Risk factors and evolution of Ventilator-associated pneumonia by Staphylococcus aureus sensitive or resistant to oxacillin in patients at the intensive care unit of a Brazilian University Hospital

ORIGINAL PAPERS

Risk factors and evolution of Ventilator-associated pneumonia by Staphylococcus aureus sensitive or resistant to oxacillin in patients at the intensive care unit of a Brazilian University Hospital

Michel R. Moreira^I; Renata L. Cardoso^I; Alair B. Almeida^II; Paulo P. Gontijo Filho^I

^IUberlândia Federal University, Laboratory of Microbiology

^IIUberlândia Federal University Hospital Clinic; Uberlândia, MG, Brazil

^{Address for correspondence}

ABSTRACT

This study investigated the participation and risk factors of VAP by resistant (ORSA) or sensitive (OSSA) S. aureus to oxacillin and evaluated the implications of adequate or inadequate empirical antimicrobial therapeutics in its evolution in patients interned in a mixing ICU of adults. A patient control-case study with PAVs by ORSA and OSSA was carried out from May 2005 to April 2007 involving 993 patients. VAP was defined based on clinical, radiological, and microbiological (> 10⁶ CFU/mL count in the tracheal aspirate) criteria. Four hundred and seventy four (47.7%) patients were submitted to mechanical ventilation with 141 (29.7%) VAPs, with S. aureus as the most frequent agent (41.2%). The phenotype ORSA accounted for 47.5% and OSSA for 52.5%, predominant in late-onset VAPs with frequencies of 93.1% and 68.7%, respectively. Age > 60, use of corticoid and previous antibiotic therapy were related (p<0.05) with the development of VAP by ORSA. Mortality rate was higher (p>0.05) in the group with VAP by ORSA (37.9%). S. aureus was the main agent of VAPs, around half by ORSA, associated with age, late-onset VAP development and previous use of antibiotics and corticoids, but with no significant difference in mortality compared with VAP by OSSA.

Key-Words: Ventilator-associated pneumonia, Hospital infection, Staphylococcus aureus, Resistant microorganisms.

Ventilator-associated pneumonia (VAP) is a hospital infection frequently occurring at the ICU [1,2] and Staphylococcus aureus is one of its most common agents [2,3]. Its frequency, as well as proportion of isolates resistant to oxacillin (ORSA) varies among hospitals and ICUs [4]. Increasing hospital infections by oxacillin-resistant Staphylococcus aureus [4,5] led to a greater consumption of vancomycin, the choice antibiotic for hospital infections caused by Gram-positive resistant cocci [6,7].

Due to its gravity, treatment of VAP must be initiated quickly, remaining empirical until the culture and antimicrobial susceptibility test results become available, since VAP may be polymicrobial and can be caused by a wide spectrum of bacterial pathogens, or involve microorganisms, which are multiresistant to antibiotics [8-10].

Until recently, the glycopeptides (teicoplanin and vancomycin) were the only antimicrobials available to treat infections by ORSA [8,11]. Although vancomycin is still considered the choice agent to treat infections by ORSA, studies suggest that treatment with vancomycin may vary and may be ineffective, although laboratory data show that the pathogen is susceptible to the antibiotic [8,12]. The problem becomes worse in lung infections due to its unsatisfactory pharmacokynetic profile [12]. Its tissue penetration and concentration in the epithelial lining fluid does not exceed 20% of the plasma level, with high intra and inter-individual variations [13].

New therapeutic options, but still reduced for ORSA treatment, were developed, such as tigecycline and linezolid [9]. The latter, a synthetic oxazolidinone, presents a good pharmacokinetic profile, with oral bio-availability reaching 100%, allowing sequential therapeutics with oral-parenteral transition, after hospital release [8,9,11]. In addition to these properties, it is a small molecule that penetrates well in the tissues, including the lung tissues [9,14]. Although its use is well-tolerated, it is associated with various side effects [9].

The objective of this work was to investigate the etiology and risk factors of VAP by S. aureus resistant or sensitive to oxacillin and to evaluate its evolution when an adequate empirical antimicrobial therapeutics was applied to patients interned in a mixing ICU of adults.

Material and Methods

Hospital

The Hospital de Clínicas da Universidade Federal de Uberlândia (Uberlândia Federal University Hospital Clinic/HC-UFU) is a teaching hospital, with 500 beds, and a mixing ICU of adults with 15 beds.

Study Design

A control-case study was carried out using patients with VAP by ORSA and OSSA from May 2005 to April 2007, when 993 patients were admitted. The VAPs were defined based on clinical, radiological and microbiological criteria.

Definition of Hospital VAP

The patients were under mechanical ventilator for a period > 48 hours after being admitted to the ICU, with new and/or progressive radiological infiltrate and at least under two of the following criteria: purulent sputum, temperature higher than 38.5º C or lower than 35º C, and leukocyte count higher than 10,000/µL with deviation to the left or lower than 3,000/ µL; and positive quantitative culture of the endotracheal aspirate (count > 10⁶ CFU/mL) [1,2,15].

