Current control and treatment of multidrug-resistant Acinetobacter baumannii infections

Review

Current control and treatment of multidrug-resistant Acinetobacter baumannii infections Drosos E Karageorgopoulos, Matthew E Falagas

Institutional outbreaks caused by Acinetobacter baumannii strains that have acquired multiple mechanisms of antimicrobial drug resistance constitute a growing public-health problem. Because of complex epidemiology, infection control of these outbreaks is difficult to attain. Identification of potential common sources of an outbreak, through surveillance cultures and epidemiological typing studies, can aid in the implementation of specific control measures. Adherence to a series of infection control methods including strict environmental cleaning, effective sterilisation of reusable medical equipment, attention to proper hand hygiene practices, and use of contact precautions, together with appropriate administrative guidance and support, are required for the containment of an outbreak. Effective antibiotic treatment of A baumannii infections, such as ventilator-associated pneumonia and bloodstream infections, is also of paramount importance. Carbapenems have long been regarded as the agents of choice, but resistance rates have risen substantially in some areas. Sulbactam has been successfully used in the treatment of serious A baumannii infections; however, the activity of this agent against carbapenem-resistant isolates is decreasing. Polymyxins show reliable antimicrobial activity against A baumannii isolates. Available clinical reports, although consisting of smallsized studies, support their effectiveness and mitigate previous concerns for toxicity. Minocycline, and particularly its derivative, tigecycline, have shown high antimicrobial activity against A baumannii, though relevant clinical evidence is still scarce. Several issues regarding the optimum therapeutic choices for multidrug-resistant A baumannii infections need to be clarified by future research.

Introduction The genus Acinetobacter is classified under the family Moraxellaceae and comprises strictly aerobic, Gramnegative, non-motile, non-lactose-fermenting, oxidasenegative, catalase-positive coccobacilli.1,2 More than 30 genomic species have been identified within this genus, of which 17 have been assigned valid names.3 Acinetobacter baumannii (gen sp 2) is the species primarily associated with human disease.4,5 Acinetobacter gen sp 3 and 13TU are also pathogenic in human beings, although they are less frequently encountered.5,6 These three species are closely related genetically, and cannot be accurately differentiated by routine phenotypic methods; the term A baumannii has therefore been used to refer to all three.2 A baumannii can be found in various environmental sources such as soil, and foods, including vegetables, meat, and fish.2,6 A baumannii may rather infrequently colonise the skin of healthy human beings, typically at a low density and for short-term duration.7,8 Colonisation of other body sites such as the throat, nares, and the intestinal tract, has been found rarely in healthy individuals.8,9 A baumannii infections are typically encountered in hospitalised patients, particularly critically ill ones.10 Specific characteristics of affected patients include advanced age, presence of serious underlying diseases, immune suppression, major trauma or burn injuries, performance of invasive procedures, as well as presence of indwelling catheters, support with mechanical ventilation, extended hospital stay, and previous administration of antibiotics.1,4,10–13 The main clinical syndromes reported include pneumonia and bacteraemia, along with surgical site infection, skin and soft tissue www.thelancet.com/infection Vol 8 December 2008

Lancet Infect Dis 2008; 8: 751–62 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece (D E Karageorgopoulos MD, M E Falagas MD); Department of Medicine, Henry Dunant Hospital, Athens, Greece (M E Falagas); and Department of Medicine, Tufts University School of Medicine, Boston, MA, USA (M E Falagas) Correspondence to: Dr Matthew E Falagas, Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 15 123, Marousi, Greece [email protected]

infection, and urinary tract infection.1,4,14 A baumannii can also be the cause of secondary meningitis, particularly in patients with ventricular draining tubes,15,16 or of peritonitis in patients undergoing peritoneal dialysis.1 A baumannii can also cause community-acquired infections, which are encountered mainly in southeast Asia and tropical Australia.17 Pneumonia is the most common clinical syndrome reported in this setting, followed by bacteraemia. Community-acquired A baumannii pneumonia typically affects patients with underlying chronic obstructive pulmonary disease, renal failure, or diabetes mellitus, as well as individuals who are heavy smokers or excessive alcohol consumers. The course of the disease is typically severe.17 A baumannii infections have increasingly been reported in victims of mass destruction or war conflicts. Clinical syndromes seen in such settings are mainly wound infections, and to a lesser extent bacteraemia.18 They have been mainly attributed to A baumannii transmission within contaminated field hospitals or acute care facilities.19 The reported incidence of A baumannii infections has substantially increased during the past decades.14,20 This increase could be attributed to a rise in the proportion of the susceptible population as a result of advancements in medical support of critically ill and frail patients.1 A substantial increase in the rates of antibiotic resistance of A baumannii has also been documented during the past decades.14,20 Recent microbiological surveillance trials have reported rates of multidrug resistance in A baumannii of approximately 30%.21 However, geographical differences in resistance patterns are evident.21–23 Institutional outbreaks caused by multidrugresistant strains are a growing public-health problem. 751

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We review the current control and treatment options for multidrug-resistant A baumannii infections.

