Drugs & Aging

, Volume 26, Issue 5, pp 363–379 | Cite as

Current Treatment of Pseudomonal Infections in the Elderly

  • Georgios Pappas
  • Kaiti Saplaoura
  • Matthew E. Falagas
Review Article

Abstract

Pseudomonas aeruginosa infections have emerged as a major infectious disease threat in recent decades as a result of the significant mortality of pseudomonal pneumonia and bacteraemia, and the evolving resistance exhibited by the pathogen to numerous antibacterials. Pseudomonas possesses a large genome; thus, the pathogen is environmentally adaptable, metabolically flexible, able to overcome antibacterial pressure by selecting for resistant strains and even able to accumulate resistance mechanisms, leading to multi-drug resistance (MDR), an increasingly recognized therapeutic challenge. In fact, most research currently does not focus on maximizing the efficacy of available antibacterials; rather, it focuses on maximizing their ecological safety.

The elderly population may be particularly prone to pseudomonal infection as a result of increased co-morbidities (such as diabetes mellitus and structural lung disease), the presence of invasive devices such as urinary catheters and feeding tubes, polypharmacy that includes antibacterials, and immune compromise related to age. However, age per se, as well as residence in nursing homes, may not predispose individuals to an increased risk for pseudomonal infection. On the other hand, age has been repeatedly outlined as a risk factor for MDR pseudomonal infections.

The severity of pseudomonal infections necessitates prompt administration of appropriate antibacterials upon suspicion. Progress has been made in recognizing risk factors for P. aeruginosa infections both in hospitalized and community-residing patients. Antimicrobial therapy may be instituted as a combination or monotherapy: the debate cannot be definitively resolved since the available data are extracted from studies with varying targeted populations and varying definitions of response, adequacy and MDR. Empirical combination therapy maximizes the chances of bacterial coverage and exerts a lower resistance selection pressure. Although associated with increased percentages of adverse events, mainly as a result of the included aminoglycosides, empirical combination therapy seems a reasonable choice. Upon confirmation of Pseudomonas as the causative agent and awareness of its susceptibility profile, monotherapy is advocated by many, but not all, experts. Infections involving MDR strains can be treated with colistin, which has adequate efficacy and few renal adverse events, or doripenem. In the elderly, in addition to making dose modifications that are needed because of loss of renal function, the prescriber should be more cautious about the use of aminoglycoside-containing regimens, possibly replacing them with a combination of quinolone and a β-lactam, notwithstanding the possible increased pressure for selection of resistance with the latter combination.

Traditionally considered an opportunistic pathogen occasionally troubling burn and surgical patients, the impact of Pseudomonas aeruginosa on morbidity and mortality in special populations has rapidly increased and continues to rise.[1] The emerging importance of P. aeruginosa can be partly considered iatrogenic: medical progress has expanded the human pool of patients targeted by P. aeruginosa through improved care of patients with solid or haematological malignancies; transplantation and the AIDS epidemic have significantly increased the numbers of patients with acquired immune disorders at risk of P. aeruginosa infection; and enhanced care of the elderly has led to a subsequent increase in life expectancy and an increased overall percentage of patients with concomitant underlying morbidity of various types. However, medical progress alone does not explain the emergence of Pseudomonas: pseudomonal genomic plasticity allows for rapid adaptation to a variety of environmental conditions and to applied antibacterial pressure.

As noted, medical progress has led to more people living longer, at least in the developed world.[2] Thus, novel medical and social issues have emerged, not only related to aging and its physical consequences (increased percentage of long-standing morbidity), but also to the delivery of healthcare to this population. It has been shown that healthcare expenditures for healthy elderly individuals are roughly similar to those for elderly individuals with underlying morbidity,[3] and that for certain racial and educational subgroups, morbidity increases with age.[4] Furthermore, increasing delivery of care to elderly people in nursing homes[5] has led to the development of novel environments with unique characteristics[6,7] and new subcategories of specific diseases with distinct epidemiological, clinical and therapeutic parameters. A typical case is pneumonia, which is now considered differently when it emerges in the community (community-acquired pneumonia [CAP]) compared with when it emerges in nursing homes and similar settings (healthcare-associated CAP [HCAP]). P. aeruginosa plays an important role in both groups, but particularly in the latter.

