Ian R. Friedland

Surveillance for Antimicrobial Susceptibility among Clinical Isolates of Pseudomonas aeruginosa and Acinetobacter baumannii from Hospitalized Patients in the United States, 1998 to 2001

ABSTRACT Pseudomonas aeruginosa and Acinetobacter baumannii are the most prevalent nonfermentative bacterial species isolated from clinical specimens of hospitalized patients. A surveillance study of 65 laboratories in the United States from 1998 to 2001 found >90% of isolates of P. aeruginosa from hospitalized patients to be susceptible to amikacin and piperacillin-tazobactam; 80 to 90% of isolates to be susceptible to cefepime, ceftazidime, imipenem, and meropenem; and 70 to 80% of isolates to be susceptible to ciprofloxacin, gentamicin, levofloxacin, and ticarcillin-clavulanate. From 1998 to 2001, decreases in antimicrobial susceptibility (percents) among non-intensive-care-unit (non-ICU) inpatients and ICU patients, respectively, were greatest for ciprofloxacin (6.1 and 6.5), levofloxacin (6.6 and 3.5), and ceftazidime (4.8 and 3.3). Combined 1998 to 2001 results for A. baumannii isolated from non-ICU inpatients and ICU patients, respectively, demonstrated that >90% of isolates tested were susceptible to imipenem (96.5 and 96.6%) and meropenem (91.6 and 91.7%); fewer isolates from both non-ICU inpatients and ICU patients were susceptible to amikacin and ticarcillin-clavulanate (70 to 80% susceptible); and <60% of isolates were susceptible to ceftazidime, ciprofloxacin, gentamicin, or levofloxacin. From 1998 to 2001, rates of multidrug resistance (resistance to at least three of the drugs ceftazidime, ciprofloxacin, gentamicin, and imipenem) showed small increases among P. aeruginosa strains isolated from non-ICU inpatients (5.5 to 7.0%) and ICU patients (7.4 to 9.1%). From 1998 to 2001, rates of multidrug resistance among A. baumannii strains isolated from non-ICU inpatients (27.6 to 32.5%) and ICU patients (11.6 to 24.2%) were higher and more variable than those observed for P. aeruginosa. Isolates concurrently susceptible, intermediate, or resistant to both imipenem and meropenem accounted for 89.8 and 91.2% of P. aeruginosa and A. baumannii isolates, respectively, studied from 1998 to 2001. In conclusion, for aminoglycosides and most β-lactams susceptibility rates for P. aeruginosa and A. baumannii were constant or decreased only marginally (≤3%) from 1998 to 2001. Greater decreases in susceptibility rates were, however, observed for fluoroquinolones and ceftazidime among P. aeruginosa isolates.

Comparison of the response to antimicrobial therapy of penicillin-resistant and penicillin-susceptible pneumococcal disease.

The continued spread of penicillin-resistant pneumococci raises therapeutic concerns. Optimal therapy for resistant infections is unknown and it is not clear whether the efficacy of penicillin or equally active beta-lactam agents is compromised in non-meningeal-resistant infections. A prospective nonintervention study was undertaken to compare the clinical response in penicillin-resistant vs. penicillin-susceptible bacteremic pneumococcal infections, excluding meningitis. Of 108 children enrolled, 35 (32%) had penicillin-resistant (one highly resistant) isolates. Seventy-eight children had pneumonia, 21 had occult bacteremia (sepsis) and 9 had peritonitis. Children with resistant infections were more likely to have underlying disorders, especially human immunodeficiency virus infection, and to have received antimicrobial therapy in the previous month. After 48 hours of therapy 64% of penicillin-susceptible infections showed improvement vs. 60% of penicillin-resistant infections (odds ratio, 1.2; 95% confidence intervals, 0.5 to 3.0). In children with pneumonia treated with ampicillin or an equivalent beta-lactam agent, 93% with penicillin-susceptible infections had improved by Day 7 of therapy compared with 88% with resistant infections (odds ratio, 1.9; 95% confidence interval 0.3 to 15.9). The durations of respiratory distress, fever and oxygen requirement were similar in penicillin-susceptible and -resistant infections. These results suggest that intermediate penicillin resistance is of little significance in pneumococcal pneumonia or sepsis and that standard beta-lactam therapy is still highly effective. Further studies of highly penicillin-resistant infections are necessary.

