The last decade is characterized by a visibly decreasing tendency to introduce new antibacterial drugs. However, relatively widespread use of antibiotics creates favourable conditions for selection of new multidrug-resistant strains of pathogens, which are called multidrug-resistant (MDR), extensively drug-resistant (XDR) or pandrug-resistant (PDR) [1].

Infections with multidrug-resistant pathogens develop mainly in patients with impaired immunity treated in ITUs. The majority are patients with neutropaenia caused by the disease itself who receive immunosuppressant drugs. This group also includes long-hospitalized patients with severe underlying diseases who undergo invasive diagnostic and therapeutic procedures requiring multiple surgical interventions with the drains left and thus on parenteral feeding for many months.

The risk factors of infections with multidrug-resistant pathogens are numerous. The importance of spread of such infections by hands of the medical staff is increasingly stressed. ITU is the centre of selection and spread of resistant pathogens in hospitals [2]. The choice of an antibiotic depends on antibiotic susceptibility of the isolated strain. Determination of the minimal inhibitory concentration (MIC) of isolated strains seems equally relevant (especially in critically ill patients) [2].

The objective of this report was to present a case of effective treatment of multidrug-resistant bacterial infection.

CASE REPORT

A 59-year-old male patient was admitted to ITU after re-laparotomy due to wound dehiscence. The primary procedure was pacreatoduodenectomy because of tumour of the Vater`s ampulla. The patient`s past history included coronary disease, myocardial infarction (9 years earlier) and well-controlled arterial hypertension. Prophylactically, cephamandole 1 g was administered perioperatively in three doses followed by amoxicillin/clavulanic acid over 10 days. Since the general condition of the patient deteriorated and inflammation parameters increased (CRP 304 mgL-1, leucocytosis 30 G L-1, PCT 20 ng mL-1), the patient was re-operated on day 12. On day 2 of ITU therapy, the patient ran a fever – 39.8 oC. Cultures were collected and the peritoneal lavage performed; no purulent content was found. The additional tests revealed elevated levels of troponin – to 10 ng mL-1 without ECG features of acute myocardial ischaemia. On day 3, body temperature increased to
40o C; shivers, supraventricular tachycardia (150 min-1), decreased SpO2 to 80%, and SAP/DAP to 70/40 mmHg were observed.

The patient was intubated and SIMV instituted at FIO2 0.5. Septic shock was diagnosed and catecholamines were introduced. Samples for further cultures were collected. ECG showed the ST depression in V4-V6 leads and an increase in troponin to 16.7 ng mL-1. The patient was diagnosed with acute coronary syndrome; he remained feverish. The discharge of the brown, intestinal content from the surgical wound was observed and the patient was scheduled for another surgery.

From the first ITU cultures, Enterobacter cloacae (extended-spectrum beta lactamase – ESBL) sensitive only to imipenem and fully sensitive Klebsiella pneumoniae were isolated in blood and peritoneal fluid. In accordance with the antibiogram, imipenem 4 g per day was included in the continuous infusion. In the next culture (day 5 of ITU therapy) from the peritoneal cavity, Klebsiella pneumoniae and Acinetobacter baumannii were detected. Both strains were sensitive to doxycycline and tigecycline. Acinetobacter baumannii was sensitive to ampicillin/sulbactam and cefoperazone/sulbactam. In the same material, Enterobacter cloacae and Klebsiella pneumoniae were additionally isolated. Considering the persistent fever and severe condition of the patient despite peritoneal lavage, the administration of tigecycline was decided, on day 1 the first dose – 100 mg followed by 50 mg, and 50 mg 2 times a day for further two days. Tigecycline was administered simultaneously with imipenem using the prolonged infusion. Antibiotics were administered in turns. After the inclusion of tigecycline, the time of imipenem/cilastatin infusion was shortened (from the continuous to prolonged infusion). For safety reasons, between successive doses of antibiotics, the 30-minute infusion of 0.9% NaCl was administered. After two days of combined therapy, the patient`s condition improved considerably (decrease in leucocytosis, CRP, PCT and body temperature).

On day 4 of combined therapy, bacteriological tests showed eradication of strains. On day 5, the patient was extubated and respired spontaneously. On day 7, he was operated on due to alimentary haemorrhage. The next laparotomy did not reveal purulent foci in the peritoneal cavity. After 10 days, antibiotics were discontinued. The patient`s condition improved during the successive days and he was transferred to the referring ward.

DISCUSSION

Multidrug-resistant bacterial infections are one of the major problems in patients treated in ITUs. Numerous risk factors and possible patient-patient spread of strains may result in multiple, repeated infections deteriorating the patients` condition. The etiological factors are likely to include various or even the same strains. The Enterobacter strain is the fifth most common pathogen causing ITU infections [3]. The common causes of ITU infections are type I beta-lactamase producing strains, which in the majority of cases are resistant to beta-lactamase inhibitors, such as clavulanic acid, sulbactam or tazobactam, hence the treatment with them is ineffective [3]. In our patient, who underwent the extensive surgical procedure due to the underlying disease, therapy with amoxicillin/clavulanic acid was the probable risk factor of ESBL-producing strain infection.

Extended substrate spectrum enzymes are encoded on plasmids [3]. The genetic material can be transferred between the Enterobacteriaceae strains and between the strains of other Gram-negative bacteria [1, 3]. Moreover, the ESBL-producing strain limits markedly the therapeutic options to few available antibiotics. The use of imipenem/cilastatin seems to be the only proper choice. The extensive zone of growth inhibition (sensitivity was determined using the disc diffusion method – growth inhibition zone >24 mm, and the automated method in which MIC <4 µg mL-1) is likely to eradicate the pathogens.

