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The susceptibilities of 142 Acinetobacter baumannii-calcoaceticus complex isolates (95 from wounded U.S. soldiers deployed overseas) to 13 antimicrobial agents were determined by broth microdilution. The most active antimicrobial agents (> or =95% of isolates susceptible) were colistin, polymyxin B, and minocycline.
A total of 144 clinical isolates of Acinetobacter species, i.e., A. baumannii (n = 60), genospecies 3 (n = 48), A. haemolyticus (n = 12), and genospecies 6 (n = 24), were examined comparatively with the agar dilution method of the National Committee for Clinical Laboratory Standards for susceptibility to 25 antimicrobial drugs. Only minor species differences were noted.
Antimicrobial susceptibility testing was performed on 54 epidemiologically unrelated clinical isolates of Acinetobacter baumannii by using a standard agar dilution technique. On the basis of the in vitro activities, imipenem and doxycycline were the most active agents, whereas amikacin, isepamicin, and the new fluorquinolones ciprofloxacin and ofloxacin presented moderate activity. Cephalosporinase activity was found in 98% of the strains, whereas lactamases of TEM type 1 and one with a pI of 7 to 7.5 were present in 16 and 11% of the strains, respectively. Resistance to aminoglycosides was explained by the production of the three classes of aminoglycoside-modifying enzymes, with predominance of aminoglycoside-3'-phosphotransferase VI in 28% of the strains.
The gyrA gene mutations associated with quinolone resistance were determined in 21 epidemiologically unrelated clinical isolates of Acinetobacter baumannii. Our studies highlight the conserved sequences in the quinolone resistance-determining region of the gyrA gene from A. baumannii and other bacteria. All 15 isolates for which the MIC of ciprofloxacin is > or = 4 micrograms/ml showed a change at Ser-83 to Leu. Six strains for which the MIC of ciprofloxacin is 1 microgram/ml did not show any change at Ser-83, although a strain for which the MIC of ciprofloxacin is 1 microgram/ml exhibited a change at Gly-81 to Val. Although it is possible that mutations in other locations of the gyrA gene, the gyrB gene, or in other genes may also contribute to the modulation of the MIC level, our results suggest that a gyrA mutation at Ser-83 is associated with quinolone resistance in A. baumannii.
Acinetobacter baumannii is responsible for severe nosocomial pneumonia. To evaluate new therapeutic regimens for infections due to multiresistant strains and to study the pharmacodynamic properties of various antibiotics, we developed an experimental mouse model of acute A. baumannii pneumonia. C3H/HeN mice rendered transiently neutropenic were infected intratracheally with 5 x 10(6) CFU of A. baumannii. The mean log10 CFU/g of lung homogenate (+/- the standard deviation) were 9 +/- 0.9, 9.4 +/- 0.8, 8.6 +/- 1.2, and 7.7 +/- 1.4 on days 1, 2, 3, and 4 postinoculation. The lung pathology was characterized by pneumonitis with edema and a patchy distribution of hemorrhages in the peribronchovascular spaces of both lungs. Abscesses formed on days 3 and 4. Four days after inoculation, subacute pneumonitis characterized by alveolar macrophage proliferation and areas of fibrosis was observed. The cumulative mortality on day 4 was 85%. This new model was used to study the effects of 1, 2, or 3 50-mg/kg doses of imipenem. Imipenem concentrations in lungs were above the MIC for 2 h after the last dose. The in vivo postantibiotic effect (PAE) was determined during the 9-h period following the last dose; it decreased in duration with the number of doses: 9.6, 6.4, and 4 h after 1, 2, and 3 50-mg/kg doses, respectively. In contrast, no in vitro PAE was observed. This model offers a reproducible acute course of A. baumannii pneumonia. The presence of a prolonged in vivo PAE supports the currently recommended dosing intervals of imipenem for the treatment of human infections due to A. baumannii, i.e., 15 mg/kg three times a day.