The present review focuses on specific issues related to the epidemiology and therapy of pseudomonal infections in this particular subgroup of patients — the elderly. Available literature was sought through the PubMed and Scopus databases, using the following keyword combinations: ‘Pseudomonas aeruginosa’ AND ‘elderly’, ‘Pseudomonas aeruginosa’ AND ‘nursing homes’, ‘Pseudomonas aeruginosa’ AND ‘treatment’ AND ‘age’, ‘Gram-negative infections’ AND ‘elderly’, ‘Gram-negative infections’ AND ‘nursing homes’. References for the retrieved articles were further evaluated for identification of other relevant literature. No specific search periods were preset. All articles were thoroughly reviewed regarding their inclusion of information on pseudomonal infections in the elderly. When such information was not provided, articles focusing on all aspects of pseudomonal infections were utilized as sources of information, and the relevant data were further projected to the specific age group as discussed in the manuscript.

1. Pseudomonas: How it Survives, Who is Attacked and How

1.1 Ecology

P. aeruginosa is a Gram-negative aerobic pathogen that possesses one of the largest prokaryotic genomes.[8] P. aeruginosa is characterized by metabolic versatility, having minimal requirements and being able to utilize numerous nutrients for its survival. A relatively large percentage of the genome’s encoded proteins are directly or indirectly related to virulence, and 0.3% of the organism’s total genes are related to the development of antibacterial resistance.[9] The pathogen has a predilection for aqueous environments, including swimming pools and bath tubs; the abundance of bacterial flora in such environments further enhances the potential for acquisition of resistance mechanisms through exchange. P. aeruginosa can also be found in plants, fruit and their derivatives, and subsequently in the food chain. The pathogen can be traced in diverse relevant nosocomial surfaces, including sinks, disinfectant solutions and soaps, irrigation fluids and nebulizers. Tap-water samples are often positive for the pathogen in such settings and water may serve as a continuous source of infection.[10,11] Pseudomonas can also spread to hospitalized patients through human carriers, a particular example being outbreaks in neonatal intensive care units (ICUs) attributed to carriage of the pathogen by nurses with long fingernails.[12] Outbreaks related to other contaminated medical devices have increasingly been reported, such as mouth swabs.[13] Human colonization is considered infrequent, at least for healthy individuals. Again, there is a predilection for humid areas of the body surface such as the perineum, axillary folds and nasal mucosa. In immunocompromised carriers who eventually develop disease, the intestine is considered a major source of the bacterium.[14] Dental plaque has also been outlined as a potential microbial source.[15,16] Contaminated toothbrushes can serve as the means of entry to the oral cavity and the gastrointestinal tract in general; ironically, the use of a protective cap to prevent toothbrush contamination is associated with an increased likelihood for pseudomonal contamination.[17]

1.2 Virulence

Pseudomonas is not only flexible and adaptable, but also a very ‘clever’ microbe, as demonstrated by the ways it expresses its virulence. A major determinant in pseudomonal virulence is quorum-sensing,[18] which is not only crucial for biofilm formation, but also regulates virulence depending on the host: simplified, this means that Pseudomonas attacks the host only under optimal circumstances, i.e. when the odds of the microbe prevailing are high. This tactic allows for minimal induction of immunity and thus serves to maintain the overall severity of pseudomonal infections.[19]

1.3 Clinical Presentation: Susceptible Population

In most cases of human pseudomonal infection, disruption or the bypassing of physical barriers is a pre-requisite, and the dysfunctional immune system serves as a major predisposing factor. An example of this is cancer patients receiving chemotherapy. Chemotherapy induces neutropenia, thus predisposing the patient to infection, but it often also causes mucosal ulcers, thus disrupting the human body’s integrity and allowing the pathogen to enter. The population at risk includes patients with solid and haematological malignancies and those who have undergone transplantation. Hospitalized patients, particularly in ICUs, are also at high risk. Multiple factors intervene here: these patients are typically severely ill, are low birthweight neonates if in paediatric ICUs, have impaired immune responses, have probably been exposed to numerous antibacterials, have undergone numerous invasive procedures and often reside in an environment colonized by Pseudomonas. Patients with impaired immune systems, such as those with AIDS (patients with very low CD4 counts)[20] or hereditary immunodeficiencies, are also at high risk. The targeted population also includes surgical patients and patients with burns, patients who have undergone invasive procedures (including bronchoscopy and urinary tract catheterization), patients with diabetes mellitus and patients with structural lung diseases such as bronchiectasis or obstructive lung disease.[21,22] The importance of P. aeruginosa for patients with cystic fibrosis[23] and the unique characteristics of pseudomonal infection in these patients are beyond the scope of this review and will not be further discussed here.

