Increasingly high drug-resistance of pathogens and wider use of antibiotics are the major problems of modern medicine.  Ineffective antibiotic therapy is responsible for increased mortality rates, prolonged hospitalizations, which translates into treatment costs. The induction of bacterial resistance is often attributed to III generation cephalosporins or rather their improper administration.

Cefoperazone/sulbactam is the only medication with the ß-laktamase inhibitor (sulbactam). Thanks to such a combination, the drug is effective against positive extended-spectrum β-lactamase (ESBL) pathogens [1]. In patients with severe infections, i.e. excess of ESBLs or ESBLs of reduced sensitivity to the inhibitor, the efficacy of therapy may be lower [1, 2].

Proper therapeutic decisions should be based on antibiotic susceptibility of cultured pathogens and the pharmacokinetic / pharmacodynamic profile of an antibiotic. Both factors ought to be considered to make optimal therapeutic choices. Additionally, the general status and defensive abilities of a patient, as the parameters modifying the therapy, are important.

The aim of the study was to assess the efficacy of antibacterial therapeutic management with cefoperazone/sulbactam.

METHODS

The retrospective study was conducted. The efficacy of therapy was assessed by patients assigned to four groups according to the main diagnosis on discharge: group I – out-of-hospital pneumonia requiring hospitalization, group II- severe sepsis/septic shock, group III- COPD, and group IV – other causes.

The main parameters of efficacy included mortality rates in a given group compared to mean mortality in the study period.

Immediately after admission, yet before the institution of an antibiotic, the bronchial tree secretion and blood were collected; general status of patients was evaluated using the TISS-28 according to the current recommendations. The therapy was started with the initial dose of cefoperazone/sulbactam 2 g and continued with 4 g in the 24-hour infusion.

The markers of the efficacy of therapy were reduced body temperature, WBC and C-reactive protein levels. Proper choices of therapy were confirmed by microbiological tests of the material collected before the antibiotic administration. When the pathogens resistant to cefoperazone/sulbactam were cultured, the targeted antibiotic therapy was used according to the antibiograms obtained. After therapy, the mortality and duration of ITU stay in the selected group were compared with the data of the entire population treated in the study period.

RESULTS

The analysis involved medical records of 80 out of 560 patients treated in ITU in 2007-2008. Mean TISS-29 scores of all patients are presented in Table 1.

Group I consisted of 15 (18.75%) patients with acute circulatory-respiratory failure. In 73% of cases, the pathogens resistant to cefoperazone/sulbactam were cultured (Fig. 1).The treatment with this antibiotic was continued over 6.52 days on average; monotherapy was used in 53%. The antibiotic reduced body temperature in 54% of patients, lowered the number of leukocytes in 67% and decreased C-reactive protein levels in 78%. The mortality in this group was 20%. 

Group II included 14 (17.5%) patients. Cefoperazone/sulbactam-resistant bacteria were cultured in 50 % of cases (Fig. 2). Cefoperazone/sulbactam alone was used in 50% of patients in this group and the mean length of administration was 6.57 days. Reduced body temperature was observed in 80% of patients, low leukocyte count in 71 % and decreased levels of C-reactive proteins in 78%; 42.85% of patients diagnosed with sepsis and /or septic shock died.

Twelve (15%) out of 80 patients included in group III were undergoing artificial lung ventilation. Microbiological cultures revealed the susceptibility of pathogens to cefoperazone/sulbactam in 54% of patients (Fig. 3). Cefoperazone/sulbactam was administered for 6 days, in 70% of cases as the sole antibiotic. Reduced body temperature was found in 67% of patients, low leukocyte count in 50% and decreased levels of C-reactive proteins in 67%; 25% of patients in this group died. 

Group IV included 39 (48.75%) patients treated due to acute circulatory-respiratory failure of various aetiologies. In the majority (87%), cefoperazone/sulbactam-susceptible pathogens were isolated. The therapy was continued over 6.7 days on average. Monotherapy was used in 79.5% of patients. A decrease in body temperature was achieved in 68% of patients, lowered number of leukocytes in 59% and decreased levels of C-reactive proteins in 46%.

In the entire group of 80 patients, 57 (71.25%) had cefoperazone/sulbactam-susceptible pathogens. The mortality in this group was 26.25% compared to 51.4% in the total population treated in ITU.

DISCUSSION

The highest percentage (33-65%) of patients treated in ITU is diagnosed with infections, including 25% with nosocomial infections [3]. Proper and early instituted antibiotic therapy decreases the mortality rates, duration of ITU stay and treatment-related costs [4, 5].

