Literature Review On Pseudomonas Aeruginosa
Abstract Pseudomonas aeruginosa is an important cause of nosocomial pneumonia associated with a high morbidity and mortality rate. This bacterium expresses a variety of factors that confer resistance to a broad array of antimicrobial agents. Empirical antibiotic therapy is often inadequate because cultures from initial specimens grow strains that are resistant to initial antibiotics. Surveillance data, hospital antibiogram and individualization of regimens based on prior antibiotic use may reduce the risk of inadequate therapy.
The use of combination therapies for P. Aeruginosa pneumonia has been a long-advocated practice, but the potential increased value of combination therapy over monotherapy remains controversial. Doripenem and biapenem are new carbapenems that have excellent activity against P. Aeruginosa; however, they lack activity against strains that express resistance to the currently available carbapenems. The polymyxins remain the most consistently effective agents against multidrug-resistant P. Strains that are panantibiotic-resistant are rare, but their incidence is increasing. Antibiotic combinations that yield some degree of susceptibility in vitro are the recourse, although the efficacy of these regimens has yet to be established in clinical studies.
Experimental polypeptides may provide a new therapeutic approach. Among these, the anti-PcrV immunoglobulin G antibody that blocks the type III secretion system-mediated virulence of P. Aeruginosa has recently entered Phase I/II clinical trials. Introduction Pseudomonas aeruginosa is a Gram-negative non-fermenting bacillus that belongs to the family Pseudomonadaceae. It was first isolated from green pus in 1882. More than half of all clinical isolates produce the blue-green pigment pyocyanin.
It has minimal nutrition requirements, which contribute to its broad ecological adaptability and distribution. The large genome of P. Aeruginosa provides a tremendous amount of flexibility and the metabolic capability to thrive in environments that are inhospitable to most other organisms. The complete sequencing of wild-type P. Aeruginosa (PA01) at the turn of the century has provided a great deal of useful information, concerning not only its pathogenicity but also its potential for resistance. In addition to mediator activation via release of endotoxin, P. Aeruginosa possesses a repertoire of exotoxins and enzymatic products designed to evade host defences.
It has also an array of chromosomal and plasmid-mediated antibiotic resistance factors, making antibiotic treatment difficult and potentially unsuccessful. According to data from the US Centers for Disease Control and Prevention and the National Nosocomial Infection Surveillance System, P.
Aeruginosa is the second most common cause of nosocomial pneumonia (17%), the third most common cause of urinary tract infection (7%), the fourth most common cause of surgical site infection (8%), the seventh most frequently isolated pathogen from the bloodstream (2%) and the fifth most common isolate (9%) overall from all sites. More importantly, it is the most common multidrug-resistant (MDR) Gram-negative pathogen causing pneumonia in hospitalized patients. Over the last decade, substantial attention has been given to the development of agents to combat Gram-positive cocci while the pursuit of antimicrobials for use in infections caused by Gram-negative bacilli has lagged behind.
Pseudomonas aeruginosa causes serious nosocomial infections, and an important virulence factor produced by this organism is lipopolysaccharide (LPS). This review summarizes knowledge about. Pseudomonas aeruginosa is an important cause of nosocomial pneumonia associated with a high morbidity and mortality rate. This bacterium expresses a variety of factors that confer resistance to a broad array of antimicrobial agents.
With the pipeline of new antimicrobial agents running dry, treatment of P. Aeruginosa continues to rely on the theoretical advantages of combination therapy and the revival of old drugs previously abandoned because of serious toxicity. The purpose of this review is to discuss the current approach to antimicrobial therapy for P.
Aeruginosa pneumonia and to present the novel therapeutic modalities under development. Approach to treatment of P. Aeruginosa pneumonia Selection of antibiotics The array of traditional antibiotics with antipseudomonal activity includes the aminoglycosides, ticarcillin, ureidopenicillins, ceftazidime, cefepime, aztreonam, the carbapenems (except for ertapenem), ciprofloxacin and levofloxacin.
The question of which of these agents is the preferred antimicrobial in the treatment of P. Aeruginosa pneumonia is difficult to answer because of a lack of comparative randomized double-blinded studies showing significant differences in efficacy. The current guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) on the management of community and hospital-acquired pneumonia, advocate a therapeutic selection based on the severity of the infection, awareness of underlying risk factors and co-morbid diseases, recognition of the epidemiology and resistance phenotypes in individual settings, and knowledge of pharmacokinetic–pharmacodynamic parameters. However, certain antibiotics are more prone to resistance developing during therapy, leading potentially to treatment failures.