Inadequate Empirical Therapeutics

Treatment of PAV by ORSA with beta-lactam and by OSSA with vancomycin instead of beta-lactam [8,13].

Additionally, the following patient data were collected: age, gender, invasive procedures, admission diagnosis, previous use of antibiotics and corticoids, hospitalization and mechanical ventilation times. The Ethics Committee for Human Research of the Uberlândia Federal University (UFU) approved the project.

Microbiological Techniques

Endotracheal aspirate was collected by probe no. 12 early in the morning by health professionals in charge of the procedure (physiotherapists and nurses), and transported in a sterile tube to the Microbiology Laboratory of the UFU. Quantitative culture was carried out in salty Manitol agar (Biobrás, Brazil), MacConckey agar (Difco, France) and Pseudomonas agar (Difco, France). The Staphylococcus aureus samples were identified by manitol fermentation, Gram stain, and catalase, free coagulase and bond coagulase tests. Resistance to oxacillin was detected by means of a screening test in Mueller Hinton agar (Micromed, Brazil) incorporated with 6µg/mL of oxacillin and 4.5% of NaCl. The Pseudomonas aeruginosa and the other Gram-negatives were identified by classic techniques routinely applied by the UFU Microbiology Laboratory.

Statistical Analysis

Univariant comparisons were carried out by the chi-square (χ²) and Fisher's Exact tests and the results were considered statistically significant at level of 5%. The epidemiological data were analyzed through the program Statística 4.5 for Windows and Epi-Info version 5.0 [16].

Results

A total of 993 patients were admitted to the adult ICU of the HC-UFU. 474 (47.7%) patients were submitted to mechanical ventilation, with 141 (29.7%) VAPs, with S. aureus being the most frequent agent (41.2%) (Figure1). The phenotype ORSA accounted for 47.5% and OSSA, 52.5% (Figure 2), predominant in late-onset VAPs with frequencies of 93.1% and 68.7%, respectively (Table 1).

Age>60, use of corticoids and previous antibiotic therapy (p<0.05) were related with the development of VAPs by ORSA (Table 1). Inadequate antibiotic therapy in this group was 37.9%, lower (p>0.05) than that observed in the cases of VAP by OSSA. Mortality rate was higher (p>0.05) in the group with VAP by ORSA, 37.9% vs. 25% in the group with OSSA, but with no statistical significance (Tables 1 and 2 ).

Discussion

S. aureus was the main agent of the VAPs (41.2%) among adult patients at the ICU of the HC-UFU, with approximately half (47.5%) the episodes being caused by the ORSA samples. Age>60, use of corticoid and previous antibiotic therapy were the risk factors associated with development of VAPs by ORSA. These factors correspond to those reported in the literature, with the following also predominating: chronic obstructive pulmonary disease and prolonged time of mechanical ventilation [3,9,15,17,18]. The VAPs by OSSA occur more frequently in younger patients with traumatic brain injury [1,3,17], as confirmed in our study, with 46.9% vs. 31.0% in those infected by ORSA.

The proportion of S. aureus samples resistant to oxacillin in the USA is approximately 50% in critical patients [19,20]. In Brazil, data vary with studies conducted in Rio Grande do Sul and Paraná reporting a participation of 86.7% and 42,0% of ORSA, respectively [21,22]. In our work, this proportion was closer to the American data.

Resistance to beta-lactams is located on the staphylococcal cassette chromosome (SCCmec), a mobile genetic element, and is encoded by a gene known as mecA, which is regulated by two other genes called mec1 and mecR1. The resistance results of a penicillin-binding protein (PBP2') with lower affinity by this antibiotics. Besides the resistance to beta-lactams, the SCCmec includes transposons and plasmids with genes associated to resistance to others antimicrobial agents like: aminoglycosides, macrolides, quinolones, tetracyclines and clindamicin [23,24].

Currently, three clinically relevant types of ORSA strain exist. The original ORSA that emerged in hospitals in the 1970s is referred to as hospital-acquired ORSA (HA-ORSA). Over the past few decades, HA-ORSA strains made their way into the community. HA-ORSA from the community later admitted to hospitals are referred to as community-onset ORSA (CO-ORSA). For these reasons, CO-ORSA strains have the same clinical features/virulence, and are effectively treated as HA-ORSA strains. The latest recognized strain type of ORSA is community-acquired ORSA (CA-ORSA), that is exceptionally virulent when have the Panton-Valentine leucocidin and is sensitive to antibiotics such clindamycin, cotrimoxazole and doxycycline, which are not tradicionally active against HA-ORSA [25].

Measures to prevent the development of multidrug-resistant microorganisms, specially the ORSA VAP are composed of general VAP prevention strategies, like basic hygiene [19,26]. Appropriate antimicrobial stewardship that includes optimal selection, dose, and duration of treatment, as well as control of antibiotic use, will prevent or slow the emergence of resistance among the microorganisms [27,28].

