Gentamicin-resistant Gram-negative Bacilli Research Articles

Impact of enhanced infection control at 2 neonatal intensive care units in the Philippines.

The growing burden of neonatal mortality associated with hospital-acquired neonatal sepsis in the developing world creates an urgent need for cost-effective infection-control measures in resource-limited settings. Using a before-and-after comparison design, we measured how rates of staff hand-hygiene compliance, colonization with drug-resistant pathogens (defined as ceftazidime- and/or gentamicin-resistant gram-negative bacilli and drug-resistant gram-positive cocci), bacteremia, and overall mortality changed after the introduction of a simplified package of infection-control measures at 2 neonatal intensive care units (NICUs) in Manila, The Philippines. Of all 1827 neonates admitted to the NICU, 561 (30.7%) arrived from delivery already colonized with drug-resistant bacteria. Of the 1266 neonates who were not already colonized, 578 (45.6%) became newly colonized with drug-resistant bacteria. Of all 1827 neonates, 358 (19.6%) became bacteremic (78.2% were infected with gram-negative bacilli) and 615 (33.7%) died. Of 2903 identified drug-resistant colonizing bacteria, 85% were drug-resistant gram-negative bacilli (predominantly Klebsiella species, Pseudomonas species, and Acinetobacter species) and 14% were methicillin-resistant Staphylococcus aureus. Contrasting the control period with the intervention period at each NICU revealed that staff hand-hygiene compliance improved (NICU 1: relative risk, 1.3; 95% confidence interval 1.1-1.5; NICU 2: relative risk, 1.6; 95% confidence interval, 1.4-2.0) and that overall mortality decreased (NICU 1: relative risk, 0.5; 95% confidence interval, 0.4-0.6; NICU 2: relative risk, 0.8; 95% confidence interval, 0.7-0.9). However, rates of colonization with drug-resistant pathogens and of sepsis did not change significantly at either NICU. Nosocomial transmission of drug-resistant pathogens was intense at these 2 NICUs in The Philippines; transmission involved mostly drug-resistant gram-negative bacilli. Infection-control interventions are feasible and are possibly effective in resource-limited hospital settings.

Carriage of resistant microorganisms in repatriates from foreign hospitals to The Netherlands

In a prospective survey conducted between May 1998 and September 2001, the prevalence of carriage of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and gentamicin-resistant Gram-negative bacilli (GGNB) was determined in 1167 patients repatriated from foreign hospitals to The Netherlands. Swab specimens, demographic data and clinical data were obtained during transfer of the patients from the foreign hospitals. The total prevalence of carriage of resistant microorganisms was 18.2%. MRSA was carried by 2.7% of all patients, and by 4.7% of the patients repatriated to a Dutch hospital. Antimicrobial treatment (adjusted odds ratio (OR) 3.4; 95% confidence interval (CI) 1.2-9.7), length of stay in a foreign hospital of > 14 days (adjusted OR 5.4; 95% CI 2.3-12) and artificial ventilation (adjusted OR 8.5; 95% CI 1.8-41) were risk factors for carriage of MRSA. VRE and GGNB were isolated from 2.7% and 14.1% of the patients, respectively. Transfer from Asia, and southern, southeastern and eastern Europe, were risk factors for carriage of GGNB. These carriage rates were high compared to those found in patients in Dutch hospitals, where the rates are < 1% for MRSA, 2% for VRE, and 4.5% for GGNB. The highest risk of acquisition of GGNB was associated with the country from where the patient was repatriated, rather than with the antimicrobial treatment received by the individual patient in the foreign hospital.

Meningitis in the Neonate.