In three controlled studies comparing imipenem with ceftazidime, ciprofloxacin or piperacillin/tazobactam, emergence of resistance to imipenem was reported more frequently. The adjusted hazard ratio for developing imipenem resistance in P. Aeruginosa strains was 2.8 compared with 0.7 for ceftazidime, 0.8 for ciprofloxacin and 1.7 for piperacillin.
Faced with these uncertainties, general principles have been adopted over the last few years based mostly on expert opinion. Upon suspicion of P. Aeruginosa pneumonia, an aggressive approach for pathogen retrieval should be initiated, preferably prior to initiation of the first dose of antimicrobial therapy. Reliance on prescribing the same antibiotic regimens for all patients suspected with similar infection is no longer considered a logical approach. Increased rates of resistance leading to inadequate empirical therapy may well result in adverse patient outcomes. However, initiation of antibiotics may not necessarily await sampling of the respiratory tract. Delay in treatment has been linked to increased mortality even when a patient is considered clinically stable.
Four methods have been suggested to improve the adequacy of antimicrobial coverage against P. First, examination of national surveillance data provides an important gauge of the extent of resistance against antipseudomonal agents. While the reliability of these reports may be questionable because of interlaboratory variations, the overall trend in pathogen susceptibility may suggest a geographical cluster of resistant strains to a particular class of antibiotics. This could prove helpful to clinicians when prescribing empirical coverage for presumed P. Aeruginosa pneumonia in patients transferred from other facilities.
Second, knowledge of the susceptibility profile of recently isolated pathogens may predict not only the causative organisms but also the resistance pattern of P. Aeruginosa if it was determined to be the culprit pathogen. For example, in patients who are ventilated, colonization with antibiotic-resistant P. Aeruginosa predisposes the patient to subsequent infection with these same highly virulent microorganisms. Two recent studies have shown that routine quantitative cultures of endotracheal aspirates conducted once or twice weekly in all mechanically ventilated patients may help to improve the adequacy of empirical antibiotic therapy for ventilator-associated pneumonia (VAP)., Third, presence of risk factors for MDR P.
Aeruginosa and prior exposure to antibiotics may determine the extent of broad-spectrum coverage. In a secondary analysis of a large multicentre study with suspected VAP, independent risk factors for isolation of MDR P. Aeruginosa included the number of days (≥48 h) in hospital prior to intensive care unit (ICU) admission and prolonged duration of ICU stay. These results were in keeping with earlier work by Trouillet et al., who found that prior duration of mechanical ventilation is associated with increased rates of infection with MDR P. Comparable studies, identified exposure to previous antimicrobial therapy as a significant factor for drug-resistant P. Contrary to previous reports that have typically found only one or two antibiotic classes to be predictive of MDR P. Aeruginosa, all antipseudomonal agents can be linked to MDR P.
However, the duration of prior antibiotic exposure associated with MDR P. Aeruginosa may vary among the antipseudomonal classes. The shortest duration of prior antibiotic exposure associated with MDR P. Aeruginosa was observed for the carbapenems and fluoroquinolones; the longest duration was noted for cefepime and piperacillin/tazobactam.
Fourth, access to local antibiograms can be useful in assessing local susceptibility rates in P. Aeruginosa and in monitoring resistance trends over time. Based on the ATS/IDSA recommendations of using combination therapy in cases of nosocomial pneumonia, one centre devised a local ‘combination’ antibiogram to achieve optimal coverage for P. Although this new combination antibiogram modality allowed modest fine-tuning of empirical antimicrobial regimens, the antimicrobial choices did not differ substantively from those based on a standard antibiogram. It should be pointed out that while antibiograms provide susceptibility data and aid in monitoring resistance trends over time, they do not reveal additional information concerning the timing of the isolate in relation to the patient's hospital admission.
Monotherapy versus combination coverage The potential clinical significance of combination therapy over monotherapy for P. Aeruginosa pneumonia has been a controversial subject for many years.
The use of combination therapy is thought to minimize the emergence of resistance and to increase the likelihood of therapeutic success through antimicrobial synergy. A contemporary in vitro study suggested that levofloxacin and imipenem might be an effective combination for preventing the emergence of resistance during treatment of P.
Aeruginosa infections. The theory behind the use of this combination is that the molecular mechanisms responsible for P. Aeruginosa developing resistance to fluoroquinolones and imipenem during therapy do not overlap.
