment, controlling infections seems to require other measures that can interfere with germ exposure and with the particular response of the host to infection(1,6).
The Escherichia coli strain was producing ESBL and had resistance to first-line antibiotic treatment piperacillin-tazobactam, which was recommended for betalactamases producing strains. This profile of resistance is observed more and more frequently in patients with cancer, hematological malignancies and in those who are assisted in intensive care units(5,13,14). In the same studies, the mortality, in particular the 30‑day mortality, was found associated with the infections with ESBL producing Escherichia coli strains(5,13,14). This mortality is explained, from an etiological point of view, by the delay in the administration of the adequate antibiotic therapy(13,14). In our presented case, after the antibiogram has been done, the patient received ertapenem, part of carbapenems, which are widely regarded as the antibiotics of choice for the treatment of severe Escherichia coli ESBL infections, having at the present moment the lowest resistant rates(4,13). These facts underline the importance of knowing the sensitivity profile of the local circulating strains, especially in intensive care unit, the information allowing the rapid identification of the effective first intention antibiotic treatment, before the result of bacteriological determinations.
In the case of intensive care, devices and medication, which are necessary to maintain vital function of a patient with a hematological malignancy in a critical phase of evolution, would create risks that cannot be timely assessed because of the rapid change of the patient’s condition. The invasive medical acts and devices implanted and frequently manipulated represent portals of entry of selected resistant hospital germs. The different medication needed to be concomitantly administered can have many adverse drug reactions (ADRs) or can be involved in drug interactions leading to ADRs. ADRs may be responsible for aggravating the patient’s condition, thus increasing hospitalization costs due to the need to make additional clinical investigations, and may trigger the prescription of new medications for the often unrecognized ADRs(15). It remains to elucidate, in similar cases, if other mechanisms are involved as a cause or they have only an amplifying effect in the severe patient’s condition(13,16).
The patient presented two episodes of healthcare-associated infections, first a central venous catheter sepsis with Listeria monocitogenes associated to hemodialysis, and secondly, an intensive care unit acquired Escherichia coli sepsis with unknown origin. The multitude of invasive medical acts necessary for the treatment of an immunocompromised patient increases the risk of healthcare-associated infections and makes difficult the identification of the source of a systemic infection. A better understanding of the hematological malignant critically ill patient’s characteristics can clarify the ways of improvement of the medical assistance they need to prolong their life.
We thank to Hasan Ali Hameed for the interest manifested for studying the healthcare-associated infections in patients with hematological malignancies and for the contribution to drafting and critically reading the paper.
Conflictofinterests: The authors declare no conflict of interests.
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