It is easily recognized that the elderly, although not specifically acknowledged as a particular risk group, comprise the majority of the risk groups mentioned above. Advanced age has been related to immune defence deterioration and increased existence of morbidity that may predispose to Pseudomonas infections, such as diabetes, bronchiectasias and obstructive lung disease. Furthermore, underlying morbidity in the elderly is usually long standing, which may have a maximal effect on the patient’s immune status. Moreover, use of devices that can bypass physical barriers and predispose individuals to pseudomonal infection, as well as serve as substrates for the development of pseudomonal biofilms, is more common among the elderly. Such devices include indwelling urinary catheters, nasogastric feeding tubes (which have been associated with an increased risk for Pseudomonas isolation from gastric fluids)[24] and nebulizers.

There are limited data on the effect of age on colonization by P. aeruginosa: although increasing age and residence in nursing homes have been considered risk factors for increased colonization of the upper respiratory tract by various Gram-negative bacteria, including P. aeruginosa,[25] a recent study showed that age was inversely related to aztreonam-resistant pseudomonal colonization,[26] and a study of pseudomonal CAP showed that nursing home residency and age were not risk factors.[27]

The clinical presentation of Pseudomonas infection in the elderly, along with the specific characteristics of each organ involved, is summarized in table I. P. aeruginosa is the second most common cause of hospital-acquired pneumonia (HAP), the commonest or second commonest cause of ventilator-associated pneumonia (VAP),[35] the commonest cause of HAP in paediatric ICUs, and the second or third commonest cause of HCAP.[36] The pathogen also accounts in some studies for 7% of CAP, a percentage extending to 16% of bacteriologically proven cases in certain settings.[37] Furthermore, P. aeruginosa is the third commonest cause of nosocomial bacteraemia,[38] and accounts for 30% of culture-proven bloodstream infections in cancer patients. It is also the third commonest cause of hospital-acquired urinary tract infection (European data classify it fifth) and the fourth commonest cause of asymptomatic bacteriuria in institutionalized individuals.[39] Mortality is high in certain pseudomonal infections, reaching or exceeding 50% in HAP/VAP, bacteraemia and neutropenic patients, with most deaths observed during the first 3–5 days.[38] Even in CAP, mortality rates of 28% have been reported (table I).[27] Conversely, mortality is lower for infections arising from or localized to the urinary tract.[33]
Table I

Clinical presentation of Pseudomonas aeruginosa infections in the elderly, with syndromes listed in descending order of frequency

The clinical presentation of Pseudomonas infection in the elderly may be blunted, particularly in the case of bacteraemia, as with all Gram-negative bacteraemias in advanced age. Recognition of pseudomonal sepsis in the elderly requires a low threshold of clinical suspicion and demands urgent empirical antibacterial coverage. Data on the influence of age on the mortality of pseudomonal infections are limited: although age has not been identified as a risk factor for mortality in pseudomonal CAP,[27] extended data are missing from the literature. For example, a source of P. aeruginosa CAP can be contaminated humidifiers and/or contaminated humidity reservoirs for continuous positive airway pressure (CPAP) breathing machines. It is not known though whether the increased use of such devices by the elderly is correlated to the development of P. aeruginosa CAP.

As discussed in section 3.3, age is a risk factor for multidrug resistant (MDR) pseudomonal infections, and these theoretically have a worse prognosis; thus, age should theoretically indirectly affect prognosis.

Elderly people comprise the majority of the nursing home population. However, reports of outbreaks in nursing homes[40] are limited, despite the latter being considered environments that exert significant antibacterial pressure.[41]

2. Available Antibacterials

P. aeruginosa is resistant to a wide array of antibacterials, including many β-lactams, older fluoroquinolones, tetracycline, macrolides, chloramphenicol, rifampicin (rifampin) and cotrimoxazole (trimethoprim/sulfamethoxazole). Various indigenous mechanisms of resistance explain this pattern, including low membrane permeability, the production of β-lactamases (cephalosporinases) and active efflux pumps.[42]

Antibacterials that are traditionally considered active against Pseudomonas can be broadly categorized into the following seven groups:
  1. 1.

