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


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.



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.


  1. 1.
    Giamarellou H, Kanellakopoulou K. Current therapies for Pseudomonas aeruginosa. Crit Care Clin 2008; 24(2): 261–78PubMedCrossRefGoogle Scholar
  2. 2.
    Mathers CD, Iburg KM, Salomon JA, et al. Global patterns of healthy life expectancy in the year 2002. BMC Public Health 2004; 4: 66PubMedCrossRefGoogle Scholar
  3. 3.
    Lubitz J, Cai L, Kramarow E, et al. Health, life expectancy, and health care spending among the elderly. N Engl J Med 2003; 349(11): 1048–55PubMedCrossRefGoogle Scholar
  4. 4.
    Crimmins EM, Saito Y. Trends in healthy life expectancy in the United States, 1970–1990: gender, racial, and educational differences. Soc Sci Med 2001; 52(11): 1629–41PubMedCrossRefGoogle Scholar
  5. 5.
    Van Rensbergen G, Nawrot TS, Van Hecke E, et al. Where do the elderly die? The impact of nursing home utilisation on the place of death: observations from a mortality cohort study in Flanders. BMC Public Health 2006; 6: 178PubMedCrossRefGoogle Scholar
  6. 6.
    Cohen-Mansfield J, Marx MS, Lipson S, et al. Predictors of mortality in nursing home residents. J Clin Epidemiol 1999; 52: 273–80PubMedCrossRefGoogle Scholar
  7. 7.
    Nicolle LE, Strausbaugh LJ, Garibaldi RA. Infections and antibiotic resistance in nursing homes. Clin Microbiol Rev 1996; 9(1): 1–17PubMedGoogle Scholar
  8. 8.
    Stover CK, Pham XQ, Erwin AL, et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 2000; 406(6799): 959–64PubMedCrossRefGoogle Scholar
  9. 9.
    Mesaros N, Nordmann P, Plesiat P, et al. Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium. Clin Microbiol Infect 2007; 13(6): 560–78PubMedCrossRefGoogle Scholar
  10. 10.
    Rogues AM, Boulestreau H, Lasheras A, et al. Contribution of tap water to patient colonisation with Pseudomonas aeruginosa in a medical intensive care unit. J Hosp Infect 2007; 67(1): 72–8PubMedCrossRefGoogle Scholar
  11. 11.
    Reuter S, Sigge A, Wiedeck H, et al. Analysis of transmission pathways of Pseudomonas aeruginosa between patients and tap water outlets. Crit Care Med 2002; 30(10): 2222–8PubMedCrossRefGoogle Scholar
  12. 12.
    Moolenaar RL, Crutcher JM, San Joaquin VH, et al. A prolonged outbreak of Pseudomonas aeruginosa in a neonatal intensive care unit: did staff fingernails play a role in disease transmission? Infect Control Hosp Epidemiol 2000; 21(2): 80–5PubMedCrossRefGoogle Scholar
  13. 13.
    Iversen BG, Jacobsen T, Eriksen HM, et al. An outbreak of Pseudomonas aeruginosa infection caused by contaminated mouth swabs. Clin Infect Dis 2007; 44(6): 794–801PubMedCrossRefGoogle Scholar
  14. 14.
    Bonten MJ, Bergmans DC, Speijer H, et al. Characteristics of polyclonal endemicity of Pseudomonas aeruginosa colonization in intensive care units: implications for infection control. Am J Respir Crit Care Med 1999; 160(4): 1212–9PubMedGoogle Scholar
  15. 15.
    Adachi M, Ishihara K, Abe S, et al. Professional oral health care by dental hygienists reduced respiratory infections in elderly persons requiring nursing care. Int J Dent Hyg 2007; 5(2): 69–74PubMedCrossRefGoogle Scholar
  16. 16.
    El-Solh AA, Pietrantoni C, Bhat A, et al. Colonization of dental plaques: a reservoir of respiratory pathogens for hospital-acquired pneumonia in institutionalized elders. Chest 2004; 126: 1575–82PubMedCrossRefGoogle Scholar
  17. 17.
    Sammons RL, Kaur D, Neal P. Bacterial survival and biofilm formation on conventional and antibacterial toothbrushes. Biofilms 2004; 1: 123–30CrossRefGoogle Scholar
  18. 18.
