Antimicrobial therapy in severe infections with multidrug-resistant Gram-negative bacteria
I Department of Anaesthesiology and Intensive Therapy, Medical University of Wrocław
Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings, and are especially prevalent and problematic in intensive therapy units. Recently, the emergence of pandrug-resistance in Gram-negative bacteria poses additional concerns. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of increased morbidity and mortality among ITU patients. Beta-lactamases, cephalosporinases and carbapenemases play the most important role in resistance to antibiotics.
Despite the tendency to increased resistance, carbapenems administered by continuous infusion remain the most effective drugs in severe sepsis. Drug concentration monitoring, albeit rarely used in practice, is necessary to ensure an effective therapeutic effect.
Infections with Gram-negative bacteria generate a serious therapeutic problem in ITU patients because of a high percentage of multidrug-resistant bacterial strains . Increasingly high resistance to antibiotics of at least three antibiotic groups has narrowed the therapeutic options. In many cases, due to this multiple-drug resistance (MDR) observed in Gram-negative bacteria, the treatment is limited to carbapenems and polymixins E or B. A particularly dangerous phenomenon is the emergence of pan-drug resistance in Gram-negative bacteria. Although the literature offers numerous guidelines and recommendations for the therapy of severe infections [2, 3, 4, 5], the choice of an appropriate antibiotic for empiric therapy should be additionally supported by the epidemiological analysis of a given ward in nosocomial infections and of the region or country in cases of out-of-hospital infections. Depending on the mechanism of resistance, fluoroguinolones (particularly ciprofloxacin), aminoglycosides (particularly amikacin), piperacillin with tazobactam, and tigecycline might also prove effective. In cases of infections with multidrug-resistant non-fermenting bacteria, the combined therapy using colistine with rifampicin , colistin with imipenem or meropenem should be considered. The clinical cases published indicate the effectiveness of therapy with colistine combined with meropenem, ofloxacine and gentamicin , and colistine combined with meropenem and tigecycline . Moreover, in infections of the lower respiratory tract, antibiotics can be administered by inhalation [9, 10].
MDR has become a global public health problem. Amongst six most dangerous pathogens with rapidly increasing antibiotic resistance, called “alert-pathogens” and defined in 2004 by the Infectious Diseases Society of America (IDSA) as ESCAPE, four types of Gram-negative bacteria were listed, i.e. Klebsiella, Enterobacter, Pseudomonas aeruginosa and Acinetobacter Baumanni .
The major resistance mechanisms of Gram-negative bacteria are associated with:
- extended-spectrum-beta-lactamases (ESBLs), which occur most commonly in Klebsiella pneumoniae, Escherichia coli as well as Proteus spp, Serratia spp, Enterobacter spp, Pseudomonas spp, and Salmonella spp,
- AmpC cephalosporinases occurring predominantly in Enterobacter spp, Citrobacter spp, Serratia spp,
- carbapenemases found mainly in Enterobacter cloacae, Serratia marcescens, Citrobacter freundii, Klebsiella pneumoniae, Proteus spp as well as Pseudomonas aeruginosa, Acinetobacter and Alcaligenes [12, 13].
According to the Ambler classification, carbapenemases belong to molecular class A (penicilinases), class D (oxacilinases) – serine enzymes or class B (metallo-beta-lactamases) requiring a bivalent metal (most often zinc) ion as a cofactor of enzymatic reactions .
In clinical practice, the occurrence of the mechanisms listed above provides information about therapeutic possibilities and their potential clinical efficacy although this efficacy is affected by many other factors depending not only on the pathogen but also on the clinical status of a patient and the kind of an antibiotic.
In ESBL strains, the drugs of choice are carbapenems, yet piperacillin with tazobactam (Pip/Taz), aminoglycosides, and fluoroquinolones may also be effective. These strains are always resistant to penicillins, cephalosporins and monobactams. Pip/Taz, aminoglycosides and fluoroquinolones should be used only for target therapy with monitoring of MIC and, if possible, of serum concentrations and pharmacokinetic and inflammatory parameters as the markers of clinical efficacy. Piperacillin with tazobactam should not be used for empiric therapy of severe pneumonias and abdominal infections when the pathogens are ESBL-producing Gram-negative bacteria due to the inoculum effect. However, this combination can be used for urinary infections. The percentage of strains producing ESBLs amongst Enterobacteriaceae strains in Polish hospitals in the Beta-P1 Study Group was 11.1% .
In cases of chromosomal AmpC cephalosporinases, carbapenems and cefepime are found clinically effective. The latter will not be useful if the strain with AmpC cephalosporinases produces also ESBLs . The majority of carbapenemases is active towards not only carbapenems but also penicillins, cephalosporins, or monobactams.
Metallo-beta-lactamases do not undergo inactivation under the influence of beta-lactamase inhibitors (tazobactam, sulbactam, clavulanic acid). The substrate range of metallo-enzymes does not include monobactams; hence, almost all metallo-beta-lactamases induce the resistance to all beta-lactam antibiotics, except for aztreonam. Serine carbapenemases of class A and D are, though to a various extent, susceptible to the inhibitory activity of clavulanic acid, tazobactam and sulbactam; therefore, combinations of beta-lactam antibiotic with beta-lactamase inhibitor may be used [15, 17]. It should be remembered, however, that Gram-negative bacteria are likely to exhibit several independent mechanisms of resistance.