    Active penicillins, including piperacillin and ticarcillin. This group also includes the subgroups of β-lactam/β-lactamase inhibitor combinations (ticarcillin/clavulanic acid, piperacillin/tazobactam). Of these combinations, piperacillin/tazobactam is considered preferable because of its optimal pharmacokinetics, the fact that, excluding the effect of β-lactamase inhibitor addition, piperacillin is optimal compared with ticarcillin and the potential antagonism to ticarcillin by induction of AmpC by clavulanic acid.[43] A recent study demonstrated that prolonged infusion of piperacillin/tazobactam (4 hours vs 1 hour) may achieve pharmacodynamic targets more efficiently in severely ill patients.[44] On the other hand, concerns have been expressed regarding the appropriateness of the current Clinical Laboratory Standards Institute resistance breakpoint for piperacillin/tazobactam,[45] which may yield false-susceptibility results and result in therapeutic failures.

     
  2. 2.

    Cephalosporins active against P. aeruginosa, including ceftazidime, cefepime and cefoperazone.

     
  3. 3.

    Aztreonam. This monobactam is active against P. aeruginosa, and its potency is becoming more obvious from data generated in Europe.[46] One should note, however, that these data are possibly subject to the different breakpoints used in different continents.

     
  4. 4.

    The active carbapenems, which include imipenem, meropenem and doripenem, but not ertapenem. Meropenem is considered preferable to imipenem with respect to selection for resistance.[47] Extended (3-hour) infusions of meropenem have been shown to exert a beneficial effect.[48] In vitro data suggest a 2-fold superiority for doripenem over meropenem, a 4-fold superiority to imipenem[49] and reduced potential for selection of resistance.[50] Furthermore, prolonged infusions may enhance the antibacterial activity of doripenem in infections caused by less susceptible strains.[51]

     
  5. 5.

    The fluoroquinolone group with activity against Pseudomonas basically consists of ciprofloxacin and levofloxacin. Ciprofloxacin is more potent based upon minimal inhibitory concentrations; however, the superior pharmacokinetics of maximum doses of levofloxacin balance the decreased potency, so much so that these two fluoroquinolones are pharmacodynamically equivalent against P. aeruginosa.[52] Data about the role of sitafloxacin are also needed, given that its in vitro profile shows antipseudomonal activity similar to that of ciprofloxacin and a potential for enhanced activity against GyrA mutants.[9] Of note is that clinafloxacin exhibited enhanced antipseudomonal activity compared with that of ciprofloxacin,[53,54] although its production was suspended.

     
  6. 6.

    Antipseudomonal aminoglycosides, including gentamicin, tobramycin, netilmicin and amikacin. In vitro data support a synergistic role for aminoglycosides when combined with β-lactams,[55] and a significant post-antibacterial effect with amikacin combinations.[56]

     
  7. 7.

    The polymyxin colistin has recently re-emerged as a potential solution to MDR.[1,57, 58, 59] The much discussed toxicity of this drug (mainly nephrotoxicity, but also ototoxicity and neuromuscular blockade) has been shown to be in fact lower than first thought and controllable,[60] and preliminary experimental data suggest that colixin can be administered even in aerosolized form to mechanically ventilated, non-cystic fibrosis patients with pseudomonal infections.[61] Colistin is now considered the leading therapeutic option for strains with advanced MDR pattern.[62, 63, 64] Some confusion still exists concerning the different formulations used.[65] Polymyxin B also belongs to this category, although clinical experience with this agent is generally limited. Its use as salvage therapy has been reported in a series of patients with nosocomial pneumonia caused by MDR P. aeruginosa.[66]

     
Table II summarizes administration regimens for commonly used antibacterials in pseudomonal infections, suggested dosing regimens in normal and impaired renal function, and recent resistance data.
Table II

Available antipseudomonal agents: doses, dose modification in the renally impaired and resistance rates

Apart from these antibacterial classes, a potential synergistic role for rifampicin has been suggested.[68] Fosfomycin is another agent that in vitro exhibits some potential for use in pseudomonal infections, although relevant research has been limited.[69,70] It should be noted that drug-development targeting Pseudomonas is proceeding very slowly: one should not expect any major novel agents in the foreseeable future.

2.1 Use of Available Antibacterials in the Elderly

Pharmacotherapy in the elderly often requires major modifications to the administered regimens. Age unavoidably, even in the absence of co-existing morbidity, may induce partial loss of renal function, which is not necessarily represented in serum creatinine measurements. Glomerular filtration rate (GFR) is a more precise indicator of the actual renal function in the elderly, and should always be taken into account in elderly patients who have been prescribed antibacterials. A 50% reduction in GFR is typical of a 70-year old compared with a 30-year-old.[71] Creatinine clearance estimation in any elderly patient is thus of paramount importance in order to optimize administered regimens.