Group B beta-hemolytic streptococci and Escherichia coli strains account for approximately two thirds of all cases of neonatal meningitis, while bacteria that typically account for meningitis in older age groups (Haemophilus influenzae type B, Neisseria meningitidis, and Streptococcus pneumoniae) are infrequent causes of meningitis in the neonatal population. As with other medical problems in neonates, signs and symptoms of bacterial infection of the central nervous system are generally few in number and nonspecific in nature. Manifestations that can suggest meningitis, as well as other serious illnesses, include temperature instability, lethargy, respiratory distress, poor feeding, vomiting, and diarrhea. Signs suggestive of meningeal irritation, including stiff neck, bulging fontanelle, convulsions, and opisthotonus, occur only in a minority of neonates with bacterial meningitis and cannot be relied on solely to identify such patients. Ampicillin and either gentamicin or cefotaxime are recommended for initial empiric therapy of neonatal meningitis. When the results of the cerebrospinal fluid (CSF) culture and susceptibilities are known, therapy can be narrowed to cover the specific pathogen identified. In general, penicillin G or ampicillin is preferred for group B streptococcal meningitis, ampicillin for Listeria monocytogenes meningitis, and ampicillin plus either an aminoglycoside or cefotaxime for gram-negative meningitis. For the very low birth weight neonate who has been in the nursery for a prolonged period of time, organisms such as enterococci and gentamicin-resistant gram-negative enteric bacilli must also be considered. In patients with long-term vascular catheters, Staphylococcus aureus or coagulase-negative staphylococci must also be considered. Empiric combinations of antibiotics for such patients would include ampicillin or vancomycin, plus amikacin or cefotaxime. All neonates should undergo repeat CSF examination and culture at 48 to 72 hours after initiation of therapy. If organisms are observed on gram stain, modification of the therapeutic regimen should be considered, and neuroimaging should be performed. In general, therapy should be continued for 14 to 21 days for neonatal meningitis caused by group B streptococci or L. monocytogenes, and for at least 21 days for disease caused by gram-negative enteric bacilli. All patients with neonatal meningitis should have hearing and development monitored serially. The first audiologic evaluation should occur 4 to 6 weeks after resolution of the meningitis.

Making sense of antimicrobial use and resistance surveillance data: application of ARIMA and transfer function models

Making sense of antimicrobial use and resistance surveillance data: application of ARIMA and transfer function models

The Aminoglycosides

Despite the introduction of newer, less toxic antimicrobial agents, the aminoglycosides continue to serve a useful role in the treatment of serious enterococcal, mycobacterial, and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Typically, it is administered in combination with β-lactam antibiotics, but it may also be used as monotherapy for urinary tract infections or tularemia. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. Streptomycin serves an important role in the treatment of multidrug-resistant tuberculosis and may be useful in the treatment of some gentamicin-resistant enterococcal infections. Despite an alarming increase in aminoglycoside-resistant enterococci, most institutions have noted little change in patterns of resistance among gram-negative bacilli. Although the development of newer, less toxic aminoglycosides is unlikely in the near future, single daily dosing regimens have been proposed as a convenient, cost-effective strategy. In selected patients, this novel approach seems to be as safe and effective as traditional, multidose regimens. Despite the introduction of newer, less toxic antimicrobial agents, the aminoglycosides continue to serve a useful role in the treatment of serious enterococcal, mycobacterial, and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Typically, it is administered in combination with β-lactam antibiotics, but it may also be used as monotherapy for urinary tract infections or tularemia. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. Streptomycin serves an important role in the treatment of multidrug-resistant tuberculosis and may be useful in the treatment of some gentamicin-resistant enterococcal infections. Despite an alarming increase in aminoglycoside-resistant enterococci, most institutions have noted little change in patterns of resistance among gram-negative bacilli. Although the development of newer, less toxic aminoglycosides is unlikely in the near future, single daily dosing regimens have been proposed as a convenient, cost-effective strategy. In selected patients, this novel approach seems to be as safe and effective as traditional, multidose regimens.

The Aminoglycosides

Despite the introduction of newer, less toxic antimicrobial agents, the aminoglycosides continue to serve a useful role in the treatment of serious enterococcal, mycobacterial, and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Typically, it is administered in combination with beta-lactam antibiotics, but it may also be used as monotherapy for urinary tract infections or tularemia. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. Streptomycin serves an important role in the treatment of multidrug-resistant tuberculosis and may be useful in the treatment of some gentamicin-resistant enterococcal infections. Despite an alarming increase in aminoglycoside-resistant enterococci, most institutions have noted little change in patterns of resistance among gram-negative bacilli. Although the development of newer, less toxic aminoglycosides is unlikely in the near future, single daily dosing regimens have been proposed as a convenient, cost-effective strategy. In selected patients, this novel approach seems to be as safe and effective as traditional, multidose regimens.

The Aminoglycosides

Despite the introduction of newer, less toxic antimicrobial agents, the aminoglycosides continue to serve a useful role in the treatment of serious enterococcal and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. An alarming increase in resistance to aminoglycosides among enterococci has been noted, despite little change in susceptibility patterns among gram-negative bacilli. Future efforts will need to be directed toward a better understanding of mechanisms of antimicrobial resistance and toward the prevention of aminoglycoside-induced toxicity.