Klebsiella pneumoniae carbapenemases (KPCs) hydrolyze all carbapenems and all the remaining beta-lactam antibiotics. They occur most commonly in Klebsiella pneumoniae, oxytoca as well as Enterobacteriacae and Pseudomonas (aeruginosa, putida). Strains of Klebsiella pneumoniae KPC+ are usually sensitive only to colistin, tigecycline, gentamicin, sometimes to amikacin . The clinical efficacy of the drugs listed was not confirmed by clinical trials. The guidelines for the family of KPC-producing Enterobacteriaceae are available on the Web site of the National Reference Centre for Drug Susceptibility of Microorganisms – www.korld.edu.pl.
The resistance of bacteria to carbapenems is likely to result not only from the production of enzymes inactivating beta-lactamases but also decreased permeability of the external membrane, changes in penicillin-binding proteins, and active removal of the an antibiotic from the cell .
Despite alarmingly increasing resistance of Gram-negative bacteria, carbapenems are still a relevant therapeutic option for patients with severe sepsis and septic shock. Three carbapenems of group II (imipenem, meropenem, doripenem) and one of group I (ertapenem) registered currently in Poland have a wide spectrum of action against Gram-negative bacteria (except for Stenotrophomonas maltophilia, Burkholderia cepacia, Chrysobacterium meningosepticum (and Pseudomonas aeruginosa in the case of ertapenem) and Gram-positive bacteria (except for Enterococus faecium, MRSA, MRSE, Corynebacterium jejkeium), including anaerobes. Their different references, pharmacokinetic parameters and dosages are of interest [18, 19, 20] and are listed in Table 1.
Prior to antibiotic therapy, the parameters determining the highest probability of a beneficial clinical effect ought to be considered and the toxic action minimized; moreover, the therapy should be relatively short (pharmacoeconomic effect), and risk of increasing resistance minimized [21, 22]. The pharmacokinetic parameters of an antibiotic are also relevant, i.e. Vd, T1/2, the type of metabolism, excretion pathway, penetration to the infection site, affinity of an antibiotic to water or fat. Some antibiotics/chemotherapeutics require the correction of doses in renal or hepatic failure, obesity, and renal replacement therapy. In the therapy with aminoglycosides and vancomycin, monitoring of their blood concentrations is needed because of high toxicity if overdosed.
The pharmacokinetic-pharmacodynamic (PK/PD) modelling is the management of infections aimed at increased efficacy and safety as well as reduced treatment-related costs. The changes in physiological and biochemical parameters in patients with severe sepsis and septic shock, such as reduced arterial blood pressure and cardiac output, increased permeability of capillaries, features of venostasis, acid-base imbalance, hypo- or hypervolaemia, decreased protein/albumin levels, features of renal and/or hepatic failure, affect the pharmacokinetic parameters of antibiotics [22, 23, 24].
Due to the changes in pharmacokinetic parameters of antibiotics (e.g. distribution volume, T1/2, clearance as well as metabolism and excretion) in patients with severe sepsis or septic shock, the action of the drug inside the body cannot be accurately anticipated. Monitoring of drug concentrations, particularly in patients undergoing intensive therapy, seems to be fully grounded.
The principles of PK/PD modelling, which are based on indices attributed to various antibiotics or their groups, provide higher probability of the clinical effect expected. The expected probability of bacteriostatic or bactericidal target attainment (%) for various antibiotics and their different doses against various pathogens in a given population was called the cumulative fraction of response (CFR). The PK/PD targets (the percentage of time between successive doses of the antibiotic when the concentration of free fraction exceeds MIC) determined for achieving a bacteriostatic / bactericidal effect are 30/50% for penicillins, 40/70% for cephalosporins, 20/40% for carbapenems, respectively [23, 25, 26, 27]. The clinical studies demonstrate that beta-lactam antibiotics reach their highest expected clinical efficacy when the stationary concentration of drug free fraction (Cssff) maintains for over 50-70% of time between successive doses, exceeding the MIC for the pathogen four times. The exceptions are carbapenems, which is associated with slight post-antibiotic effects against Gram-negative bacteria [28, 29, 39]. Infections caused by Gram-negative bacteria require higher values of PD index (optimal % T>MIC should fluctuate around 100%) compared to those induced by Gram-positive bacteria. Aminoglycoside antibiotics, quinolons, macrolides, tetracyclines, glycopeptides, glycyclines, and echinocandins have different pharmacodynamic indices and the anticipated therapeutic success depends on Cmax/MIC and/or AUC 24/MIC [29, 30, 33, 43, 46].
According to the PK/PD principles, to optimize beta-lactam antibiotic treatment, prolonged or continuous venous infusions should be used taking into account their time of pharmacological stability (in the solution administered) at room temperature.
The benefits of continuous or prolonged intravenous infusions of antibiotics include better clinical efficacy and eradication, better action against multi-resistant strains, reduced resistance, lower incidence of side effects, shorter therapy, and lower costs [24, 28]. The pharmacokinetic consequences of continuous or prolonged infusions are quick saturation with the drug proper dose, maintenance of the drug concentration - minimal and maximal stationary concentration – throughout the administration period, prolonged mean time the drug stays in the body, quick clinical effects thanks to better availability of the drug.
Improper empiric therapy or wrong timing of its implementation decreases the chances for survival [31, 32]. Numerous studies concerning antibiotic therapy search for the proper strategy of their dosing and optimal clinical doses under given circumstances [44, 45, 46, 47, 48, 49, 50]. The use of continuous and prolonged infusions requires further clinical studies to become the evidence-based management. According to the guidelines for management in severe sepsis and septic shock, the drug concentration should be determined, as an element of PK/PD monitoring. Table 2, presenting the shortened principles of antibiotic therapy, contains some comments regarding the management in question .
With increased resistance of bacterial strains to the antibiotics used, severe infections cannot be properly treated without the cooperation of clinicians, microbiologists and clinical pharmacologists.
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Katedra i I Klinika Anestezjologii i Intensywnej Terapii
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