A typical example of the need for dose adjustment in these settings would be in a patient receiving imipenem, the dose of which should be adjusted in the elderly according to predicted renal function in order to avoid the significant risk for seizures.[72] Table II includes recommended dose modifications according to GFR.

Aminoglycoside nephrotoxicity is a major concern in the elderly patient with pseudomonal infection, given that combined empirical regimens usually include such an agent. It has been proposed that nephrotoxicity in the elderly can be lowered if aminoglycoside administration is restricted to <1 week,[73] multiple daily-dose regimens are used[74] (although most of the published literature in adults in general suggests otherwise)[75] or, in the case of single daily-dose regimens, if trough levels are monitored systematically.[76]

The elderly are also prone to polypharmacy,[77] and drug interactions should therefore be taken into account when considering antipseudomonal agents. Patients of advanced age often use diuretics with a subsequent increased risk for nephrotoxicity; they are also often taking medications for heart failure, which may be a concern when administering fluoroquinolones in relation to possible ECG adverse events. Neurotropic agents used for dementia or memory impairment may interact with antibacterials such as fluoroquinolones and imipenem and lower the threshold for seizures in susceptible individuals.

3. Antibacterial Resistance

Resistance has become such a major issue that scientists are now discussing not which antibacterial is optimal against Pseudomonas, but which is ecologically safer. Resistance to individual antipseudomonal agents is continuously rising, with geographical variations mostly related to local antimicrobial policies. Increased resistance is particularly a problem in ICUs, especially in Europe, and applies to the majority of the available antipseudomonal agents. Certain studies support the possibility that piperacillin/tazobactam and amikacin may be exceptions to this trend.[46] In general, the antibacterial class for which resistance rates are increasing most rapidly is the fluoroquinolones; however, geographical variation exists, with resistance to aminoglycosides and β-lactams being more significant in Europe. Although theoretically considered to be resistance proof because of its mechanism of action (disruption of the cytoplasmic membrane), reports of colistin-resistant strains are emerging.[78, 79, 80, 81]

The importance of resistance lies not only in its prevalence and consequences, but also in its potential for accumulation. MDR has been linked to a 3-fold increase in mortality, a 9-fold increase in secondary bacteraemia, a 2-fold prolongation of duration of hospitalization and major increases in healthcare costs.[82]

However, what actually constitutes MDR remains ill-defined, and this absence of a common language can often be incriminated in the development of numerous therapeutic dilemmas.[83] For example, a recent review[84] defines MDR as the presence of diminished susceptibility to more than one of five antibacterial classes, namely, cephalosporins, carbapenems, β-lactam and inhibitor combinations, quinolones and aminoglycosides. According to this definition, a strain resistant to ceftazidime and amikacin will be considered MDR, although there are relatively adequate therapeutic options. Others define MDR as the presence of resistance to three or more of four antibacterial categories, namely, β-lactams (including combinations), carbapenems, quinolones and aminoglycosides. However, such classifications have substantial problems. A major problem that has not been discussed is that such definitions of MDR essentially include in the same group (i) strains that are resistant to β-lactams and combinations, quinolones and aminoglycosides, but susceptible to carbapenems, and (ii) strains that are resistant to β-lactams, carbapenems and fluoroquinolones, but are susceptible to aminoglycosides. In the former situation, use of a carbapenem can induce a satisfactory therapeutic result; in the latter situation, however, use of an aminoglycoside as monotherapy is not an accepted approach.

Thus, all instances of MDR are not the same. Furthermore, MDR, irrespective of how it is defined, also exhibits geographical variations. In general, MDR is more common in Latin America, where 8% of total isolates are MDR, and Europe (5% but increasing), while rates for Asia and the US are 2%.[85] The pattern is different when ICU isolates only are evaluated; in that case, MDR isolates exceed 30% in Asian ICUs and 20% in US ICUs, and there have been increasing numbers of reports of outbreaks of extensively resistant isolates.