Control of outbreaks of multidrug-resistant A baumannii Ability to cause outbreaks The rising incidence of multidrug-resistant A baumannii infections in health-care settings may in part be attributed to the ability of this organism to cause outbreaks.24 Acinetobacter spp are able to survive on dry inanimate surfaces for a prolonged time. Most studies have reported survival of about 1 month,25–28 although survival for up to 5 months has been noted.29 Furthermore, A baumannii has mechanisms that facilitate colonisation of patients or of equipment used in medical care. Specific strains can attach to human epithelial cells30 through fimbriae or lipopolysaccharide side chains, bind to salivary mucins,31 and develop biofilm in contact with plastic or glass surfaces.30 The latter property may be of particular clinical relevance regarding catheter-associated infections.32 Last but not least, resistance to antimicrobial agents is one of the most important factors for the perpetuation of acinetobacter infections in health-care settings.10,28,31

Epidemiology of outbreaks Specific resistant clones are the predominant cause of outbreaks.24,33 Three pan-European clones (designated as I, II, and III) have disseminated in geographically distinct areas,34 and new epidemic clones are emerging. In specific institutional outbreaks, the majority of A baumannii isolates usually belong to a single clone;10 however, polyclonal outbreaks have been reported,28,35,36 while sporadic strains frequently coexist with epidemic ones.10,28,37 Nosocomial A baumannii outbreaks mainly involve intensive care units (ICUs), although epidemic strains can also be found in other hospital departments.26–28

Epidemiological analysis of an outbreak Surveillance cultures obtained from patients, health-care personnel, and environmental sites could aid in the identification of potential common sources of an outbreak and in the implementation of specific control measures.38–41 Axillary, pharyngeal, or rectal swabs, and cultures of tracheal washings, can be used for detection of patient colonisation with A baumannii.38,42 A strategy of weekly pharyngeal and rectal swab cultures in 73 patients newly admitted in an ICU identified 46 (96%) of the 48 patients who became colonised with A baumannii.38 The use of epidemiological typing methods helps further in the delineation of the modes of transmission of A baumannii during an outbreak, through the differentiation between sporadic and outbreak strains.26,27,43,44 Phenotypic tests, such as antibiotyping, biotyping, and electrophoretic typing, are not as discriminatory as more sophisticated genotyping methods, including plasmid profiles analysis, pulse field 752

gel electrophoresis, ribotyping, amplified fragment length polymorphism, PCR-based tests, and multilocus sequence typing.12,34,36,39,43,45,46 Additionally, a case-control study can be done to identify potential risk factors for the acquisition of epidemic strains during an outbreak, in the case that surveillance cultures or epidemiological typing methods have not provided adequate information on the modes of spread of A baumannii.45

Potential common sources Colonisation of the inanimate hospital environment is of great importance for the transmission of multidrugresistant A baumannii in institutions during outbreaks.40,47 Colonisation can be facilitated by the spread of droplets through opening the respiratory circuit of mechanical ventilators.48–51 Environmental sites that are most likely to be colonised are those in the vicinity of affected patients49,52—for example, fomites such as feather pillows, bed linen, and surrounding curtains,42,53 along with bedrails,54–56 bedside tables,56,57 water used for nasogastric feeding or ventilator rinsing,56 and gas taps behind the beds.42 Furthermore, sites that are often touched by hands might also become colonised with A baumannii, such as door handles,42,58 computer keyboards,42 sinks,55,56 or even cleaning equipment.42 In accordance, the hands of healthcare personnel can be colonised with A baumannii outbreak strains, thus facilitating spread to patients.39,40,49 Health-care workers with damaged skin are at increased risk of developing hand colonisation with A baumannii. Various types of devices used in patient management have also been found contaminated with multidrugresistant A baumannii during outbreaks. Most relevant reports refer to respiratory equipment used for mechanical ventilation,56,59–61 or suctioning.50 Additionally, devices related to intravascular access, such as infusion pumps,56,57 pressure transducers,62 and continuous haemofiltration systems,59 can also serve as a source of transmission of A baumannii. Other types of medical equipment that might become contaminated with A baumannii include blood pressure cuffs,57,63 pulse oximeters,57 and laryngoscope blades.42 Furthermore, certain types of procedures have been related epidemiologically with the transmission of A baumannii during outbreaks, presumably because of contamination of the specific materials used. Examples include hydrotherapy or pulsatile lavage treatment of wounds,64 specific surgical interventions,27,37,65,66 catheterisation,65,67 and tracheostomy.68