Antibiotics are commonly used in ITU patients; however, the number of cases in which they are improperly administered amounts to about 50%. The main causes of failures include wrong indications, inappropriate choice or dosage of drugs and duration of therapy. The documented data explicitly associate increased mortality and prolonged hospitalization with improper antibiotic therapy [6, 7].

Therapeutic failures, despite proper antibiotic therapy, are also related to the general status of patients and resistance of pathogens [8]. One of possible solutions is the combined supply of several antibiotics to make use of their synergistic antibacterial action.

Despite effective antibiotic therapy, the expected outcome, i.e. recovery, is not always achieved. The factors responsible for bad outcomes are errors in antibiotic therapy and inefficient protective mechanisms of hosts. The treatment instituted is effective when the homeostasis system is capable of protective responses. Proper antibiotic therapy not always provides successful therapy, which is documented in patients with immune system deficiencies [9].

In ITU patients, mechanical lung ventilation, efficiency of individual organs, extracorporeal organ support have to be considered. An extremely relevant factor affecting the concentration of a drug is its composition and fluid distribution in the organism [10]; due to these factors, the therapeutic dose may not be achieved and the elimination time may not be shortened, which is directly responsible for ineffective therapy.

The choice of optimal strategy of treatment is based on proper identification of a pathogen as well as pharmacokinetic (PK) (concentration/time of action ratio) and pharmacodynamic (PD) (concentration/pharmacological effect ratio) factors.

The basic parameter describing the efficacy of an antibiotic is the in vitro minimum inhibitory concentration (MIC). Based on the PK model, the parameters describing the drug action are the peak serum concentration (Cmax), minimum concentration (Cmin) and the area under the curve of maximum serum concentration. The above parameters define the distribution, concentration and time (T) of drug maintenance in serum. To asses the efficacy of antibiotics, both MIC and PK should be taken into account [11]. The pharmacodynamic parameters in ITU patients may be modified by the medical techniques used during treatment.

Based on the pharmacokinetic model, antibiotics can be divided into those dependent on the peak concentration, time of concentration maintenance above MIC and the mixed group.

The first group includes antibiotics whose effects depend on the maximum serum concentration of the drug; their post-antibiotic effect is long. This group involves aminoglycosides, fluoroquinones, deptomycin, ketolids. Such antibiotics should be administered to maintain the maximum Peak/MIC [12, 13].

The second group contains antibiotics without post-antibiotic effects whose efficacy depends on the time of exposure of bacteria to a particular drug. These criteria are met by carbapenems, β–lactams, erythromycin, linezolid [4, 5]. The efficacy of antibiotics of this group is best reflected by the T>MIC parameter.

The third group includes antibiotics whose efficacy depends on the time of exposure; their post-antibiotic effect is short-term, e.g. vancomycin, tetracyclines, oxazolidones, klindamycin. The optimal dosage demands the maximization of the dose.

Once all the above factors are considered while making decisions about rational antibiotic therapy, the clinical efficacy should be high and adverse side effects minimized.

ß-lactam antibiotics bind strongly with proteins. In cases of fractionated dosage, the concentration between individual doses reduces markedly. To maintain the efficient therapeutic outcome, the drug should be administered in accordance with the T>MIC pattern. When the antibiotic concentration is <MIC, as observed in fractionated dosage, persisting microorganisms multiply almost immediately, which increases antibiotic resistance, particularly if the time of decreased concentration is longer than half of the period between successive doses [16, 17].

In cases of cephalosporins, to achieve the maximum efficacy and limit the increase in drug resistance it is recommended to maintain 4-5 times higher MIC between doses, or to use continuous infusions to avoid concentration decreases below MIC [16, 18].

The drug dosage in the form of single injections induces the unnecessary increase in concentration with a subsequent decrease in therapeutic concentration below MIC through the most of the period between repeated doses [19, 20]. 

An extremely important factor reducing the concentration of β-lactam antibiotics is the change in distribution volume in patients with multiple organ failure, caused by sepsis, in particular. It is suggested that increased distribution volume results in lower actual concentration of the antibiotic than that anticipated in fractionated dosage [19, 21, 22].

In patients treated due to sepsis without multiple organ failure, increased β-lactam clearance is observed; with standard dosage, the expected concentration of cephalosporins is lower than the actual one.

CONCLUSIONS

1. The bacteria profile in the study population showed susceptibility to cefoperazone/sulbactam.

2. Cefoperazone/sulbactam used in continuous infusion according to the pharmacokinetic/pharmacodynamic profile is effective in the therapy of critically ill patients.

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REFERENCES

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received: 19.03.2010
accepted: 21.05.2010