Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.

Acinetobacter baumannii: Emergence of a Successful Pathogen

Summary: Bacteroides species are significant clinical pathogens and are found in most anaerobic infections, with an associated mortality of more than 19%. The bacteria maintain a complex and generally beneficial relationship with the host when retained in the gut, but when they escape this environment they can cause significant pathology, including bacteremia and abscess formation in multiple body sites. Genomic and proteomic analyses have vastly added to our understanding of the manner in which Bacteroides species adapt to, and thrive in, the human gut. A few examples are (i) complex systems to sense and adapt to nutrient availability, (ii) multiple pump systems to expel toxic substances, and (iii) the ability to influence the host immune system so that it controls other (competing) pathogens. B. fragilis, which accounts for only 0.5% of the human colonic flora, is the most commonly isolated anaerobic pathogen due, in part, to its potent virulence factors. Species of the genus Bacteroides have the most antibiotic resistance mechanisms and the highest resistance rates of all anaerobic pathogens. Clinically, Bacteroides species have exhibited increasing resistance to many antibiotics, including cefoxitin, clindamycin, metronidazole, carbapenems, and fluoroquinolones (e.g., gatifloxacin, levofloxacin, and moxifloxacin).

Bacteroides: the Good, the Bad, and the Nitty-Gritty

Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.

Antibiotics and Bacterial Resistance in the 21st Century

We may soon be facing the end of the “antibiotic era.” The initial and seemingly unstoppable success of antibiotics, the fruit of human ingenuity, has been countered by an escalation of resistance mechanisms in bacteria. This crisis has been described as an “unwinnable war” (www.wellcome.org). The statistics compiled as a result of surveillance efforts illustrate the emergence of many genera of bacteria that are resistant to all antibiotics (57, 60). The genus Acinetobacter epitomizes this trend and deserves close attention. Acinetobacter spp. display mechanisms of resistance to all existing antibiotic classes as well as a prodigious capacity to acquire new determinants of resistance (7). The increasing recovery in the clinic of multidrug-resistant (MDR) Acinetobacter baumannii is a frightening reality (112). This review summarizes the worldwide emergence of antibiotic-resistant A. baumannii as a nosocomial pathogen and focuses on its mechanisms of resistance against selected antibiotics. It concludes with a summary of current strategies in the treatment of MDR A. baumannii and offers perspectives on the control of this global public health threat.

Global Challenge of Multidrug-Resistant Acinetobacter baumannii

Background Vancomycin treatment failure in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not uncommon, even when MRSA is susceptible to vancomycin. The aim of our study was to evaluate whether vancomycin minimum inhibitory concentration has any influence on the mortality associated with MRSA bacteremia. Methods A total of 414 episodes of MRSA bacteremia were prospectively followed-up from 1991 through 2005. MIC of vancomycin for the first isolate was determined by E-test. Clinical variables recorded were age, comorbidity, prior administration of vancomycin, use of corticosteroids, prognosis of underlying disease, source of bacteremia, the need for mechanical ventilation, shock, and mortality. A "treatment group" variable was created and defined as follows: (1) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 1 microg/mL (38 episodes), (2) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 1.5 microg/mL (90 episodes), (3) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 2 microg/mL (40 episodes), and (4) receipt of inappropriate empirical therapy (246 episodes). Univariate and multivariate analyses were performed. Results Episodes caused by strains with a vancomycin MIC of 2 microg/mL were independently associated with a lower risk of shock (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.15-0.75). Multivariate analysis selected receipt of empirical vancomycin and an isolate with a vancomycin MIC of 2 microg/mL (OR, 6.39; 95% CI, 1.68-24.3), receipt of inappropriate empirical therapy (OR, 3.62; 95% CI, 1.20-10.9), increasing age (OR, 1.02; 95% CI, 1.00-1.04), use of corticosteroids (OR, 1.85; 95% CI, 1.04-3.29), an ultimately (OR, 10.2; 95% CI, 2.85-36.8) or rapidly (OR, 1.81; 95% CI, 1.06-3.10) fatal underlying disease, high-risk (OR, 3.60; 95% CI, 1.89-6.88) and intermediate-risk (OR, 2.18; 95% CI, 1.17-4.04) sources of bacteremia, and shock (OR, 7.38; 95% CI, 4.11-13.3) as the best predictors of mortality. Conclusions Mortality associated with MRSA bacteremia was significantly higher when the empirical antibiotic was inappropriate and when vancomycin was empirically used for treatment of infection with strains with a high vancomycin MIC (>1 microg/mL).