Risk factors for acquisition of outbreak strains Several studies have identified general characteristics of patients that place them at increased risk for the acquisition of multidrug-resistant outbreak strains.69 Such risk factors include support with mechanical ventilation,12,27,62,65,70 particularly of prolonged duration,40,51,68 longer hospital or ICU stay,45,66 greater degree of exposure to infected or colonised patients in the neighbouring hospital www.thelancet.com/infection Vol 8 December 2008

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environment,35,71 a higher number of interventions,72 receipt of transfusions of blood products,40 greater disease severity as measured by relevant scoring systems,51,73 and administration of broad-spectrum antimicrobial agents,27,46,65,66,70 particularly third-generation cephalosporins,45,74 carbapenems,67 and fluoroquinolones.51

Infection control measures Apart from the routine general control measures recommended for institutional outbreaks caused by multidrug-resistant organisms,75 the identification of common sources of transmission of multidrug-resistant A baumannii guides the implementation of specific control measures (figure). Moreover, because of the complex epidemiology of A baumannii outbreaks, a comprehensive intensified infection control strategy is often required.75 The successful management of an outbreak involves the cooperation of all levels of healthcare personnel involved. Thus, administrative measures for organising an effective team and providing timely feedback of information regarding the outbreak are fundamental.76 Education of hospital staff on a regular basis and frequent revision of the control measures used are also essential.44,49,55,58,61,68 Particular attention should be paid to effective environmental cleaning.40–42,47,49,53,55,56,61,72 Disinfectants should be applied for an adequate period of time to achieve sterilisation.77 Appropriate use of solutions containing ethanol is particularly important because if

applied at very low concentrations, this agent may induce alteration of A baumannii organisms to a more pathogenic phenotype with increased survival.78 Disinfection of potentially contaminated medical equipment should be done meticulously.42,55,57 Special attention is required for the sterilisation of mechanical ventilators.27,48,55,59 Use of closed suction systems can also prevent environmental contamination with A baumannii.42,49 Furthermore, improved adherence of health-care workers to hand-hygiene protocols is of paramount importance for the containment of A baumannii transmission.40,43,49,55,56,58,68 Notably, only 32% of health-care workers washed their hands after contact with a patient in one study.74 Readily available handrub antiseptic solutions might help to increase hand hygiene compliance.42 Additionally, contact precautions for infected or colonised patients should be appropriately im plemented.27,41,43,44,55,68,72 Patients harbouring outbreak strains should ideally be isolated or cohorted.36,40,41,44,55,76 Appointment of dedicated personnel,56 and use of individual medical equipment,55 might also contribute in the control of A baumannii outbreaks. Finally, the use of effective antimicrobials for the treatment of infections caused by the outbreak strain is essential for the prevention of further spread.39,44,53 It should also be mentioned that infection control measures might need to be implemented for a long time before control of the outbreak is achieved.28 In some cases, this might require the closure of hospital

Patient infected/colonised with epidemic strain

Health-care personnel

Environmental contamination

Control measures • Regular education • Adherence to contact precautions • Implementation of hand-hygiene protocols • Ready access to handrub antiseptic solutions • Routine cultures from health-care personnel • Appointment of dedicated personnel for infected/colonised patients

Medical equipment

Control measures • Identification of environmental sites serving as common sources of transmission • Sites of the immediate patient environment (fomites, bedrails, taps, suction water) • Sites that personnel often contact (door handles, keyboards, sinks) • Effective environmental cleaning • Application of disinfectants in effective concentration for provisioned time • Closed suctioning of intubated patients • Isolation or cohorting of infected/colonised patients • Closure of hospital units/wards for sterilisation

Control measures • Disinfection of potentially contaminated medical equipment • Related to respiratory procedures, intravascular access, surgery, wound care, skin contact • Use of individual medical equipment

Patient infected/colonised with epidemic strain

Figure: Measures aiming to control patient-to-patient cross-transmission of multidrug-resistant A baumannii during institutional outbreaks Pink boxes list control measures targeted at interrupting the specific modes of transmission represented by the vertical arrows.

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Panel 1: Currently available antimicrobial classes/agents potentially effective against A baumannii • • • • • • • • • •

Sulbactam Anti-pseudomonal penicillins Anti-pseudomonal cephalosporins Anti-pseudomonal carbapenems Monobactams Aminoglycosides Fluoroquinolones Tetracyclines Glycylcyclines Polymyxins

Panel 2: Main mechanisms of antimicrobial resistance of A baumannii Remarkable capacity to show resistance to antibiotics of most classes • Intrinsically, or • Following acquisition of resistance Various mechanisms of resistance • Production of β lactamases • Efflux pumps • Lower permeability of the outer membrane • Mutations in antibiotic targets (eg, for quinolones) • Production of enzymes inactivating aminoglycosides

units.40,48,57,66,73 It is also noteworthy that the control of outbreaks involving long-term care facilities may be more demanding than nosocomial ones, because of the relative shortage of appropriate resources.79