Mutational decreases in the expression of OprD in the outer membrane of P. Aeruginosa can lead to the development of resistance to imipenem during the course of therapy, but this mechanism does not affect susceptibility to fluoroquinolones.
Likewise, mutational changes in fluoroquinolone targets or mutations leading to increased expression of multidrug efflux pumps can result in the emergence of resistance to fluoroquinolones during therapy but do not directly affect susceptibility to imipenem. The one potential exception associated with the levofloxacin/imipenem combination is the dual resistance to fluoroquinolones and imipenem that develops when mutants overexpress the mexEF– oprN efflux pump. Although this efflux pump does not directly affect imipenem activity, mutational increases in the expression of this pump are associated with a concurrent decrease in the transcriptional and translational expression of oprD, leading to dual resistance to both drugs. While this is plausible in theory, prevention of this type of antibiotic resistance by combination therapy has yet to be validated in clinical trials. The clinical utility for combination therapy in P.
Aeruginosa pneumonia ultimately rests on reducing the likelihood of inappropriate treatment. In a retrospective, multicentre, observational study of Spanish hospitals that included 183 episodes of monomicrobial P. Aeruginosa VAP, the use of two empirical antipseudomonal antibiotics resulted in less microbiological failure and improved survival.
However, the use of monotherapy in the definitive regimen did not influence mortality, length of stay, development of resistance or appearance of recurrences. In contrast, a recent meta-analysis of 11 trials, of which 13.8% were infected with Pseudomonas species, compared monotherapy with combination therapy in clinically suspected VAP. No mortality differences were observed between any of the regimens compared. Rates of mortality and treatment failure for monotherapy compared with combination therapy were also similar. The study was limited by the low percentage of episodes of VAP caused by MDR or difficult-to-treat organisms in the trials.
Because these patients would be expected to benefit the most from empirical combination therapy, it was not surprising that there was no benefit of empirical combination therapy over monotherapy. Heyland and co-workers subsequently conducted a multicentre, randomized trial to compare the effect of combination therapy with the effect of monotherapy with broad-spectrum antibiotics on 28 day mortality in the initial treatment of critically ill patients who had suspected late-onset VAP. Overall, monotherapy was associated with similar outcomes compared with combination therapy, but in a subgroup of patients who had infection due to Pseudomonas species, Acinetobacter species and MDR Gram-negative bacilli at enrolment, the adequacy of initial antibiotics (84.2% versus 18.8%, P 4 weeks) of colistin. In comparison, 7%–29% of colistin recipients develop neurotoxicity in the form of oral and perioral paraesthesias, visual disturbances and polyneuropathy, with rare cases of respiratory failure or respiratory apnoea., The in vitro synergy between colistin and rifampicin has resulted in the use of combination therapy in a few patients with pneumonia due to MDR P. Aeruginosa infection., However, the evidence from the limited clinical studies suggests that this combination therapy was not superior to colistin monotherapy., Other antimicrobial agents have also been used in combination with colistin, including imipenem, meropenem, aztreonam, piperacillin, ceftazidime and ciprofloxacin, but none of these regimens showed improved outcome in clinical studies.
Sporadic cases, of infections by colistin-resistant P. Aeruginosa have been reported. Colistin resistance has been also confirmed in metallo-β-lactamase-producing P. In one report, clinical cure of these infections was observed in two out of three suspected pneumonia patients with combination of colistin and β-lactam antibiotics. Prolonged colistin exposure (2 weeks) was a prerequisite for resistance development in these particular strains. The mechanism involves an altered PmrAB activated by a sensor phosphokinase, with concomitant selective suppression of the corresponding deactivator PmrB phosphatase. This results in constitutive activation of the PmrA regulon, which stimulates aminoarabinose synthesis.
Other proposed mechanisms include overexpression of OprH caused by mutation or as a result of adaptation to an Mg 2+-deficient medium. Compared with colistin, there is very limited clinical experience with polymyxin B in the treatment of P. Aeruginosa pneumonia. To our knowledge, four studies have examined the use of intravenous polymyxin B for treatment of lower respiratory tract infections caused by MDR P. Furtado and co-workers analysed retrospectively 74 patients with MDR P.
Aeruginosa pneumonia who were treated with polymyxin B by continuous infusion over 24 h. Concomitant antibiotic therapy was prescribed for 28 patients (37.8%). Imipenem was the most common agent administered in combination.