    Girard G, Bloemberg GV. Central role of quorum sensing in regulating the production of pathogenicity factors in Pseudomonas aeruginosa. Future Microbiol 2008; 3(1): 97–106PubMedCrossRefGoogle Scholar
  19. 19.
    Van Delden C, Iglewski BH. Cell-to-cell signaling and Pseudomonas aeruginosa infections. Emerg Infect Dis 1998; 4(4): 551–60PubMedCrossRefGoogle Scholar
  20. 20.
    Fichtenbaum CJ, Woeltje KF, Powderly WG. Serious Pseudomonas aeruginosa infections in patients infected with human immunodeficiency virus: a case-control study. Clin Infect Dis 1994; 19(3): 417–22PubMedCrossRefGoogle Scholar
  21. 21.
    Monso E, Garcia-Aymerich J, Soler N, et al. Bacterial infection in exacerbated COPD with changes in sputum characteristics. Epidemiol Infect 2003; 131(1): 799–804PubMedCrossRefGoogle Scholar
  22. 22.
    Murphy TF, Brauer AL, Eschberger K, et al. Pseudomonas aeruginosa in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177(8): 853–60PubMedCrossRefGoogle Scholar
  23. 23.
    Taccetti G, Campana S, Neri AS, et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis. J Chemother 2008; 20(2): 166–9PubMedGoogle Scholar
  24. 24.
    Segal R, Dan M, Pogoreliuk I, et al. Pathogenic colonization of the stomach in enterally fed elderly patients: comparing percutaneous endoscopic gastrostomy with nasogastric tube. J Am Geriatr Soc 2006; 54(12): 1905–8PubMedCrossRefGoogle Scholar
  25. 25.
    Valenti WM, Trudell RG, Bentley DW. Factors predisposing to oropharyngeal colonization with Gram-negative bacilli in the aged. N Engl J Med 1978; 298(20): 1108–11PubMedCrossRefGoogle Scholar
  26. 26.
    Gasink LB, Fishman NO, Nachamkin I, et al. Risk factors for and impact of infection or colonization with aztreonam-resistant Pseudomonas aeruginosa. Infect Control Hosp Epidemiol 2007; 28(10): 1175–80PubMedCrossRefGoogle Scholar
  27. 27.
    Arancibia F, Bauer TT, Ewig S, et al. Community-acquired pneumonia due to Gram-negative bacteria and pseudomonas aeruginosa: incidence, risk, and prognosis. Arch Intern Med 2002; 162(16): 1849–58PubMedCrossRefGoogle Scholar
  28. 28.
    Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 2003; 37(11): 1405–33PubMedCrossRefGoogle Scholar
  29. 29.
    Almirall J, Mesalles E, Klamburg J, et al. Prognostic factors of pneumonia requiring admission to the intensive care unit. Chest 1995; 107(2): 511–6PubMedCrossRefGoogle Scholar
  30. 30.
    Hatchette TF, Gupta R, Marrie TJ. Pseudomonas aeruginosa community-acquired pneumonia in previously healthy adults: case report and review of the literature. Clin Infect Dis 2000; 31(6): 1349–56PubMedCrossRefGoogle Scholar
  31. 31.
    Vidal F, Mensa J, Almela M, et al. Epidemiology and outcome of Pseudomonas aeruginosa bacteremia, with special emphasis on the influence of antibiotic treatment: analysis of 189 episodes. Arch Intern Med 1996; 156(18): 2121–6PubMedCrossRefGoogle Scholar
  32. 32.
    Chatzinikolaou I, Abi-Said D, Bodey GP, et al. Recent experience with Pseudomonas aeruginosa bacteremia in patients with cancer: retrospective analysis of 245 episodes. Arch Intern Med 2000; 160(4): 501–9PubMedCrossRefGoogle Scholar
  33. 33.
    Cheong HS, Kang CI, Wi YM, et al. Clinical significance and predictors of community-onset Pseudomonas aeruginosa bacteremia. Am J Med 2008; 121(8): 709–14PubMedCrossRefGoogle Scholar
  34. 34.
    Johansen TE, Cek M, Naber KG, et al. Hospital acquired urinary tract infections in urology departments: pathogens, susceptibility and use of antibiotics. Data from the PEP and PEAP-studies. Int J Antimicrob Agents 2006; 28Suppl. 1: S91–107PubMedCrossRefGoogle Scholar
  35. 35.