Treatment of multidrug-resistant A baumannii infections Pathogenicity of A baumannii and infection outcomes The crude mortality rate for nosocomial bloodstream infections caused by A baumannii was 34% in a large US study, a higher rate than for all other common bacterial pathogens apart from Pseudomonas aeruginosa.13 This figure rose to 43% for bloodstream infections involving ICU patients. Substantial mortality rates have also been associated with ventilator-associated pneumonia caused by A baumannii.80 Whether the high mortality related to A baumannii infections is attributed to the virulence of this organism or to the severity of underlying diseases has been a controversial issue.1 A systematic review of relevant studies found that the mortality rate attributed to A baumannii infection per se varies from 7·8% to 23% for hospitalised patients, and from 10% to 43% for ICUadmitted patients.80 Furthermore, in a retrospective study, bacteraemia caused by A baumannii was independently associated with worse patient outcomes, compared with bacteraemia caused by Klebsiella pneumoniae.11 Notably, 754

outcomes of patients with A baumannii infections seem to be poorer if caused by isolates with resistance to multiple classes of antimicrobial agents.20 This finding may be related to the potential administration of inappropriate antimicrobial therapy for infections caused by highly resistant pathogens.81–83

Antimicrobial therapy The classes of antimicrobial agents that are considered as potentially effective for the treatment of A baumannii infections are shown in panel 1. However, the choice of appropriate antimicrobial therapy is limited by the fact that resistance rates of A baumannii to many of these agents can be very high. The most common mechanisms of antimicrobial resistance of A baumannii are listed in panel 2. Evidence regarding the effectiveness of different treatment regimens is principally derived from retrospective studies or from small prospective studies lacking a randomised design.

Carbapenems The antipseudomonal group 2 carbapenems—namely, imipenem and meropenem, have been regarded as the treatment of choice for severe A baumannii infections.1,3 However, several recent microbiological studies have found susceptibility rates of A baumannii isolates to carbapenems of nearly 90%.3,4,22 In a recent large surveillance study, susceptibility of A baumannii to imipenem was lower for isolates in Latin America and the Asia–Pacific rim (60·6% of 188 and 69·2% of 156 isolates, respectively) than in those from Europe and North America (85·9% of 669 and 88·6% of 1805, respectively).23 Notably, carbapenem-resistant A baumannii strains might only rarely be susceptible to other antipseudomonal β-lactams, by contrast with carbapenem-resistant P aeruginosa strains, which might not show crossresistance.22,39 Carbapenem resistance in A baumannii is mediated by several potential mechanisms, including plasmid or chromosomally encoded carbapenemases (mainly OXA-23-like, OXA-24-like, or OXA-58-like class D β lactamases), as well as metallo-β lactamases (class B β lactamases), efflux pump mechanisms, penicillinbinding protein alterations, and modifications or loss of outer membrane proteins (porins).84 More than one of these resistance determinants could be present in the same strain conferring high-level resistance.

Polymyxins Polymyxins are cationic polypeptides that interact with the lipopolysaccharide layer of Gram-negative bacteria. Because of toxicity concerns, polymyxins were abandoned from clinical use in the early 1980s, except for the treatment of patients with cystic fibrosis. Two agents of this class are currently available for clinical use—namely, polymyxin B and colistin (polymyxin E). Colistin is available in two forms, colistin sulfate and colistimethate www.thelancet.com/infection Vol 8 December 2008