The in vitro susceptibilities of 69 nosocomial Acinetobacter isolates were determined by the broth microdilution method. Fourteen (20%) isolates were resistant to at least two aminoglycosides and two extended-spectrum penicillins. Nine antimicrobial combinations were then tested for synergy against these 14 isolates by checkerboard titration: imipenem with ciprofloxacin, amikacin, and tobramycin and ampicillin-sulbactam, piperacillin-tazobactam, and ticarcillin-clavulanate with amikacin and tobramycin. Synergy was detected with one or more antimicrobial combinations against 9 of 14 (64%) isolates, partial synergy was detected with one or more combinations against all 14 isolates, and an additive effect alone was observed with two different combinations against two isolates. No antagonism was detected with any combination. Imipenem plus either amikacin or tobramycin resulted in a synergistic or partial synergistic response against all 14 isolates. Specific combinations showing synergy against A. baumannii isolates were imipenem with tobramycin (four isolates), imipenem with amikacin (three isolates), ampicillin-sulbactam with tobramycin (six isolates), ampicillin-sulbactam with amikacin (three isolates), and ticarcillin-clavulanate with tobramycin (one isolate). Genotyping by randomly amplified polymorphic DNA analysis showed that 9 of the 14 isolates were of one strain, 4 isolates were of a second strain, and the remaining isolate was of a different strain. Eight of 14 (57%) patients infected with resistant A. baumannii isolates died. Only 3 of 14 patients had received a therapeutic regimen which was tested for synergy. Clinical studies are needed to determine the significance of these findings.
The effects of various regimens containing combinations of beta-lactams, beta-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of Acinetobacter baumannii pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345-351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (>/=3-log10 reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of >/=65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (>/=80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of beta-lactams, beta-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to A. baumannii.
A clinical strain of Acinetobacter baumannii (strain Ab RYC 52763/97) that was isolated during an outbreak in our hospital and that was resistant to all beta-lactam antibiotics tested produced three beta-lactamases: a TEM-1-type (pI, 5.4) plasmid-mediated beta-lactamase, a chromosomally mediated OXA-derived (pI, 9.0) beta-lactamase, and a presumptive chromosomal cephalosporinase (pI, 9.4). The nucleotide sequence of the chromosomal cephalosporinase gene shows for the first time the gene encoding an AmpC beta-lactamase in A. baumannii. In addition, we report here the biochemical properties of this A. baumannii AmpC beta-lactamase.
Fifteen multiresistant Acinetobacter baumannii isolates from patients in intensive care units and 14 nonoutbreak strains were tested to determine in vitro activities of nontraditional antimicrobials, including cefepime, meropenem, netilmicin, azithromycin, doxycycline, rifampin, sulbactam, and trovafloxacin. The latter five drugs were further tested against four of the strains for bactericidal or bacteriostatic activity by performing kill-curve studies at 0.5, 1, 2, and 4 times their MICs. In addition, novel combinations of drugs with sulbactam were examined for synergistic interactions by using a checkerboard configuration. MICs at which 90% of the isolates tested were inhibited for antimicrobials showing activity against the multiresistant A. baumannii strains were as follows (in parentheses): doxycycline (1 microg/ml), azithromycin (4 microg/ml), netilmicin (1 microg/ml), rifampin (8 microg/ml), polymyxin (0.8 U/ml), meropenem (4 microg/ml), trovafloxacin (4 microg/ml), and sulbactam (8 microg/ml). In the kill-curve studies, azithromycin and rifampin were rapidly bactericidal while sulbactam was more slowly bactericidal. Trovafloxacin and doxycycline were bacteriostatic. None of the antimicrobials tested were bactericidal against all strains tested. The synergy studies demonstrated that the combinations of sulbactam with azithromycin, rifampin, doxycycline, or trovafloxacin were generally additive or indifferent.
In vitro activities of seven fluoroquinolones against 140 clinical Acinetobacter baumannii isolates representing 138 different strain types were determined. The rank order of activity was clinafloxacin > gatifloxacin > levofloxacin > trovafloxacin > gemifloxacin = moxifloxacin > ciprofloxacin. The 31 outbreak-related A. baumannii strains were significantly more resistant than were 109 sporadic strains.
Integron carriage by 36 epidemiologically unrelated Acinetobacter baumannii isolates collected over an 11-year period from patients in six different Italian hospitals was investigated. Sixteen type 1 integron-positive isolates (44%) were found, 13 of which carried the same array of cassettes, i.e., aacC1, orfX, orfX', and aadA1a. As ribotype analysis of the isolates demonstrated a notable genetic diversity, horizontal transfer of the entire integron structure or ancient acquisition was hypothesized.