3.1 Mechanisms of Resistance

Mechanisms of resistance, summarized in table III, can be categorized as alterations of permeability, active efflux, antibacterial inactivation mechanisms (including production of β-lactamases and aminoglycoside modifying enzymes) and target modifications.[9] Resistance patterns occur in different frequencies. For example, OprD loss is frequent (10−7, or 1 in 107 random mutations), and thus resistance to imipenem can be relatively easily selected.[47] On the other hand, for significant resistance to meropenem to develop, overexpression of MexAB is required in addition to loss of OprD, a pattern that occurs less frequently (10−14). This difference has been proposed as a potential reason for preferring meropenem over imipenem in the treatment of pseudomonal infections, particularly as low-level meropenem resistance can be overcome by dose increases.[47]
Table III

Mechanisms of antibacterial resistance in Pseudomonas aeruginosa

3.2 Risk Factors for Resistance

Exposure to antibacterials remains the major risk factor for emergence of pseudomonal resistance. Exposure to a single antibacterial can select for resistance not only to that drug but to other antibacterial classes too. Resistance to the particular antibacterial can extend for varying time periods: it may disappear rapidly for piperacillin/tazobactam but not for ciprofloxacin or imipenem.[90] Resistance to other classes is more significant: fluoroquinolones can select an efflux pump that inactivates a β-lactam or an aminoglycoside (table III). Imipenem consumption has been shown to select resistance for ceftazidime and piperacillin-tazobactam.[91] In a study published in 1999,[92] ceftazidime was shown to be the antibacterial least able to induce resistance-selection pressure; however, this study also showed that quinolones, along with ticarcillin, selected resistance only for their own classes, which is contrary to the results of previous studies.[93] Doubts over this reported advantage of ceftazidime have also been expressed elsewhere.[94]

Suboptimal antimicrobial regimens are also risk factors for resistance, since low intrabacterial antimicrobial concentrations favour the development of target mutations. Exposure to antibacterials with no antipseudomonal activity can also select resistance. For example, a study involving imipenem showed that, in addition to exposure to piperacillin/tazobactam and aminoglycosides, risk factors for imipenem resistance included exposure to vancomycin.[95]

Pseudomonal resistance is greatly associated with biofilm formation.[96] This is not only a problem for patients with cystic fibrosis, but also applies to VAP and infection related to indwelling devices.[96] The complex nature of biofilm formation and its resistance mechanisms are beyond the scope of this review.

An MDR phenotype can be achieved in a single step, through selection of a multidrug efflux pump or by clustered resistance determinants in a genetic element,[97] but is usually the result of sequential, accumulated mutations.[87] Risk factors for MDR have been identified, and include age (>60 years), prolonged hospitalization, ICU stay and mechanical ventilation, a history of diabetes or end-stage renal disease, and the presence of decubitus ulcers.[98] In this study, exposure to any antipseudomonal antibacterial was also a risk factor for MDR development, with lower exposure time required for carbapenems and quinolones than for piperacillin/tazobactam and cefepime. Quinolones have been systematically related to the development of MDR.[84,99, 100, 101, 102, 103] MDR bacteraemia has also been correlated with quinolone use, together with age, HIV infection and intravenous drug abuse, in an Italian study.[99]

3.3 Resistance and the Elderly

Isolated resistance to any antipseudomonal antibacterial has not been related to age in the literature; however, limited relevant information exists. On the other hand, as outlined in the previous section, age has been consistently identified as a risk factor for the presence of MDR. The proneness of the elderly to polypharmacy, including multiple antibacterial courses and the increased percentage of elderly with diabetes, may account for this. The consequences of this correlation, though, cannot be ignored. A typical scenario is that of the senior patient with an indwelling urinary catheter who has received numerous oral antibacterial courses with quinolones as chemoprophylaxis for urinary tract infection and has been hospitalized repeatedly for such infections. This patient is at risk for pseudomonal infection because of the presence of the catheter and his/her multiple hospitalizations, and is at risk for MDR because of his/her age, multiple hospitalizations and repeated quinolone use. Such patients are not rare in everyday clinical practice, particularly at nursing homes, and underline the need for appropriate antibacterial prescribing.

4. Empirical Treatment

Given the high mortality associated with pseudomonal infections, empirical treatment targeting Pseudomonas should be administered upon suspicion. It is accepted that early, even within 1 hour, administration of an active antibacterial can be life-saving for septic patients,[104] particularly for bacteraemic patients.[67] Use of an agent with known antipseudomonal activity in patients at risk for P. aeruginosa infection is of paramount importance in order to lower mortality: in cases of bacteraemia, mortality was lowered almost by half, from 30.7% to 17.8%, when the appropriate antipseudomonal agent was included in the initial empirical therapeutic regimen.[105] Another study showed that the risk of death at day 30 was increased 2.6-fold when an inadequate empirical regimen was used.[106]