Antimicrobial Activity of Isepamicin (SCH21420, 1-N-HAPA Gentamicin B) Combinations with Cefotaxime, Ceftazidime, Ceftriaxone, Ciprofloxacin, Imipenem, Mezlocillin and Piperacillin Tested Against Gentamicin-Resistant and Susceptible Gram-Negative Bacilli and Enterococci

Isepamicin, formerly SCH21420 or 1-N-HAPA gentamicin B, is an aminoglycoside that was tested alone or in combination with one of seven broad spectrum drugs against 80 clinical isolates. Half of the strains were gentamicin-resistant but only one isolate (1.3%) was resistant to isepamicin. The broadest spectrum comparison drugs tested alone (ciprofloxacin at 3.8% resistance and imipenem at 5.0% resistance) were associated with the lowest synergy rates when combined with isepamicin. The rank order of synergy (complete or partial) was; cefotaxime = ceftazidime = ceftriaxone = mezlocillin = piperacillin (75% to 80%) greater than imipenem (66%) greater than ciprofloxacin (38%). Isepamicin/ampicillin combinations produced synergistic killing of those enterococci not having high-grade resistance to gentamicin or kanamycin. Enterococcus faecium strains were also refractory to isepamicin/ampicillin synergy. Isepamicin appears to be widely useable against gentamicin-resistant gram-negative bacilli either alone or combined with most commonly used broad spectrum beta-lactams.

Gentamicin-resistant klebsiella spp. and escherichia coli in a neonatal intensive care unit

A case of septicemia in a 7-day-old infant with a gentamicin-resistant strain of Klebsiella oxytoca prompted an epidemiological survey in a neonatal unit. Within a 3-month period 7 patients presented with symptomatic infection with gentamicin-resistant gram-negative bacilli. Another 3 patients were asymptomatic and only harboured the organisms in the stool. The aminoglycoside modifying enzyme ANT(2")-a was identified with a probe technique in different gram-negative species indicating the spread of a plasmid. After the replacement of gentamicin with amikacin and the adherence to proper barrier precautions the gentamicin-resistant strains disappeared from the ward.

Endogenous colonization by gentamicin-resistant gram-negative bacilli elaborating aminoglycoside (3)-5-acetyltransferase

Members of the family Enterobacteriaceae that elaborate aminoglycoside 3-5-acetyltransferase [AAC(3)-5] caused a nosocomial outbreak at the Vanderbilt University Medical Center and have persisted. To see whether the gene for AAC(3)-5 was present in the community, stool cultures of newly admitted patients and ambulatory persons were examined with a specific gene probe. AAC(3)-5-positive strains were present in the intestinal flora examined.

Development of a DNA probe from the deoxyribonucleotide sequence of a 3-N-aminoglycoside acetyltransferase [AAC(3)-I] resistance gene.

The aacC1 gene encoding the 3-N-aminoglycoside acetyltransferase [AAC(3)-I] was cloned from enteric plasmid pJR88, and its deoxyribonucleotide sequence was determined. Significant nucleotide homology was noted in the region extending from the proposed -35 sequences through the first 59 base pairs of the aacC1 gene open reading frame (ORF) and the upstream flanking regions and ORFs of several other antibiotic resistance genes. Sequences were noted to be homologous with the 6'-N-aminoglycoside acetyltransferase [AAC(6')-I], 2''-O-aminoglycoside adenylyltransferase [AAD(2'')], and 3''-O-aminoglycoside adenylyltransferase [AAD(3'')] resistance genes; the OXA-1, OXA-2, and PSE-2 beta-lactamase genes; and several dihydrofolate reductase genes. Small regions of homology were noted in the 3'-flanking regions of these resistance genes as well. A DNA probe for the aacC1 gene was selected from the nucleotide sequence information and was tested against a series of genetically and enzymatically defined strains. The probe, which proved specific for the aacC1 gene, was then tested against a series of 58 gentamicin-susceptible and 219 gentamicin-resistant gram-negative bacilli isolated from patients at the Seattle Veterans Administration Medical Center. Only six clinical isolates were noted to carry the aacC1 gene. Each was resistant to gentamicin but susceptible to kanamycin, tobramycin, and amikacin. The presence of homologous regions of DNA at both the 3' and 5' ends of the aacC1 gene reinforces the importance of choosing probes from within the ORFs of genes and of avoiding flanking sequences. When the homology with other sequences extends into the ORF, as it does with the aacC1 gene, development of a specific probe may require determination of the nucleotide sequence.

Prevalence of colonization with antibiotic resistant gram-negative bacilli in a nursing home care unit: the importance of cross-colonization as documented by plasmid analysis.