The treatment of life-threatening infections due to carbapenem-resistant Acinetobacter baumannii has become a serious challenge for physicians worldwide. Often, only colistin shows in general good in vitro activity against these carbapenem-resistant strains, but its antibacterial efficacy in comparison with the antibiotics most used in clinical practice is not well known. We studied the efficacy of colistin versus those of imipenem, sulbactam, tobramycin, and rifampin in an experimental pneumonia model with immunocompetent mice. We used three strains of A. baumannii corresponding to the main clones (A, D, and E) involved in the outbreaks of our hospital, with different grades of resistance to imipenem (imipenem MICs of 1, 8, and 512 microg/ml, respectively) and to the other antibiotics. The MIC of colistin was 0.5 microg/ml for the three strains. Reduction of log(10) CFU/g in lung bacterial counts, clearance of bacteremia, and survival versus results with controls were used as parameters of efficacy. Imipenem and sulbactam (Deltalung counts: -5.38 and -4.64 log(10) CFU/ml) showed the highest level of bactericidal efficacy in infections by susceptible and even intermediate strains. Tobramycin and rifampin (-4.16 and -5.15 log(10) CFU/ml) provided good results against intermediate or moderately resistant strains, in agreement with killing curves and pharmacodynamics. On the contrary, colistin showed the weakest antibacterial effect among the antibiotics tested, both in killing curves and in the in vivo model (-2.39 log(10) CFU/ml; P < 0.05). We conclude that colistin did not appear as a good option for treatment of patients with pneumonia due to carbapenem-resistant A. baumannii strains. Other alternatives, including combinations with rifampin, may offer better therapeutic profiles and thus should be studied.
Risk factors for the nosocomial occurrence of imipenem-resistant Acinetobacter baumannii (IRAB) were determined. A case-control study design was used for a comparison of two groups of A. baumannii-positive patients with control patients. Nosocomial IRAB was isolated from the first group of A. baumannii-positive patients, and imipenem-susceptible A. baumannii (ISAB) was isolated from the second group. The control patients were randomly selected in a 4:1 ratio from the same medical or surgical services from which the A. baumannii-positive patients were receiving care when the isolation of IRAB occurred. Risk factors analyzed included demographic variables, comorbid conditions, variables related to hospitalization, and the antimicrobials used. IRAB was isolated from 104 patients, and ISAB was isolated from 387 patients between January and December 2000. The risk factors for IRAB were a previous intensive care unit (ICU) stay (odds ratio [OR], 21.54; 95% confidence interval [CI], 10.73 to 43.23) and prior exposure to imipenem (OR, 9.18; 95% CI, 3.99 to 21.13) or third-generation cephalosporins (OR, 2.11; 95% CI, 1.13 to 3.95). Risk factors for ISAB were a previous ICU stay (OR, 8.05; 95% CI, 5.67 to 11.44) and exposure to third-generation cephalosporins (OR, 2.07; 95% CI, 1.47 to 2.91). Our results suggest that the nosocomial occurrence of IRAB or ISAB is strongly related to an ICU stay, and IRAB occurrence may be favored by the selection pressure of imipenem.
The lactoferrin-derived peptide hLF(1-11), but not its control peptide, was highly effective against five multidrug-resistant Acinetobacter baumannii strains in vitro (3 to 4 log reduction) and against four of these strains in an experimental infection in mice (2 to 3 log reduction). Therefore, this peptide is a promising candidate as a novel agent against infections with multidrug-resistant A. baumannii.
The bactericidal activity of moxifloxacin alone and in combination with cefepime or piperacillin-tazobactam against clinical isolates of Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii was evaluated by using time-kill methods and antimicrobial concentrations of one-half and one times the MIC. Synergy was observed in 58 to 88% of the strains and resulted in bactericidal activity against 60 to 100% of the strains. Combinations including moxifloxacin demonstrated enhanced bactericidal activity compared with that of either agent tested alone.
An acid extract of human neutrophil granules was fractionated on a Sephadex G-100 column and tested for microbicidal activity against Acinetobacter calcoaceticus HO-1 as described previously (M.C. Modrzakowski and C. M. Paranavitana, Infect. Immun. 32:668-674, 1981). The low-molecular-weight protein fraction, peak D, accounted for about 30% of the protein and nearly all of the activity of the crude extract against strain HO-1. Peak D protein proved to be a mixture of the three human defensin peptides HNP1, HNP2, and HNP3. Purified defensins reproduced the microbicidal activity of peak D. The data suggest that defensins could play a major role in the killing of A. calcoaceticus by human neutrophils.
We report the first Shiga toxin 2-producing Acinetobacter haemolyticus strain that was isolated from the feces of a 3-month-old infant with bloody diarrhea. Usual enteropathogenic bacteria were not detected. This finding suggests that any Shiga toxin-producing microorganism capable of colonizing the human gut may have the potential to cause illness.
Acinetobacter isolates associated with casualties from the Iraq conflict from the United States were compared with those from the United Kingdom by pulsed-field gel electrophoresis and integron analysis. Representatives of the main outbreak strain associated with casualties from both countries were indistinguishable in DNA profile. Two further outbreak strains were common to both sets of isolates.