Early and late-onset VAPs in the HC-UFU were related respectively, to OSSA (83.3%) and ORSA (55.1%), as reported by other authors [2,8,29]. Late-onset VAPs are associated with predisposing factors such as hospitalization time, use of mechanical ventilator and previous use of antimicrobials, having as etiological agents, more frequently, multiresistant bacteria such as ORSA [15,28,29].

Infections by ORSA demand a more rigorous treatment evaluation, including choice of antibiotics, since they relate with greater morbidity and mortality, as compared to those caused by OSSA [8]. Metanalysis studies by Whitby, McLaws and Berry (2001) [30] and Cosgrove et al. (2002) [31], including results from various publications comparing the mortality risk among patients with bacteremia, those by ORSA presented increased mortality, when compared to OSSA-associated infections. Little data are available on VAPs, but Rello et al. (1994) [18]reported that the mortality rate directly related to VAPs by ORSA was significantly higher than that by OSSA. In our study, the mortality rate observed was also higher, but without statistical significance in the group with VAPs by ORSA (37.9%) when compared to that of the group with OSSA (25%).

The initial choice of the empirical antimicrobial scheme for the treatment of VAPs is of critical importance in determining a patient's clinical evolution, particularly against hospital mortality [32]. Early aggressive therapeutics and use of large-spectrum antibiotics, directed against more probable microorganisms, based on local vigilance data, is associated to reduced mortality rates [10,33-35]. Once the causal agent is defined, one must opt for the use of reduced spectrum antibiotics, compatible with the existing microorganism, i.e., treatment must be conducted based on the culture result, promoting de-escalating antibiotic strategy [10,34]. In our investigation, most patients (57.4%, 35/61) were given three or more antibiotics empirically, without adopting the de-escalating antibiotic strategy after the microbiological results were provided. These conditions contribute to the emergence of antibiotics-resistant and multiresistant microorganisms reported by many authors [8,15].

When empirical therapeutics is applied, particularly under the existing conditions in our ICU, there is a high likelihood of inadequate therapeutics to occur. The term inadequate antibiotic therapy is not standardized, but it is usually applied to define the conditions under which the initial use of antibiotics is inactive for the microorganism identified as etiological agent of the infection [34,36]. Although the definition is restricted to the spectrum of susceptibility to the antibiotics instead to a therapeutic clinical response, focusing only on microbiologically documented infections [34,37] in the case of VAPs by OSSA, we have defined as inappropriate the use of vancomycin, because of its pharmacodynamic and pharmacokynetic characteristics related to the low levels reached in the epithelial lining fluid [8,13], and the result obtained from its use versus that of penicillin isoxazolyl [38].Among our patients, the proportion of inadequate therapy was very high (39.3%), the majority (54.2%) in patients with VAP by OSSA. The inadequate use of antibiotics was identified as the most important risk factor for hospital mortality among 2000 critical VAP patients in general [36]. In our study, ORSA-infected patients had a similar mortality rate, regardless of whether the treatment was adequate (38.9%) or inadequate (36.4%), probably a reflection of older age and corticoid immune-suppression. Moreover, they are critical patients and other factors can be related with the mortality of the same ones. However, the mortality observed among patients with VAP by ORSA under inadequate treatment was double (66.7%) that observed in pneumonias by OSSA (33.3%), but without statistical significance, suggesting a bigger virulence of the phenotype with resistance to the oxacillin.

Gonzalez et al. (1999) [38] reported a relation between mortality and vancomycin treatment in patients with pneumonia by S. aureus, with high mortality rates in infections both by ORSA and OSSA, but extremely high (50,0%) in those by ORSA, as observed in our series (53.8%).

Superior clinical efficacy of linezolid over vancomycin in the treatment of VAPs by ORSA was reported by Wunderink et al. (2003) [39] and Kollef et al.(2004) [11] in retrospective double-blind studies, with higher clinical survival and cure rates. In our hospital, vancomycin is still the choice antibiotic for therapeutics of infections by ORSA, since linezolid has not been standardized.

Conclusions

S. aureus is the main agent of VAPs in the ICU of the HC-UFU with around half the cases by ORSA, associated with the development of late VAP, age over 60, use of corticoids and antibiotics, and a higher mortality (37.9%) than that observed in the group by OSSA (25.0%), (p>0.05). Constant inadequate empirical therapeutics, including the use of vancomycin in VAPs by OSSA, was very high (~40%) in the two groups, with a greater reflection on mortality by ORSA. At the moment, this antibiotic is the only option for pneumonias by ORSA in our hospital, characterized by a more somber prognosis.

Received on 11 April 2008; revised 18 November 2008.

Finantial: Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq.

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Publication Dates

• Publication in this collection
  10 Mar 2009
• Date of issue
  Dec 2008

History

• Accepted
  18 Nov 2008
• Received
  11 Apr 2008