    Driscoll JA, Brody SL, Kollef MH. The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections. Drugs 2007; 67(3): 351–68PubMedCrossRefGoogle Scholar
  36. 36.
    Micek ST, Kollef KE, Reichley RM, et al. Health care-associated pneumonia and community-acquired pneumonia: a single-center experience. Antimicrob Agents Chemother 2007; 51(10): 3568–73PubMedCrossRefGoogle Scholar
  37. 37.
    Pareja A, Bernal C, Leyva A, et al. Etiologic study of patients with community-acquired pneumonia. Chest 1992; 101(5): 1207–10PubMedCrossRefGoogle Scholar
  38. 38.
    Van Delden C. Pseudomonas aeruginosa bloodstream infections: how should we treat them? Int J Antimicrob Agents 2007; 30Suppl. 1: S71–5PubMedCrossRefGoogle Scholar
  39. 39.
    Lin YT, Chen LK, Lin MH, et al. Asymptomatic bacteriuria among the institutionalized elderly. J Chin Med Assoc 2006; 69(5): 213–7PubMedCrossRefGoogle Scholar
  40. 40.
    Dubois V, Arpin C, Noury P, et al. Prolonged outbreak of infection due to TEM-21-producing strains of Pseudomonas aeruginosa and Enterobacteria in a nursing home. J Clin Microbiol 2005; 43(8): 4129–38PubMedCrossRefGoogle Scholar
  41. 41.
    Smith PW, Seip CW, Schaefer SC, et al. Microbiologic survey of long-term care facilities. Am J Infect Control 2000; 28(1): 8–13PubMedCrossRefGoogle Scholar
  42. 42.
    Hancock RE. Resistance mechanisms in Pseudomonas aeruginosa and other nonfermentative Gram-negative bacteria. Clin Infect Dis 1998; 27Suppl. 1: S93–9PubMedCrossRefGoogle Scholar
  43. 43.
    Lister PD. Beta-lactamase inhibitor combinations with extended-spectrum penicillins: factors influencing antibacterial activity against Enterobacteriaceae and Pseudomonas aeruginosa. Pharmacotherapy 2000; 20 (9 Pt 2): 213S–8SPubMedCrossRefGoogle Scholar
  44. 44.
    Lodise Jr TP, Lomaestro B, Drusano GL. Piperacillintazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007; 44(3): 357–63PubMedCrossRefGoogle Scholar
  45. 45.
    Tam V, Gamez EA, Weston JS, et al. Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: implications on the appropriateness of the resistance breakpoint. Clin Infect Dis 2008; 46(6): 862–7PubMedCrossRefGoogle Scholar
  46. 46.
    Jones RN, Kirby JT, Beach ML, et al. Geographic variations in activity of broad-spectrum beta-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program (1997-2000). Diagn Microbiol Infect Dis 2002; 43(3): 239–43PubMedCrossRefGoogle Scholar
  47. 47.
    Livermore DM. Of Pseudomonas porins, pumps and carbapenems. J Antimicrob Chemother 2001; 47(3): 247–50PubMedCrossRefGoogle Scholar
  48. 48.
    Santos Filho L, Eagye KJ, Kuti JL, et al. Addressing resistance evolution in Pseudomonas aeruginosa using pharmacodynamic modelling: application to meropenem dosage and combination therapy. Clin Microbiol Infect 2007; 13(6): 579–85PubMedCrossRefGoogle Scholar
  49. 49.
    Jones RN, Huynh HK, Biedenbach DJ, et al. Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations. J Antimicrob Chemother 2004; 54(1): 144–54PubMedCrossRefGoogle Scholar
  50. 50.
    Mushtaq S, Ge Y, Livermore DM. Doripenem versus Pseudomonas aeruginosa in vitro: activity against characterized isolates, mutants, and transconjugants and resistance selection potential. Antimicrob Agents Chemother 2004; 48(8): 3086–92PubMedCrossRefGoogle Scholar
  51. 51.
    Bhavnani SM, Hammel JP, Cirincione BB, et al. Use of pharmacokinetic-pharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem. Antimicrob Agents Chemother 2005; 49(9): 3944–7PubMedCrossRefGoogle Scholar
  52. 52.