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sodium. Colistimethate sodium is a non-active prodrug that is used for parenteral administration because of its lower toxicity.85 Polymyxins show bactericidal activity against A baumannii,86–88 and resistance rates against these agents have remained low,22,89,90 even in multidrug-resistant and carbapenem-resistant isolates.22,33,87,91 Few in-vivo experimental studies have assessed the effectiveness of colistin against infections caused by multidrug-resistant A baumannii. Specifically, in a mouse model of pneumonia caused by multidrug-resistant or carbapenem-resistant A baumannii, colistin was not as effective as comparators in reducing bacterial lung counts.92,93 However, colistin was found effective in a neutropenic rat thigh infection model against multidrug-resistant A baumannii.94 The first study on the clinical use of intravenous colistin for the treatment of various types of infections caused by multidrug-resistant A baumannii or P aeruginosa noted that most cases had a good clinical outcome, but shed doubt on the adequacy of colistin as monotherapy for the treatment of pneumonia.95 Further studies assessed prospectively or retrospectively treatment with colistin for patients with ventilator-associated pneumonia caused by A baumannii or P aeruginosa.96–98 Specifically, no difference in clinical response was reported between patients treated with intravenous colistin for infections caused by organisms susceptible only to polymyxins and those treated with other agents, mainly carbapenems, for infections caused by carbapenem-susceptible organisms. Favourable clinical responses have also been associated with intravenous colistin therapy in case-series of ICU patients with various types of infections, mainly ventilator-associated pneumonia, caused by multidrugresistant (including carbapenem-resistant) A baumannii or P aeruginosa.99–104 Therapy with intravenous polymyxins in combination with other antimicrobials, such as rifampicin,105–107 for nosocomial multidrug-resistant A baumannii infections has also been associated with favourable clinical outcomes.108–110 Polymyxins can also be administered via the respiratory tract in patients with pneumonia, as has been practised for the prevention and treatment of bronchopulmonary infections in patients with cystic fibrosis. Several studies have reported favourable clinical outcomes with the use of aerosolised colistin along with intravenous colistin or other parenteral antimicrobial agents for nosocomial pneumonia caused by multidrug-resistant A baumannii.111–114 Notably, in some of the few relevant cases reported in the literature, administration of nebulised colistin as the sole microbiologically active treatment against A baumannii nosocomial pneumonia has shown clinical effectiveness.111,115 This treatment method could serve as a lastresort option in cases where systemic antibiotic treatment is contraindicated or not feasible. Polymyxins have also been used for the treatment of nosocomial meningitis caused by multidrug-resistant www.thelancet.com/infection Vol 8 December 2008

A baumannii.15 Clinical effectiveness has been reported for treatment via the intravenous route alone, although studies have only included a small number of patients.95,116,117 Because of suboptimal penetration through the blood–brain barrier,116 colistin has been used via the intraventricular or the intrathecal route in addition to systemically administered colistin16,117–119 or other antibacterial agents, such as aminoglycosides.16,117 Favourable clinical responses to treatment with intrathecal or intraventricular colistin alone have also been reported.15 In a retrospective cohort study of 51 patients with nosocomial post-surgical meningitis caused by multidrug-resistant A baumannii, who received various therapeutic regimens, the combination of intravenous and intrathecal colistin was associated with higher survival in the univariate analysis, although this finding did not persist in the multivariate model.119 The toxicity of polymyxins seen in recent studies was lower than expected on the basis of earlier reports.120 Several studies have found that the rate of development of nephrotoxicity in patients treated with colistin for Gramnegative bacterial infections is similar to that related to other antimicrobial agents.96–98 Most non-comparative studies have reported a rate of renal toxicity associated with polymyxin therapy of between 8% and 21%.100,101,104,105,108–110,113,121 In a study that assessed patients who received prolonged colistin treatment, no serious toxicity was noted.122 Patients with pre-existing renal dysfunction seem to be more susceptible to the renal adverse effects of polymyxins.95,104,105 Other potential adverse effects of polymyxins include neurotoxicity, which has been infrequently reported,96,98,100,102,110,120,122 along with bronchoconstriction, chest tightness or cough following administration via the respiratory tract,114,115,120 and chemical meningitis with intraventricular or intrathecal use.16 Clinical reports of patients infected with A baumannii resistant to polymyxins are scarce.123 However, the increasing use of polymyxins in critically ill patients may lead to the emergence of resistance.123 In fact, high rates of resistance to polymyxins have recently been reported in A baumannii isolates from two South Korean hospitals.124 Notably, resistance to polymyxins was related to lower rates of multidrug resistance. Furthermore, heteroresistance of A baumannii isolates to colistin has been described.125 However, the clinical implications of this phenomenon have not been adequately clarified.125

Sulbactam Sulbactam has intrinsic antimicrobial activity against A baumannii, and is the most active of the β-lactamase inhibitors.126 The mode of activity of sulbactam is either bacteriostatic or bactericidal,88,127,128 depending on the strain examined, and is mediated via binding to penicillinbinding proteins.126 The combination of sulbactam with ampicillin, cefoperazone, or antipseudomonal penicillins does not seem to result in enhanced antimicrobial activity against A baumannii.128 755

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Study design

Infection type

Resistance pattern

Sulbactam-based regimens

Comparator regimens

Rodriguez Guardado Retrospective et al (2008)119 cohort

Post-surgical meningitis

MDR

Ampicillin/sulbactam

Carbapenem Mortality: 1/4 (25%) vs 9/21 monotherapy; combined (43%); 1/4 (25%); 2/17 (12%), NS parenteral treatment; in multivariate analysis combined parenteral and intrathecal treatment

Kuo et al (2007)135

Retrospective cohort

Bacteraemia

MDR (carbapenemresistant)

Ampicillin/sulbactam; Carbapenem; ampicillin/sulbactam carbapenem plus amikacin plus carbapenem

Mortality: 2/5 (40%); 8/26 (31%) vs 7/12 (58%); 5/10 (50%), lower mortality for ampicillin/ sulbactam plus carbapenem group vs remaining group