Furthermore, the efficacy of therapy (particularly in such a complicated case) depends on the concentration achieved at the infection site (1.8 m2 of the peritoneum) and the time when the concentration exceeds MIC for a given strain. In cases of multidrug-resistant Gram-negative bacterial strains, T>MIC is 70 % [4, 5, 6]. For pathogens with MIC<2 µg mL-1, the infusion of 1g of imipenem/cilastatin enables to maintain the concentration above MIC over 8 h [6]. Therefore, in infections caused by multidrug-resistant strains, the continuous or at least prolonged infusions seem appropriate.

Additionally, it should be emphasized that all measurements carried out regard the central compartment and the antibiotic concentration was determined in blood. The PK/PD parameters (pharmacokinetics and pharmacodynamics) neglect the tissue concentrations and all stages of antibiotic transfer from the central to tissue compartment [4, 5]. Unfortunately, determination of those concentrations in severely ill patients is still infeasible [4, 5].

In healthy individuals, Acinetobacter baumannii rarely causes infections. In severely ill patients, it is responsible for pneumonia, urinary infections, peritonitis or even cerebrospinal meningitis [7]. The strain isolated in our patient was resistant to imipenem (growth inhibition zone <13 mm, MIC >16 µg mL-1) and susceptible to tigecycline (MIC <2 µg mL-1). The combined therapy administered (together with surgery) improved the patient`s condition. Tigecycline is a minocycline derivative capable of overcoming the resistance to tetracyclines [8]. It is a bacteriostatic antibiotic. Its bacterial activity depends on time and the component is concentration-dependent [8, 9]. Tigecycline is characterized by high volume of distribution and good penetration to various sources of intra-abdominal infections. Its use in the prolonged infusion may result in success. In such cases, the concentration above MIC for a particular strain should be T >40 %. The antibiotic in question is active against Gram-positive, Gram-negative, anaerobic and atypical microorganisms [8]. According to numerous studies, tigecycline was active against such multidrug-resistant microorganisms as MRSA and VRE [8]. The activity against Acinetobacter baumannii strains is variable. There are some literature reports describing the cases of ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii effectively treated with tigecycline [10]. However, the antibiotic does not show the activity against Pseudomonas aeruginosa strains [10]. 

The studies comparing the efficacy of tigecycline and carbapenems underline their possible adverse effects on the alimentary tract and clotting system. Both antibiotics are likely to induce thrombocytopenia in about 6% of cases [10]. In the combined therapy, adverse side effects may increase. Clotting disorders occur in about 10-15% of patients with septic shock and are caused by infections (including those with multidrug-resistant strains).

In our case, no adverse side effects following combined therapy were observed. Moreover, chemical incompatibility of the antibiotics used was not noted. Extensive surgical procedures are associated with the risk of complications, especially in abdominal surgeries. Multiple re-operations, invasive diagnostics and monitoring pose the risk of infections with multidrug-resistant infections. The therapeutic success depends on the entire therapeutic management (antibiotic therapy and surgery). In extremely difficult clinical cases, combined therapy may be effective. The clinical experience with tigecycline, a novel drug, is relatively sparse. The clinical cases described suggest that tigecycline is going to be used in severe infections provided that administered with caution and according to indications or recommendations.

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REFERENCES

1.    Hryniewicz W, Gniatkowski M: Oporność na karbapenemy u pałeczek Enterobacteriacae w wyniku wytwarzania karbapenemaz – wytyczne postępowania. Nowa Klinika 2009; 16: 703-705.

2.    Silvera F, Fujitani S, Paterson DL: Antibiotic-resistant infections in the critically ill adult. Clinics in Laboratory Medicine 2004; 24: 329-341.

3.    Clark NM, Patterson J, Lynch JP: Antimicrobial resistance among Gram-negative organisms in the intensive care unit. Current Opinion in Critical Care 2003; 9: 413-423.

4.    Szałek E, Tomczak H, Smuszkiewicz P, Kamińska A, Grześkowiak E, Skóra M: Podstawowe wskaźniki PK/PD stosowane w antybiotykoterapii. Anestezjologia i Ratownictwo 2009; 3: 88-93.

5.    Frei CR, Burgess DS: Continuous infusion β-lactams for intensive care unit pulmonary infections. Clin Microbial Infect 2005; 11: 418-421.

6.    Rodloff AC, Goldstein EJC, Torres A: Two decades of imipenem therapy. Journal of Antimicrobial Chemotherapy 2006; 58: 916-929.

7.    Nicasio AM, Kuti JL, Nicolau DP: The current state of multidrug-resistant Gram-negative Bacilli in North America. Pharmacotherapy 2008; 28: 235-246.

8.    Schafer JJ, Goff DA: Ocena roli tygecykliny w dobie oporności na leki przeciwbakteryjne. Expert Reviews. Anti Infect Ther 2008; 6: 557-567.

9.    Fomin P, Buran M, Gradauskas A: Tigecycline is efficacious in the treatment of complicated intra-abdominal infections. International Journal of Surgery 2005: 3: 35-47.

10.    Chi PC, Wu CL, Hung CL, Weng YL, Lin CC, Lee SY: The experience of a novel glycycline antibiotic for a patient with infection caused by multiple drug-resistant pathogens: what is the benefit? International Journal of Gerontology 2008; 2, 3: 124-127.

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address:

*Urszula Zielińska-Borkowska
Klinika Anestezjologii i Intensywnej Terapii
SPSK CMKP w Warszawie
ul.  Czerniakowska 231, 00-416 Warszawa
tel.: 0-22 625 02 53
e-mail: ula_zielinska@poczta.onet.pl

received: 10.03.2010
accepted: 10.05.2010