    Tennenberg AM, Davis NB, Wu SC, et al. Pneumonia due to Pseudomonas aeruginosa: the levofloxacin clinical trials experience. Curr Med Res Opin 2006; 22(5): 843–50PubMedCrossRefGoogle Scholar
  53. 53.
    Piddock LJ, Johnson M, Ricci V, et al. Activities of new fluoroquinolones against fluoroquinolone-resistant pathogens of the lower respiratory tract. Antimicrob Agents Chemother 1998; 42(11): 2956–60PubMedGoogle Scholar
  54. 54.
    Shapiro MA, Sesnie JC, Desaty TM, et al. Comparative therapeutic efficacy of clinafloxacin in a Pseudomonas aeruginosa mouse renal abscess model. J Antimicrob Chemother 1998; 41(3): 403–5PubMedCrossRefGoogle Scholar
  55. 55.
    Giamarellou H, Zissis NP, Tagari G, et al. In vitro synergistic activities of aminoglycosides and new beta-lactams against multiresistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1984; 25(4): 534–6PubMedCrossRefGoogle Scholar
  56. 56.
    Giamarellos-Bourboulis EJ, Kentepozidis N, Antonopoulou A, et al. Postantibiotic effect of antimicrobial combinations on multidrug-resistant Pseudomonas aeruginosa. Diagn Microbiol Infect Dis 2005; 51(2): 113–7PubMedCrossRefGoogle Scholar
  57. 57.
    Michalopoulos AS, Tsiodras S, Rellos K, et al. Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: the renaissance of an old antibiotic. Clin Microbiol Infect 2005; 11(2): 115–21PubMedCrossRefGoogle Scholar
  58. 58.
    Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gramnegative bacterial infections. Clin Infect Dis 2005; 40(9): 1333–41PubMedCrossRefGoogle Scholar
  59. 59.
    Kasiakou SK, Michalopoulos A, Soteriades ES, et al. Combination therapy with intravenous colistin for management of infections due to multidrug-resistant Gramnegative bacteria in patients without cystic fibrosis. Antimicrob Agents Chemother 2005; 49(8): 3136–46PubMedCrossRefGoogle Scholar
  60. 60.
    Falagas ME, Fragoulis KN, Kasiakou SK, et al. Nephrotoxicity of intravenous colistin: a prospective evaluation. Int J Antimicrob Agents 2005; 26(6): 504–7PubMedCrossRefGoogle Scholar
  61. 61.
    Horianopoulou M, Lambropoulos S, Papafragas E, et al. Effect of aerosolized colistin on multidrug-resistant Pseudomonas aeruginosa in bronchial secretions of patients without cystic fibrosis. J Chemother 2005; 17(5): 536–8PubMedGoogle Scholar
  62. 62.
    Falagas ME, Kasiakou SK, Kofteridis DP, et al. Effectiveness and nephrotoxicity of intravenous colistin for treatment of patients with infections due to polymyxin-only-susceptible (POS) Gram-negative bacteria. Eur J Clin Microbiol Infect Dis 2006; 25(9): 596–9PubMedCrossRefGoogle Scholar
  63. 63.
    Kallel H, Hergafi L, Bahloul M, et al. Safety and efficacy of colistin compared with imipenem in the treatment of ventilator-associated pneumonia: a matched case-control study. Intensive Care Med 2007; 33(7): 1162–7PubMedCrossRefGoogle Scholar
  64. 64.
    Hachem RY, Chemaly RF, Ahmar CA, et al. Colistin is effective in treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in cancer patients. Antimicrob Agents Chemother 2007; 51(6): 1905–11PubMedCrossRefGoogle Scholar
  65. 65.
    Falagas ME, Kasiakou SK. Use of international units when dosing colistin will help decrease confusion related to various formulations of the drug around the world. Antimicrob Agents Chemother 2006; 50(6): 2274–5PubMedCrossRefGoogle Scholar
  66. 66.
    Furtado GH, d’Azevedo PA, Santos AF, et al. Intravenous polymyxin B for the treatment of nosocomial pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. Int J Antimicrob Agents 2007; 30(4): 315–9PubMedCrossRefGoogle Scholar
  67. 67.
    Kang CI, Kim SH, Kim HB, et al. Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin Infect Dis 2003; 37(6): 745–51PubMedCrossRefGoogle Scholar
  68. 68.