NR

Choi et al (2006)131

Retrospective cohort

Bacteraemia

Imipenem nonsusceptibility in four of 35 vs none of 12 patients

Cefoperazone/ sulbactam

Imipenem/cilastatin

Clinical response at 72 h: 27/35 (77%) vs 9/12 (75%), NS 30-day mortality: 7/35 (20%) vs 6/12 (50%), p=0·065

Aminoglycosides: 23/35 (66%) vs 7/12 (58%), NS

Smolyakov et al (2003)83

Retrospective cohort

Bacteraemia

MDR (imipenem non-susceptible) vs non-MDR

Ampicillin/sulbactam

Various other agents

All-cause mortality:† 14/33 (42%) None of those used in vs 15/37 (41%), NS sulbactam group was microbiologically active

Wood et al (2002)130

Retrospective cohort

Ventilatorassociated pneumonia

Ampicillin/sulbactam Imipenem nonsusceptibility in 12 of 14 vs none of 63 patients

Imipenem/cilastatin

All-cause mortality: 1/14 (7%) vs 12/63 (19%), NS Clinical success: 13/14 (93%) vs 52/63 (83%), NS

7/14 (50%) vs 9/63 (14%), p=0·01

Cisneros et al (1996)81

Prospective observational cohort

Bacteraemia

Ampicillin/sulbactam Most MDR, imipenem nonsusceptibility in 36 of 79 isolates

Imipenem; ceftazidime

Cure:† 7/8 (88%) vs 35/42 (83%); 3/7 (43%), NR

NR

Outcome (sulbactam-based vs comparator regimens)*

Adjunctive antibiotics* Ampicillin/sulbactam monotherapy in four patients

MDR=multidrug-resistant. NR=not reported. NS=not significant (p>0·05). *Data are n/N (%). †Data refer to patients who received microbiologically active agents.

Table: Selected clinical studies that assessed the effectiveness of sulbactam-based treatment along with other regimens for A baumannii infections

Earlier studies showed high in-vitro susceptibility rates of A baumannii isolates, including multidrug-resistant ones, to sulbactam or ampicillin/sulbactam combination.81,89 However, in recent studies, the antimicrobial activity of sulbactam against A baumannii isolates has declined substantially.22,90 Still, sulbactam has been found active against a rather small proportion of carbapenemresistant A baumannii isolates.22,39,89,91 In vivo, sulbactam, either alone or in combination with cefoperazone, has shown effectiveness similar to that of carbapenems in mouse pneumonia,93 rat thigh abscess,129 and murine intraperitoneal infection models.127 In human studies, sulbactam/β-lactam combination therapy has shown similar effectiveness to imipenem therapy in A baumannii ventilator-associated pneumonia caused by multidrug-resistant organisms,130 as well as in bacteraemia.81,131 Moreover, ampicillin/sulbactam, administered for the treatment of multidrug-resistant A baumannii bacteraemia, resulted in similar mortality rates compared with treatment with other agents administered for bacteraemia caused by non-resistant A baumannii.83 Favourable clinical outcomes have also been reported with sulbactam or combination ampicillin/ sulbactam therapy in patients with various types of nosocomial infections caused by multidrug-resistant A baumannii,128,132 including ventilator-associated pneumonia.133 Notably, use of high-dose ampicillin/ sulbactam regimens has been assessed in a few cases of ventilator-associated pneumonia as a means to overcome 756

A baumannii resistance to this agent.133 Regarding nosocomial meningitis caused by multidrug-resistant or carbapenem-resistant A baumannii, the available clinical experience with the use of ampicillin/sulbactam is limited and rather non-conclusive.119,132,134 The table summarises data from studies investigating the effectiveness of sulbactam-based treatment.

Tetracyclines and glycylcyclines Minocycline,89,91 doxycyline,136 and, less so, tetracycline,4,89 have shown high rates of antimicrobial activity against A baumannii. Minocycline has been found active against strains resistant to tetracycline89,90 or doxycycline.90,91 This finding could be attributed to the fact that the presence of the tet(A) resistance determinant that encodes for a tetracycline-specific efflux pump does not confer resistance to minocycline. In a large worldwide collection, over 90% of recent A baumannii isolates were found to be susceptible to minocycline, whereas susceptibility rates to imipenem were lower.23 Additional studies have shown substantial rates of antimicrobial activity of minocycline against multidrug-resistant or imipenem-resistant A baumannii isolates.21,33,91 However, there is a scarcity of experimental or clinical data to support the use of tetracyclines in A baumannii infections. Specifically, doxycycline has not been found as effective as imipenem in a mouse pneumonia model.137 In human beings, treatment with doxycycline or minocycline in seven patients with ventilator-associated www.thelancet.com/infection Vol 8 December 2008