A prevalence study was carried out on a 100-bed Veterans Administration nursing home care unit to determine the extent of colonization with gentamicin-resistant gram-negative bacilli (GRGNB). Hand cultures of 12 employees and 17 environmental cultures were negative. Twenty-six of 86 (30%) patients were colonized with 49 GRGNB. Sixteen patients (19%) had urinary colonization. Multivariate analysis revealed significant associations between rectal or perineal colonization (P less than 0.01), and the presence of a urinary device (82% condom catheters) (P less than 0.05), with urinary colonization. The most common isolates were Providencia stuartii (20), Escherichia coli (nine) and Klebsiella pneumoniae (nine). Twenty-six of 49 isolates carried plasmids. Restriction endonuclease digestion of plasmid DNA was performed for 21. Cross-colonization, as defined by the presence of the identical species with the identical restriction endonuclease digestion profile of purified plasmid DNA found in different patients, was observed for eight of 21 (38%) strains. All were geographically clustered. No strains could transfer gentamicin-resistance by conjugation and only two plasmids could transform our E coli recipient to gentamicin resistance. One E coli plasmid was identical to two Citrobacter freundii plasmids and a P stuartii plasmid isolated from three different patients. This 105 kb plasmid is conjugative and encodes resistance to ampicillin, carbenicillin, tetracycline, and sulfonamides. Thus, 57% of strains were cross-colonizing or contained identical R-plasmids. Southern hybridization using a 1 kb TEM-1 gene probe demonstrated sequences homologous to this probe in five of five nursing home plasmids examined.(ABSTRACT TRUNCATED AT 250 WORDS)

An investigation of the spread of gentamicin resistance in a district general hospital.

A cluster of infections caused by gentamicin-resistant gram-negative bacilli in a District General Hospital was investigated. The plasmids coding for gentamicin resistance in the infecting organisms and in isolates obtained from the ward environment and from the faeces of patients and staff were characterised. Six plasmids encoding gentamicin resistance were recognised amongst the organisms causing infection. Two of the plasmids were found in different serotypes of the same species and one plasmid was found in different genera. Three of the plasmids present in the organisms causing the infections were also present in the inanimate environment or in the bowel flora of patients and these also were found in different serotypes of the same species and in different genera.

Gentamicin-resistance plasmids in an intensive care unit.

To better understand the role of plasmids and their importance in the endemic antibiotic resistance of Enterobacteriaceae, we began a prospective study of our combined medical intensive care/coronary care unit. An initial culture survey of the patients, ward staff, and environment was followed by a prospective sampling of 139 consecutive new admissions at the time of admission to the unit, and at regular intervals thereafter for the remainder of their stay. All cultures were planted on agar-containing gentamicin. Of the 147 patients studied, 12 (8.2%) were colonized with 20 strains of gentamicin-resistant gram-negative bacilli (GRGNB) at 29 sites. An additional four GRGNB were isolated from the environment. Of the 24 GRGNB strains, 7 (29%) Enterobacteriaceae carried plasmids shown to carry the gentamicin-resistance determinant. Plasmids were further characterized by restriction endonuclease digestion profiles of plasmid DNA purified from E. coli C600 transconjugants or transformants. A 93 kb plasmid introduced to the unit by a Serratia liquefaciens colonizing a patient transferred from another area in the hospital was identical to 93 kb plasmids carried by a C. amalonaticus and an E. aerogenes subsequently colonizing another patient on the unit. A 60 kb plasmid, first isolated from a S. marcescens colonizing a sink drain was later isolated from an E. cloacae colonizing a patient. Our results indicate that spread of specific R-plasmids may be one mechanism for dissemination of antibiotic resistance on our MICU/CCU.

Evaluation of the resistance mechanisms of gentamicin-resistant Gram-negative bacilli and their susceptibility to tobramycin, netilmicin and amikacin.

Two hundred and fifty-three gentamicin-resistant Gram-negative bacilli, isolated from clinical material, were tested for sensitivity to tobramycin, netilmicin and amikacin. Amikacin was effective at 16 mg/l in 90% of cases, whereas there was no difference between netilmicin and tobramycin activity; 13.3% of strains were susceptible to 8 mg/l netilmicin, and 14.8% of strains to 4 mg/l tobramycin. The lack of difference in results between tobramycin and netilmicin is explained by local enzyme patterns. In our population, the AAC(3)II is predominant, and inactivates gentamicin, tobramycin and netilmicin, in contrast to the U.S.A. where ANT (2") seems to be the most common enzyme.