    Giamarellos-Bourboulis EJ, Sambatakou H, Galani I, et al. In vitro interaction of colistin and rifampin on multidrug-resistant Pseudomonas aeruginosa. J Chemother 2003; 15(3): 235–8PubMedGoogle Scholar
  69. 69.
    Falagas ME, Kanellopoulou MD, Karageorgopoulos DE, et al. Antimicrobial susceptibility of multidrug-resistant Gram negative bacteria to fosfomycin. Eur J Clin Microbiol Infect Dis 2008; 27(6): 439–43PubMedCrossRefGoogle Scholar
  70. 70.
    Kobayashi Y, Sumitani Y, Sugita K, et al. Antimicrobial activity of fosfomycin against multidrug-resistant Pseudomonas aeruginosa in vitro. Int J Antimicrob Agents 2007; 30(6): 563–4PubMedCrossRefGoogle Scholar
  71. 71.
    Morike K, Schwab M, Klotz U. Use of aminoglycosides in elderly patients: pharmacokinetic and clinical considerations. Drugs Aging 1997; 10(4): 259–77PubMedCrossRefGoogle Scholar
  72. 72.
    Norrby SR. Neurotoxicity of carbapenem antibacterials. Drug Saf 1996; 15(2): 87–90PubMedCrossRefGoogle Scholar
  73. 73.
    Paterson DL, Robson JM, Wagener MM. Risk factors for toxicity in elderly patients given aminoglycosides once daily. J Gen Intern Med 1998; 13(11): 735–9PubMedCrossRefGoogle Scholar
  74. 74.
    Baciewicz AM, Sokos DR, Cowan RI. Aminoglycoside-associated nephrotoxicity in the elderly. Ann Pharmacother 2003; 37(2): 182–6PubMedCrossRefGoogle Scholar
  75. 75.
    Barza M, Ioannidis JP, Cappelleri JC, et al. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312(7027): 338–45PubMedCrossRefGoogle Scholar
  76. 76.
    Raveh D, Kopyt M, Hite Y, et al. Risk factors for nephrotoxicity in elderly patients receiving once-daily aminoglycosides. QJM 2002; 95(5): 291–7PubMedCrossRefGoogle Scholar
  77. 77.
    Milton JC, Hill-Smith I, Jackson SH. Prescribing for older people. BMJ 2008; 336(7644): 606–9PubMedCrossRefGoogle Scholar
  78. 78.
    Matthaiou DK, Michalopoulos A, Rafailidis PI, et al. Risk factors associated with the isolation of colistin-resistant Gram-negative bacteria: a matched case-control study. Crit Care Med 2008; 36(3): 807–11PubMedCrossRefGoogle Scholar
  79. 79.
    Walkty A, Decorby M, Nichol K, et al. Antimicrobial susceptibility of Pseudomonas aeruginosa isolates obtained from patients in Canadian intensive care units as part of the Canadian National Intensive Care Unit study. Diagn Microbiol Infect Dis 2008; 61(2): 217–21PubMedCrossRefGoogle Scholar
  80. 80.
    Denton M, Kerr K, Mooney L, et al. Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center. Pediatr Pulmonol 2002; 34(4): 257–61PubMedCrossRefGoogle Scholar
  81. 81.
    Landman D, Bratu S, Alam M, et al. Citywide emergence of Pseudomonas aeruginosa strains with reduced susceptibility to polymyxin B. J Antimicrob Chemother 2005; 55(6): 954–7PubMedCrossRefGoogle Scholar
  82. 82.
    Carmeli Y, Troillet N, Karchmer AW, et al. Health and economic outcomes of antibiotic resistance in Pseudomonas aeruginosa. Arch Intern Med 1999; 159(10): 1127–32PubMedCrossRefGoogle Scholar
  83. 83.
    Falagas ME, Koletsi PK, Bliziotis IA. The diversity of definitions of multidrug-resistant (MDR) and pandrug-resistant (PDR) Acinetobacter baumannii and Pseudomonas aeruginosa. J Med Microbiol 2006; 55 (Pt 12): 1619–29PubMedCrossRefGoogle Scholar
  84. 84.
    Paterson DL. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis 2006; 43Suppl. 2: S43–8PubMedCrossRefGoogle Scholar
  85. 85.