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pneumonia with A baumannii resistant to all other available agents,138 or treatment with doxycycline in three ICU patients infected by multidrug-resistant A baumannii,100 has been associated with a mortality rate of 25% and 33%, respectively. Glycylcyclines are a novel class of antimicrobial agents related to the tetracyclines. Tigecycline, a semisynthetic derivative of minocycline, is the first commercially available agent of this class. It has a similar mechanism of action to that of the tetracyclines, and shows bacteriostatic activity against A baumannii.87 Tigecycline is able to evade the most common mechanisms of resistance to tetracyclines in A baumannii, including efflux pumps encoded by the tet(A) and tet(B) determinants, and ribosomal protection mechanisms.139 Large surveillance trials have shown high rates of susceptibility of A baumannii to tigecycline.21,23,89 Tigecycline has been found to be active against minocyclineresistant, multidrug-resistant, and imipenem-resistant isolates.21,33,90,91 However, there is a substantial number of reports that indicate that tigecycline may not be consistently active against the imipenem-resistant isolates.140 Furthermore, the degree of susceptibility of A baumannii isolates to tigecycline may depend on the relevant interpretative breakpoints used.140 Clinical experience regarding the use of tigecycline for the treatment of patients with multidrug-resistant A baumannii infections is accumulating. In the available relevant reports, tigecycline has been used in a small number of critically ill patients—mainly as part of combination antibiotic regimens—for the treatment of various types of infections, including ventilator-associated pneumonia and primary or secondary bacteraemia.140–142 Most patients included in these reports had a good clinical outcome. However, failure of tigecycline to clear A baumannii bacteraemia was reported in a few cases.141 Pharmacokinetic and pharmacodynamic data indicate that tigecycline blood concentrations seem to be suboptimal for maximal antibacterial activity to be exerted at this compartment.91 The emergence of resistance in A baumannii during tigecycline therapy is an additional point for consideration.141,142 In-vitro studies have shown that resistance to tigecycline is mediated by the expression of resistance-nodulation division-type multidrug efflux pumps.143

Aminoglycosides Aminoglycosides have shown moderate rates of antimicrobial activity against A baumannii. In worldwide collections of Acinetobacter spp isolates, susceptibility rates to amikacin were approximately 60%.22 The activity of aminoglycosides is lower for multidrug-resistant isolates of A baumannii compared with non-multidrugresistant ones.21 However, aminoglycosides can show activity against a small proportion of carbapenemresistant isolates.22 www.thelancet.com/infection Vol 8 December 2008

Regarding experimental in-vivo data, tobramycin was found to be very effective in a mouse pneumonia model of infection by moderately tobramycin-resistant A baumannii strains,92 though in a similar model amikacin was not as effective as imipenem.137 Reports about the clinical use of aminoglycosides in human beings are scarce, and refer to cases of bacteraemia135 or meningitis,16,119 in which aminoglycosides have been used in combination with other classes of antimicrobial agents.

Fluoroquinolones Fluoroquinolones have moderate antimicrobial activity against A baumannii. Specifically, susceptibility rates to ciprofloxacin in global collections of Acinetobacter spp isolates have been about 44%.22 However, the activity of fluoroquinolones against recent multidrug-resistant or imipenem-resistant isolates has been reported to be low.21,22,91 Regarding in-vivo data, levofloxacin has shown similar effectiveness to imipenem in a mouse pneumonia model against a strain susceptible to both agents.144 However, no comprehensive evidence exists regarding the effectiveness of fluoroquinolones for the treatment of human infections caused by A baumannii.

Combination therapy Combination of carbapenems with other antimicrobial agents has been studied with the aim to overcome carbapenem resistance in A baumannii. Specifically, the combination of imipenem with sulbactam has showed synergistic activity in vitro.87,145 The clinical usefulness of this combination in patients infected with carbapenemresistant A baumannii is not well established, though.145,146 The combination of imipenem with tobramycin, in a mouse pneumonia model, was found more effective than either imipenem or tobramycin alone, against both moderately carbapenem-resistant and highly carbapenemresistant A baumannii strains.93 In a guineapig pneumonia model of infection with an imipenem-resistant A baumannii strain, though, the combination of imipenem with amikacin was associated with inferior effectiveness than amikacin alone.147 The assessment of in-vitro synergy of the combination of imipenem with a polymyxin against carbapenem-resistant A baumannii strains has provided mixed findings.51,88,148,149 In a small retrospective cohort study of patients with infections caused by multidrug-resistant, including carbapenem-resistant, Gram-negative bacteria, the combination of colistin with meropenem was found to be inferior in terms of patient survival compared with colistin monotherapy, although infection-related outcomes did not differ.99 The combination of imipenem with rifampicin, although synergistic in vitro,88 was not associated with clinical benefits in a small study.150 The combination of imipenem and tigecycline has not been shown to be synergistic.91 Furthermore, the combination of meropenem with aztreonam has resulted in indifferent activity against metallo-β-lactamase-producing strains of A baumannii.151 757