The duration of polymyxin B therapy ranged from 5 to 38 days. Although 35 patients (47.3%) had complete or partial resolution of symptoms and signs by the end of treatment, in-hospital mortality was elevated at 74.3%. Two other studies, investigated intravenous use of polymyxin B in a subgroup from a cohort of patients with infections caused by metallo-β-lactamase-producing P.
Twenty-two patients had nosocomial pneumonia, including 10 patients with VAP. Despite receiving adequate therapy, 30 day mortality exceeded 50%. Previously, Sobieszczyk and colleagues conducted a retrospective analysis of 25 critically ill patients with pneumonia who received 29 courses of polymyxin B administered in combination with another antimicrobial agent.
Six of those courses were given in aerosolized form. Aeruginosa was isolated from 41% of the cases. The mean duration of polymyxin B therapy was 19 days (range 2–57 days).
Forty-one per cent achieved microbiological clearance. Mortality at the end of treatment was 21% and overall mortality at discharge was 48%.
Nephrotoxicity was observed in three patients (10%) and did not result in discontinuation of therapy. Considering the preliminary data from observational studies that support the non-inferiority outcome of intravenous polymyxins, therapy should be restricted to MDR strains for ≤2 weeks while optimizing pharmacokinetics and pharmacodynamics.
De-escalation should be strongly pursued whenever culture results permit replacement with another antibiotic. Meanwhile, future randomized controlled trials are needed to evaluate the efficacy of colistin monotherapy or combination therapy in the management of MDR P.
Aeruginosa pneumonia. New antipseudomonal antibiotics Doripenem Doripenem is a new carbapenem with potent in vitro activity against various aerobic and anaerobic Gram-positive and Gram-negative bacteria., It is stable against many β-lactamases, except for the class B metallo-β-lactamases, and, like meropenem, has some stability against human renal dehydropeptidase I. It binds to penicillin-binding proteins, causing cell wall damage and bacterial death.
Renal dose adjustment is required since the drug is cleared by the kidney. In vitro antibacterial activity against wild-type P. Aeruginosa is 2–4-fold more potent than meropenem and imipenem.
In a study comparing the in vitro activity of doripenem with other antipseudomonal antibiotics (imipenem, levofloxacin, piperacillin, ceftazidime, aztreonam, tobramycin and cefepime), the MIC of doripenem was lower than those of all comparative agents against P. Aeruginosa isolates. Based on MIC 50 and MIC 90 data, doripenem was the most potent carbapenem tested. Doripenem had MIC 90s of 2 and 16 mg/L for ceftazidime-susceptible and -resistant isolates, respectively, compared with meropenem (8 and 32 mg/L, respectively) and imipenem (16 and 32 mg/L, respectively). In addition, the propensity to select for resistant P.
Aeruginosa mutants in vitro was lower for doripenem than for the other carbepenems. Two clinical studies evaluating the efficacy of doripenem in nosocomial pneumonia have been published recently. The first randomized, open-label, Phase III study of 531 patients compared doripenem with imipenem. Patients were randomized to receive one of three treatment regimens: 500 mg doripenem every 8 h via 4 h intravenous infusion, 500 mg imipenem every 6 h via 30 min infusion or 1000 mg imipenem every 8 h via 60 min intravenous infusion for 7–14 days. Patients assigned to imipenem received either 500 mg every 6 h or 1000 mg every 8 h depending on the practice of the institution. These two imipenem regimens were considered pharmacodynamically equivalent.
There was no statistically significant difference in clinical cure between the two groups (68.3% for doripenem and 64.8% for imipenem). In a subgroup analysis, P.
Literature Review On Pseudomonas Aeruginosa
Aeruginosa was isolated from 28 patients in the doripenem group and 25 in the imipenem group.
Aeruginosa is an opportunistic pathogenic bacterium responsible for both acute and chronic infections. Beyond its natural resistance to many drugs, its ability to form biofilm, a complex biological system, renders ineffective the clearance by immune defense systems and antibiotherapy. The objective of this report is to provide an overview (i) on P.
Pseudomonas Aeruginosa Treatment
Aeruginosa biofilm lifestyle cycle, (ii) on the main key actors relevant in the regulation of biofilm formation by P. Aeruginosa including QS systems, GacS/ GacA and RetS/ LadS two-component systems and C-di-GMP-dependent polysaccharides biosynthesis, and (iii) finally on reported natural and synthetic products that interfere with control mechanisms of biofilm formation by P. Aeruginosa without affecting directly bacterial viability. Concluding remarks focus on perspectives to consider biofilm lifestyle as a target for eradication of resistant infections caused by P.