    Rossolini GM, Mantengoli E. Treatment and control of severe infections caused by multiresistant Pseudomonas aeruginosa. Clin Microbiol Infect 2005; 11Suppl. 4: 17–32PubMedCrossRefGoogle Scholar
  86. 86.
    Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. Clin Infect Dis 2006; 43Suppl. 2: S49–56PubMedCrossRefGoogle Scholar
  87. 87.
    Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 2002; 34(5): 634–40PubMedCrossRefGoogle Scholar
  88. 88.
    Nordmann P, Poirel L. Emerging carbapenemases in Gram-negative aerobes. Clin Microbiol Infect 2002; 8(6): 321–31PubMedCrossRefGoogle Scholar
  89. 89.
    Giakkoupi P, Petrikkos G, Tzouvelekis LS, et al. Spread of integron-associated VIM-type metallo-beta-lactamase genes among imipenem-nonsusceptible Pseudomonas aeruginosa strains in Greek hospitals. J Clin Microbiol 2003; 41(2): 822–5PubMedCrossRefGoogle Scholar
  90. 90.
    Reinhardt A, Kohler T, Wood P, et al. Development and persistence of antimicrobial resistance in Pseudomonas aeruginosa: a longitudinal observation in mechanically ventilated patients. Antimicrob Agents Chemother 2007; 51(4): 1341–50PubMedCrossRefGoogle Scholar
  91. 91.
    Lepper PM, Grusa E, Reichl H, et al. Consumption of imipenem correlates with beta-lactam resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2002; 46(9): 2920–5PubMedCrossRefGoogle Scholar
  92. 92.
    Carmeli Y, Troillet N, Eliopoulos GM, et al. Emergence of antibiotic-resistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents. Antimicrob Agents Chemother 1999; 43(6): 1379–82PubMedGoogle Scholar
  93. 93.
    Bratu S, Quale J, Cebular S, et al. Multidrug-resistant Pseudomonas aeruginosa in Brooklyn, New York: molecular epidemiology and in vitro activity of polymyxin B. Eur J Clin Microbiol Infect Dis 2005; 24(3): 196–201PubMedCrossRefGoogle Scholar
  94. 94.
    Cunha BA. Pseudomonas aeruginosa: resistance and therapy. Semin Respir Infect 2002; 17(3): 231–9PubMedCrossRefGoogle Scholar
  95. 95.
    Harris AD, Smith D, Johnson JA, et al. Risk factors for imipenem-resistant Pseudomonas aeruginosa among hospitalized patients. Clin Infect Dis 2002; 34(3): 340–5PubMedCrossRefGoogle Scholar
  96. 96.
    Drenkard E. Antimicrobial resistance of Pseudomonas aeruginosa biofilms. Microbes Infect 2003; 5(13): 1213–9PubMedCrossRefGoogle Scholar
  97. 97.
    Poirel L, Lambert T, Turkoglu S, et al. Characterization of Class 1 integrons from Pseudomonas aeruginosa that contain the bla(VIM-2) carbapenem-hydrolyzing beta-lactamase gene and of two novel aminoglycoside resistance gene cassettes. Antimicrob Agents Chemother 2001; 45(2): 546–52PubMedCrossRefGoogle Scholar
  98. 98.
    Lodise TP, Miller CD, Graves J, et al. Clinical prediction tool to identify patients with Pseudomonas aeruginosa respiratory tract infections at greatest risk for multidrug resistance. Antimicrob Agents Chemother 2007; 51(2): 417–22PubMedCrossRefGoogle Scholar
  99. 99.
    Tacconelli E, Tumbarello M, Bertagnolio S, et al. Multidrug-resistant Pseudomonas aeruginosa bloodstream infections: analysis of trends in prevalence and epidemiology. Emerg Infect Dis 2002; 8(2): 220–1PubMedCrossRefGoogle Scholar
  100. 100.
    Nouer SA, Nucci M, de-Oliveira MP, et al. Risk factors for acquisition of multidrug-resistant Pseudomonas aeruginosa producing SPM metallo-beta-lactamase. Antimicrob Agents Chemother 2005; 49(9): 3663–7PubMedCrossRefGoogle Scholar
  101. 101.