Empirical combination regimens appear to have numerous advantages over administration of a single agent with antipseudomonal activity (table IV). Enhanced 30-day survival was noted with empirical combination regimens prior to determination of the organism’s antibacterial susceptibility,[106] and a novel study in VAP also showed that, in patients at increased risk for pseudomonal infection, combination empirical regimens were associated with improved survival.[109]
Table IV

Monotherapy versus combination therapy in Pseudomonas aeruginosa infections: advantages and disadvantages

A combination of a β-lactam with an aminoglycoside is the most common combination reported in the literature; quinolones often replace β-lactams in other empirical combination regimens. The principal rationale behind combined empirical therapeutic regimens is not the potential for synergy, but rather the increased possibility of covering the responsible strain. For example, when administering a quinolone as monotherapy, for an average 80% susceptibility, there is a 1 : 5 chance of a resistant strain and, consequently, treatment failure. When administering a combined regimen, the odds of therapeutic failure are lowered because MDR is not as frequent as isolated resistance. Moreover, combination regimens have also been shown to be, strangely, ecologically safer, with lower pressure for selection of resistance applied, possibly as a result of rapid bacterial killing[110,111] (table IV).

Supporters of empirical monotherapy do exist: two meta-analyses, both of which included a significant number of patients with P. aeruginosa infections, failed to demonstrate the superiority of empirical combination regimens in febrile neutropenia and in sepsis in non-immunocompromised patients.[107,108] Combination regimens are associated with increased costs, increased frequency of adverse events (mainly as a result of the aminoglycoside component),[108] and increased risk for fungal super-infections. Conversely, another meta-analysis focusing on Gram-negative bacteraemia demonstrated a benefit in mortality, although the subgroup receiving empirical monotherapy for Pseudomonas infections included many recipients of aminoglycoside-only regimens, which are considered inferior or relatively inappropriate.[112] Nevertheless, in the best interests of the patient, a carefully chosen combination regimen seems a logical choice upon suspicion of pseudomonal infection.

An MDR phenotype can be predicted in selected situations, thus allowing for the empirical use of colistin. An example would be a patient with VAP and a history of recent VAP or recent administration of antibacterials, particularly carbapenems, that may have selected resistance.[113,114]

4.1 Empirical Treatment in the Elderly

As noted in previous sections, age is an individual risk factor for infection by MDR strains. Thus, any suspicion of pseudomonal infection in an elderly individual should take into account the possibility that an MDR pseudomonal strain is implicated. Response to the administered treatment should be checked for continuously, and upon signs of deterioration, it appears reasonable to switch to the agents least likely to be inactive against P. aeruginosa, such as colistin or ertapenem. Use of aminoglycosides is also an issue in the empirical treatment of the elderly: a basic evaluation of a patient’s renal status can usually be performed rapidly and, along with the history of the patient, can allow patients to be stratified in terms of their risk for aminoglycoside nephrotoxicity. If aminoglycosides are contraindicated, other combination therapies may be of use. An example of this is the combination of a β-lactam with ciprofloxacin. The higher respiratory penetration of the latter may prove useful in pseudomonal respiratory infections, although pressure for resistance selection with such a combination may be maximal. The combination of a carbapenem with ciprofloxacin also warrants further evaluation.[115]

5. Treatment of Confirmed Pseudomonal Infections

Upon receipt of antibacterial sensitivity data, the next dilemma arising is whether to adjust to the susceptibility information or, in cases of patient stabilization and improvement in the clinical picture, to continue with the empirically administered regimen. The most controversial dilemma in such cases arises when a patient was empirically treated with a combination regimen: should de-escalation follow? Based on guidelines issued for the treatment of HAP/VAP[116] and febrile neutropenia,[117] monotherapy can be considered a reasonable approach. Monotherapy for a confirmed pseudomonal infection has not been proven to be inferior to combination regimens in terms of 30-day mortality.[106] In this setting, the potential advantage of broad coverage with an empirical antibacterial combination does not apply since susceptibility data are available; however, the disadvantages of combined antibacterials, such as costs and adverse events, remain high. Furthermore, pressure for selection of resistance is lower with monotherapy in confirmed pseudomonal infections (table IV). These rules apply to all potential monotherapies, with the exception of aminoglycosides, the use of which has been related to an increased likelihood of an adverse outcome.[32,118] On the other hand, supporters of combination regimens for confirmed pseudomonal infections[85] focus on the potential benefit of synergistic antibacterial action.