Review

Search strategy and selection criteria Data for this Review were identified through searches of PubMed, from bibliographies of relevant articles, and the archive files of our institute. We undertook a comprehensive search in PubMed, through February 2008, using the terms “Acinetobacter AND treatment” or “Acinetobacter AND control”, without time limit, as well as the term “Acinetobacter”, with a time limit from 2005 and onwards. We meticulously assessed all of the retrieved studies that focused on the control of A baumannii institutional outbreaks, as well as the treatment of A baumannii infections. We particularly selected studies regarding multidrug-resistant or carbapenem-resistant A baumannii. Articles written in languages other than English were excluded from further assessment if they did not have an English abstract.

Regarding polymyxin-based combination regimens, the best studied one involves rifampicin, which has shown synergistic in-vitro activity against multidrugresistant A baumannii strains in most studies,86,87,136,152 although not consistently.88,149 Studies in experimental models of infection have provided rather favourable findings regarding the use of this drug combination.93,94 Analogous observations were made in three small caseseries of patients with nosocomial infections caused by carbapenem-resistant A baumannii.105–107 Among other polymyxin-based combination regimens for multidrug-resistant A baumannii, the combination of colistin with a carbapenem has shown in vitro either synergistic136,152 or indifferent activity,88,149 but clinical effectiveness has not been substantiated.99 The combination of colistin with minocycline has been found to be synergistic in vitro,153 whereas the combination of colistin with doxycycline was either partly synergistic or had an additive effect.136 By contrast, the combination of polymyxin B and tigecycline has resulted in indifferent activity.91 The combination of a polymyxin with ampicillin/ sulbactam has also not been proven synergistic in vitro,88,154 whereas mixed findings were reported when polymyxins were assessed in combination with azithromycin.136,149 Most of the in-vitro studies that have assessed the combination of sulbactam (or ampicillin/sulbactam) with either carbapenems or cefepime against multidrugresistant A baumannii strains have reported promising findings.88,127,155,156 In a murine model of infection, meropenem plus sulbactam showed more potent antimicrobial activity than each of these agents alone.127 However, imipenem combined with sulbactam was associated with inferior survival compared with imipenem combined with rifampicin in a mouse pneumonia model.155 In a retrospective study of patients with multidrug-resistant A baumannii bacteraemia, the combination of a carbapenem plus ampicillin/sulbactam was associated with superior outcomes than treatment with a carbapenem plus amikacin or a carbapenem alone.135 758

Combination therapy against multidrug-resistant A baumannii infections might be chosen by clinicians to achieve synergistic activity between agents to which the infecting strains are resistant, to maximise antimicrobial activity in severely ill patients, or to prevent the emergence of resistance during therapy, particularly if therapeutic options are limited. It should be mentioned that data regarding the best studied combination regimens, described above, refer mainly to in-vitro or in-vivo animal studies. Effectiveness shown in such studies does not necessarily correlate with clinical findings. Clinical data are currently insufficient to favour the use of specific combination regimens for the treatment of multidrug-resistant A baumannii infections.

Future prospects Despite the increasing rates of antimicrobial drug resistance in A baumannii and in other Gram-negative bacteria, drugs that are currently in the pipeline against this category of pathogens do not seem to confer a major advancement compared with readily available agents. Thus, research to assess the clinical usefulness of various investigational agents should be encouraged.

Conclusions The role of A baumannii as a pathogen causing serious infections in critically ill patients has become increasingly clear. This pathogen is associated with institutional outbreaks that are difficult to control. Potential common sources include contaminated environmental sites and medical equipment, and health-care personnel with skin colonisation. Measures to address specific modes of transmission identified during an outbreak and strict adherence to a variety of infection control measures are typically required for the containment of an outbreak. Treatment options against multidrug-resistant A baumannii infections seem to be limited. Susceptibility rates to carbapenems and to sulbactam are declining, at least in certain areas. Polymyxins have shown consistent antimicrobial activity against extensively drug-resistant isolates of this species, and have generally been associated with favourable clinical outcomes in small clinical studies. Carbapenem-resistant A baumannii may also be susceptible to tigecycline, but the clinical effectiveness of this agent in this setting needs to be further substantiated. Additional research addressing key issues in the treatment of multidrug-resistant A baumannii infections is recommended. Conflicts of interest MEF has received speaker fees from Wyeth, AstraZeneca, Merck, Cipla, and Grunenthal. DEK declares that he has no conflicts of interest. References 1 Bergogne-Berezin E, Towner KJ. Acinetobacter spp as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev 1996; 9: 148–65.

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