    Paramythiotou E, Lucet JC, Timsit JF, et al. Acquisition of multidrug-resistant Pseudomonas aeruginosa in patients in intensive care units: role of antibiotics with antipseudomonal activity. Clin Infect Dis 2004; 38(5): 670–7PubMedCrossRefGoogle Scholar
  102. 102.
    Defez C, Fabbro-Peray P, Bouziges N, et al. Risk factors for multidrug-resistant Pseudomonas aeruginosa nosocomial infection. J Hosp Infect 2004; 57(3): 209–16PubMedCrossRefGoogle Scholar
  103. 103.
    Falagas ME, Kopterides P. Risk factors for the isolation of multi-drug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa: a systematic review of the literature. J Hosp Infect 2006; 64(1): 7–15PubMedCrossRefGoogle Scholar
  104. 104.
    Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32(3): 858–73PubMedCrossRefGoogle Scholar
  105. 105.
    Micek ST, Lloyd AE, Ritchie DJ, et al. Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob Agents Chemother 2005; 49(4): 1306–11PubMedCrossRefGoogle Scholar
  106. 106.
    Chamot E, Boffi El, Amari E, et al. Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 2003; 47(9): 2756–64PubMedCrossRefGoogle Scholar
  107. 107.
    Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ 2003; 326(7399): 1111PubMedCrossRefGoogle Scholar
  108. 108.
    Paul M, Benuri-Silbiger I, Soares-Weiser K, et al. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 2004; 328(7441): 668PubMedCrossRefGoogle Scholar
  109. 109.
    Heyland DK, Dodek P, Muscedere J, et al. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med 2008; 36(3): 737–44PubMedCrossRefGoogle Scholar
  110. 110.
    El Amari EB, Chamot E, Auckenthaler R, et al. Influence of previous exposure to antibiotic therapy on the susceptibility pattern of Pseudomonas aeruginosa bacteremic isolates. Clin Infect Dis 2001; 33(11): 1859–64PubMedCrossRefGoogle Scholar
  111. 111.
    Fish DN, Piscitelli SC, Danziger LH. Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies. Pharmacotherapy 1995; 15(3): 279–91PubMedGoogle Scholar
  112. 112.
    Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis 2004; 4(8): 519–27PubMedCrossRefGoogle Scholar
  113. 113.
    Rios FG, Luna CM, Maskin B, et al. Ventilator-associated pneumonia due to colistin susceptible-only microorganisms. Eur Respir J 2007; 30(2): 307–13PubMedCrossRefGoogle Scholar
  114. 114.
    Falagas ME, Koletsi PK, Kopterides P, et al. Risk factors for isolation of strains susceptible only to polymyxin among patients with Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 2006; 50(7): 2541–3PubMedCrossRefGoogle Scholar
  115. 115.
    Erdem I, Kaynar-Tascioglu J, Kaya B, et al. The comparison of the in vitro effect of imipenem or meropenem combined with ciprofloxacin or levofloxacin against multidrug-resistant Pseudomonas aeruginosa strains. Int J Antimicrob Agents 2002; 20(5): 384–6PubMedCrossRefGoogle Scholar
  116. 116.
    American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171(4): 388–416CrossRefGoogle Scholar
  117. 117.
    Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clin Infect Dis 1997; 25(3): 551–73PubMedCrossRefGoogle Scholar
  118. 118.
    Kuikka A, Valtonen VV. Factors associated with improved outcome of Pseudomonas aeruginosa bacteremia in a Finnish university hospital. Eur J Clin Microbiol Infect Dis 1998; 17(10): 701–8PubMedCrossRefGoogle Scholar
  119. 119.
    Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 2003; 290(19): 2588–98PubMedCrossRefGoogle Scholar
  120. 120.
    Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents 2008; 31(1): 12–20PubMedCrossRefGoogle Scholar
  121. 121.
    Giamarellos-Bourboulis EJ, Bolanos N, Laoutaris G, et al. Immunomodulatory intervention in sepsis by multidrug-resistant Pseudomonas aeruginosa with thalidomide: an experimental study. BMC Infect Dis 2005; 5: 51PubMedCrossRefGoogle Scholar
  122. 122.
    Yau YH, Ho B, Tan NS, et al. High therapeutic index of factor C Sushi peptides: potent antimicrobials against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2001; 45(10): 2820–5PubMedCrossRefGoogle Scholar

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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