Influence of Vancomycin Minimum Inhibitory Concentration on the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia

The antimicrobial activities of tigecycline (GAR-936) were compared with those of other agents against 1,087 strains recently isolated in 12 Spanish medical centers. Tigecycline showed activity against a wide spectrum of aerobic and anaerobic bacteria, including strains such as methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, penicillin-resistant Streptococcus pneumoniae, Enterococcus faecium, Acinetobacter baumannii, and Stenotrophomonas maltophilia.

In Vitro Activities of Tigecycline (GAR-936) against Recently Isolated Clinical Bacteria in Spain

The aim of this study was to determine the susceptibility patterns of 100 group B streptococcal strains isolated in our hospital and to ascertain tolerance to penicillin by determining quantitative killing curves. We found two strains with intermediate susceptibility to penicillin and eight strains to ampicillin. Seventeen isolates were tolerant to penicillin, with bacterial counts decreasing 2 to 3 log during the first 8 h but still above 10(2) CFU/ml after 24 h. The kinetic study shows that penicillin tolerance is not rare among group B streptococci isolated in our hospital.

Antibiotic resistance and penicillin tolerance in clinical isolates of group B streptococci.

The rates of resistance to erythromycin and clindamycin among Streptococcus agalactiae strains isolated in our hospital increased from 4.2 and 0.8% in 1993 to 17.4 and 12.1%, respectively, in 2001. Erythromycin resistance was mainly due to the presence of an Erm(B) methylase, while the M phenotype was detected in 3.8% of the strains. Telithromycin was very active against erythromycin-resistant strains, irrespective of their mechanisms of macrolide resistance.

Erythromycin and clindamycin resistance and telithromycin susceptibility in Streptococcus agalactiae.

Objectives To compare the activity of tedizolid (formally known as torezolid and TR-700) with that of 15 agents against a collection of linezolid-resistant staphylococci (164 coagulase-negative staphylococci and 5 Staphylococcus aureus). Methods Antimicrobial susceptibility tests were performed using the broth microdilution method following the recommendations of the CLSI. Results All isolates were susceptible to vancomycin and tigecycline. Based on the MIC(90) values, the potency of tedizolid against coagulase-negative staphylococci was >16-fold greater than that of linezolid. Tedizolid retained activity against most of the linezolid-resistant staphylococci tested, including multidrug-resistant isolates with elevated linezolid MICs (32 to >128 mg/L). Of the isolates, 79.2% and 31.4% were inhibited by tedizolid at ≤ 4 mg/L and ≤ 2 mg/L, respectively. Conclusions The results of this study confirm the activity of tedizolid against linezolid-resistant staphylococci. This new oxazolidinone could have an important role as a potential therapeutic agent against multidrug-resistant staphylococci.

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In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci

The activity of tigecycline was tested against erythromycin-resistant streptococci (107 Streptococcus pyogenes and 98 Streptococcus agalactiae strains). The presence of erythromycin and tetracycline resistance genes was determined by PCR. Among S. pyogenes strains the most prevalent gene was mef(A) (91.6%). The erm(B) gene was the most prevalent (65.3%) among S. agalactiae strains. Tigecycline proved to be very active against all the isolates tested (MIC at which 90% of the isolates tested were inhibited, 0.06 μg/ml), including those resistant to tetracycline.

In Vitro Activities of Tigecycline against Erythromycin-Resistant Streptococcus pyogenes and Streptococcus agalactiae: Mechanisms of Macrolide and Tetracycline Resistance

Carmen Betriu

Papers

In Vitro Activities of Tigecycline (GAR-936) against Recently Isolated Clinical Bacteria in Spain

Antibiotic resistance and penicillin tolerance in clinical isolates of group B streptococci.

Erythromycin and clindamycin resistance and telithromycin susceptibility in Streptococcus agalactiae.

In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci

In Vitro Activities of Tigecycline against Erythromycin-Resistant Streptococcus pyogenes and Streptococcus agalactiae: Mechanisms of Macrolide and Tetracycline Resistance