Gram-negative bacteremias. Analysis of factors for clinical assessment of gentamicin resistance.

We reviewed the charts of 163 patients with 183 episodes of Gram-negative bacillary bacteremia to determine a clinical profile that would select patients at high risk for experiencing gentamicin-sulfate-resistant Gram-negative bacillary bacteremia at our hospital. Gentamicin-resistant Gram-negative bacilli were only associated with institution-acquired bacteremia. Among institution-acquired episodes, urinary tract infection, diagnostic or therapeutic procedures of the lower respiratory tract or urinary tract, presence of pneumonic infiltrate on chest roentgenogram, prior therapy with gentamicin, and prior therapy with other antibiotics were significant risk factors. Because only two of the 29 gentamicin-resistant bacteria that were tested against amikacin base were resistant to amikacin, we advocate initial treatment with amikacin for patients with evidence of an institution-acquired Gram-negative bacteremic episode. Gentamicin is still our initial choice for a community-acquired episode.

Gram-Negative Bacteremias

• We reviewed the charts of 163 patients with 183 episodes of Gram-negative bacillary bacteremia to determine a clinical profile that would select patients at high risk for experiencing gentamicin-sulfate-resistant Gram-negative bacillary bacteremia at our hospital. Gentamicin-resistant Gram-negative bacilli were only associated with institution-acquired bacteremia. Among institution-acquired episodes, urinary tract infection, diagnostic or therapeutic procedures of the lower respiratory tract or urinary tract, presence of pneumonic infiltrate on chest roentgenogram, prior therapy with gentamicin, and prior therapy with other antibiotics were significant risk factors. Because only two of the 29 gentamicin-resistant bacteria that were tested against amikacin base were resistant to amikacin, we advocate initial treatment with amikacin for patients with evidence of an institution-acquired Gram-negative bacteremic episode. Gentamicin is still our initial choice for a community-acquired episode. (<i>Arch Intern Med</i>1981;141:582-586)

Gentamicin and tobramycin resistant gram-negative bacilli in a community hospital.

The incidence and spectrum of resistance to gentamicin and tobramycin among gram-negative bacilli (GNB) isolated in a community hospital over a one-year period were studied. The overall incidence of resistance was 3.7%. Pseudomonads constituted almost half of the resistant organisms. The majority of resistant GNB was isolated from the respiratory and urinary tracts. Acquisition of resistance was correlated with both the total use of gentamicin in the hospital and recent treatment of individual patients with gentamicin plus tobramycin. The overall incidence of resistant isolates (3.7%) and the incidence of resistance for the enterobacteriaceae (1.9%) were lower than rates reported by comparable studies at several university or municipal hospitals.

Endemic aminoglycoside resistance in gram-negative bacilli: epidemiology and mechanisms.

Isolates of gentamicin-resistant gram-negative bacilli from clinical specimens peaked at nine to 10 per month in 1973-1974. Instituting barrier-type precautions during 1974-1977 was associated with a sustained 87% reduction in resistant Enterobacteriaceae. The number of resistant Pseudomonadaceae fell temporarily by 28%, paralleling gentamicin usage. During an endemic 15-month period in 1976-1977 nonenzymatically mediated resistant Pseudomonas aeruginosa often emerged after aminoglycoside therapy in patients who had prior carriage of sensitive strains of the same serotype (P = 0.002); this resistance was associated with wound or sputum isolates (P = 0.003). Resistant Enterobacteriaceae more often demonstrated the converse, that is, spread of urinary tract isolates with enzymatically mediated resistance from patients not on aminoglycoside therapy. These findings suggest that control measures to minimize occurrence of resistant bacilli include barrier-type precautions for patients with resistant Enterobacteriaceae, evaluation of transfers and readmissions as a source of resistant organisms, and reduction of aminoglycoside use to decrease the selection of nonenzymatic resistance.

The sensitivity of gentamicin-resistant gram-negative bacilli to cefotaxime, other cephalosporins and aminoglycosides.

The sensitivities of 80 gentamicin-resistant gram-negative bacilli to cefotaxime, cefuroxime, cefoxitin, cefamandole, cefazolin, tobramycin, netilmicin and amikacin were determined. Amikacin was the most active amino-glycoside. However, the percentage sensitivity to cefotaxime of most of the species was higher than, or equal to any of the other antibiotics tested. Cefotaxime was particulary active against Providencia spp., Serratia spp., Klebsiella spp., and Pseudomonas maltophilia, being 16 to 256 times more active than the next best cephalosporin or cephamycin. Clinical trials of cefotaxime are now required.