Duration of treatment is another debatable issue. There is a scientifically sound trend in favour of reducing the number of days of antibacterial administration: a widely accepted study in VAP showed that 8 days of treatment is non-inferior to more prolonged antibacterial administration.[119] Furthermore, it is also less costly, has a lower potential for adverse events and is ecologically safer. However, a higher pulmonary infection recurrence rate was noted in the subgroup that included pseudomonal infections.

5.1 Considerations in the Elderly

Once the diagnosis and susceptibility profile of P. aeruginosa have been confirmed, the increased risk in an elderly patient for development of antibacterial-related adverse events further supports administration of monotherapy. The clinician may need to choose between an optimal (according to susceptibility data) antibacterial with sub-optimal adverse events potential, or an antibacterial with lower activity but lower adverse-event risk. Such choices should be individualized and should also take into account the severity of the underlying infection; consequently, more specific general recommendations cannot be made.

6. Alternative-Adjuvant Therapeutic Approaches

The absence of promising research in antibacterial development has forced scientists to seek alternative approaches to battling Pseudomonas. Intervention in the pseudomonal pathogenetic process seems promising through the blockage of quorum-sensing, mainly with the use of azithromycin;[120] thalidomide has also been tested.[121] Immunotherapy has attracted attention predominantly in the cystic fibrosis population, and is thus beyond the scope of this review. Attempts at halting resistance mechanisms through use of efflux pump inhibitors and novel β-lactamase inhibitors are currently under investigation.[122] However, it is important to remember that the real threat is MDR, which involves the co-existence of multiple-resistance mechanisms that cannot be switched off by a narrowly targeted inhibitor. Antibacterial peptides that may act locally against pseudomonal lipopolysaccharide are also under investigation.[122]

6.1 Prevention and Control

Hygienic precautions, surveillance for incidence of colonization and resistance, and prudent use of antibacterials (optimal regimens, rotation of agents [although not definitely demonstrated to be beneficial]) should obviously be part of everyday practice in high-risk environments. Whether they are applied or not is, unfortunately, often a matter of health policies and not an inherent medical/paramedical duty.

7. Conclusions

Why is there no definite answer to the therapeutic dilemma of combination versus monotherapy for a confirmed infection by P. aeruginosa? Pseudomonal infections, because of expansion of resistance, consist of a rapidly evolving universe: the therapeutic principles of the present day may be outdated in the near future if individual antibacterial resistance rates continue to increase. Although clinical trials from which data are drawn usually contain a subgroup of P. aeruginosa infections, such trials tend to focus instead on broader entities such as neutropenic fever, Gram-negative bacteraemia or VAP. Extraction of statistically valuable data isolated for Pseudomonas is not always feasible, and may be subject to older, currently unacceptable practices (see the extended use of aminoglycosides as monotherapy in a previously discussed meta-analysis[112]). Furthermore, designing appropriate clinical trials with the aim of solving this dilemma may prove futile in the absence of a common language for other, simpler issues, such as the definition of MDR.

When these dilemmas are transferred to a population as vulnerable as the elderly, the problems are magnified. Senior patients, who often carry other co-morbidities that predispose them to pseudomonal infection, are at risk, on the basis of their age alone, to MDR P. aeruginosa infections and have a lower threshold for the development of adverse drug reactions, particularly when administered doses are not adjusted for the loss of renal function associated with age. Each elderly patient carries his/her own morbidity background and is at risk for his/her own antibacterial-related adverse events. Furthermore, each pseudomonal infection is not of the same severity. The possible combinations of an individual patient with his/her individual risks and pseudomonal infections of varying mortality potential are too numerous to allow generalized recommendations to be made. The clinician should individualize therapeutic decisions, taking into account patient and pathogen characteristics. In the elderly, the clinician should also have a low threshold of clinical suspicion for pseudomonal infections, should not be afraid to empirically use novel antibacterials such as colistin in the case of MDR suspicion, and should be vigilant for any interruption of the benefit-adverse event equilibrium that may develop.

Notes

Acknowledgements

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Georgios Pappas
    • 1
    • 2
  • Kaiti Saplaoura
    • 1
  • Matthew E. Falagas
    • 2
    • 3
  1. 1.Institute of Continuing Medical Education of IoanninaIoanninaGreece
  2. 2.Alfa Institute of Biomedical Sciences (AIBS)AthensGreece
  3. 3.Department of MedicineTufts University School of MedicineBostonUSA

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