Antibiotic pharmacodynamics in cerebrospinal fluid

The CSF half-lives of lipophilic agents, such as quinolones, are similar to those in serum and peak concentrations in CSF are achieved relatively quickly. In contrast, the pharmacokinetics of hydrophilic agents (beta-lactams and vancomycin) in CSF often differ from those in serum. In particular, the half-lives of these agents in CSF tend to be extended, and the time to achieve peak concentrations in CSF is delayed. Hydrophilic antibiotics, such as beta-lactams, penetrate poorly through the BBB, but CSF penetration is significantly increased in the presence of inflammation. In contrast, lipophilic antibiotics, such as quinolones, enter the CSF more efficiently and their penetration is not inflammation dependent. The pharmacodynamic properties of antibiotics in CSF are generally similar to those in other body sites; beta-lactam agents and vancomycin are time-dependent, whereas the quinolones and aminoglycosides are concentration-dependent. However, a notable difference from infections in other sites is that quinolones have a short PAE in CSF and need to continually exceed the MBC for maximal effectiveness. Thus, in CSF, quinolones demonstrate features of both concentration-dependency and time-dependency, evidence that the AUC/MBC is an important predictor of effectiveness. With the exception of quinolones, many antibiotics appear to have prolonged sub-MIC effects and longer half-lives in CSF than in serum, suggesting that dosing intervals longer than those used traditionally would be effective in meningitis. However, this requires clinical verification.

Dilemmas in diagnosis and management of cephalosporin-resistant Streptococcus pneumoniae meningitis

We recently managed an infant with meningitis caused by Streptococcus pneumoniae in whom ceftriaxone failed to sterilize the cerebrospinal fluid after 6 days of therapy. This strain, which had a penicillin minimal inhibitory concentration (MIC) of 2 micrograms/ml, appeared susceptible to ceftriaxone (MIC < 0.5 micrograms/ml) when evaluated by a commercial MIC panel (Microtech Medical Systems, Inc., Aurora, CO) but was found to have a ceftriaxone MIC of 4 micrograms/ml when evaluated by conventional microtiter broth dilution technique. Furthermore ceftriaxone therapy of meningitis induced with this strain in a rabbit model was ineffective. Thirteen of 112 pneumococcal strains (11.6%) isolated recently at Childrens Medical Center of Dallas were penicillin-resistant, and 3 of these were highly penicillin-resistant (MIC > or = 2 micrograms/ml). The incidence of pneumococcal strains with cefotaxime MICs > or = 1.0 micrograms/ml has increased from 0 of 258 from 1981 to 1983 to 5 of 112 (4.5%) from 1991 to 1992. The definition of cephalosporin resistance for pneumococci requires modification and further studies of the antibiotic management of meningitis caused by such strains are needed because resistance to cephalosporins is increasing and the extended spectrum cephalosporins may be ineffective as sole therapy.

Trends in Antimicrobial Susceptibilities among Enterobacteriaceae Isolated from Hospitalized Patients in the United States from 1998 to 2001

ABSTRACT Longitudinal surveillance of Enterobacteriaceae for antimicrobial susceptibility is important because species of this family are among the most significant and prevalent human pathogens. To estimate rates of in vitro antimicrobial susceptibility among hospitalized patients in the United States, data from The Surveillance Network were studied for 14 agents tested against 10 species of Enterobacteriaceae (n = 384,279) isolated from intensive-care-unit (ICU) patients and non-ICU inpatients from 1998 to 2001. Cumulative susceptibility (percent) data for all species of Enterobacteriaceae isolated from ICU patients and non-ICU inpatients, respectively, were ranked as follows: ampicillin-sulbactam (45.5 and 57.2) ≪ ticarcillin-clavulanate (74.8 and 83.5) < trimethoprim-sulfamethoxazole (87.0 and 84.5) ≅ cefotaxime (82.9 and 92.6) = ceftazidime (82.3 and 91.0) = ceftriaxone (86.5 and 93.9) = piperacillin-tazobactam (83.5 and 90.5) < levofloxacin (89.3 and 90.6) = ciprofloxacin (91.0 and 91.7) < gentamicin (91.8 and 94.3) < cefepime (95.0 and 97.9) < amikacin (98.5 and 99.2) < imipenem (100 and 100) = meropenem (100 and 100). Of those agents studied only susceptibilities to ciprofloxacin (94 to 89%) and levofloxacin (93 to 89%) decreased in a stepwise manner from 1998 to 2001. Decreased fluoroquinolone susceptibility was most pronounced for Escherichia coli, Proteus mirabilis, and Enterobacter cloacae. For all species of Enterobacteriaceae, trimethoprim-sulfamethoxazole resistance was more commonly observed in isolates with a single-drug resistance phenotype while gentamicin and fluoroquinolone resistances were more common in isolates resistant to at least one additional class of antimicrobial agent. Ongoing surveillance of Enterobacteriaceae will be particularly important to monitor changes in fluoroquinolone susceptibility, as well as changes in the prevalence of isolates resistant to multiple classes of antimicrobial agents.

Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses

ABSTRACT The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.

Effects of Amoxicillin/Clavulanate or Azithromycin on Nasopharyngeal Carriage of Streptococcus pneumoniae and Haemophilus influenzae in Children with Acute Otitis Media

The effect of antibiotic therapy on nasopharyngeal colonization by Streptococcus pneumoniae and Haemophilus influenzae was evaluated in children diagnosed with acute otitis media. Children were randomly assigned to receive either amoxicillin/clavulanate or azithromycin therapy, and nasopharyngeal swabs were obtained for culture before and after starting therapy. Amoxicillin/clavulanate therapy eradicated or suppressed all strains of S. pneumoniae susceptible to penicillin, 75% of strains with intermediate resistance, and 40% of strains resistant to penicillin. Azithromycin therapy cleared two-thirds of azithromycin-susceptible strains of S. pneumoniae but none of azithromycin-nonsusceptible strains. Selection for antibiotic-resistant strains in individual children was not observed in children who received amoxicillin/clavulanate therapy but was observed in 2 children who received azithromycin therapy. Carriage of H. influenzae was also reduced by antimicrobial therapy but more so by amoxicillin/clavulanate. Antibiotic therapy does not directly increase the number of resistant strains in the population but, by eradicating susceptible strains, allows greater opportunity for carriage and spread of resistant strains.

Increased resistance to amikacin in a neonatal unit following intensive amikacin usage.

Gram-negative isolates from blood and cerebrospinal fluid were monitored for 1 year before and for 1 year after the first-line aminoglycoside in a busy pediatric department was changed from gentamicin to amikacin. In the general pediatric wards, the switch to amikacin resulted in no change in resistance of nosocomial gram-negative infections to either amikacin (0% before and after) or gentamicin (23.9% [before] versus 26.5% [after]). In the neonatal unit, the switch to amikacin was followed by an outbreak of Serratia spp. that were commonly resistant to amikacin but susceptible to gentamicin. This outbreak abated spontaneously. In the year after the change in aminoglycoside usage, the resistance to amikacin of nosocomially acquired gram-negative infections increased from 7.6 to 27.7% (P less than 0.001), and the resistance to gentamicin decreased from 71.2 to 60.2% (P = 0.07). The increase in amikacin resistance of gram-negative bacilli other than Serratia spp. has persisted for more than a year after the introduction of amikacin as the sole aminoglycoside. The different effects observed in the two sections of the pediatric department may be related to the more intensive usage of aminoglycosides in the neonatal unit.

Worldwide Experience with the Use of Doripenem against Extended-Spectrum-β-Lactamase-Producing and Ciprofloxacin-Resistant Enterobacteriaceae: Analysis of Six Phase 3 Clinical Studies

ABSTRACT The worldwide increase in fluoroquinolone-resistant and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae pathogens has led to doripenem and other carbapenems assuming a greater role in the treatment of serious infections. We analyzed data from 6 phase 3 multinational doripenem clinical trials on ciprofloxacin-resistant Enterobacteriaceae isolates consisting of all genera (CIPRE) and ESBL-producing Enterobacteriaceae isolates consisting of Escherichia coli, Klebsiella spp., and Proteus spp. with ceftazidime MICs of ≥2 μg/ml (ESBLE) for prevalence by geographic region and disease type, in vitro activities of doripenem and comparator agents, and clinical or microbiologic outcomes in doripenem- and comparator-treated patients across disease types (complicated intra-abdominal infection [cIAI], complicated urinary tract infection [cUTI], and nosocomial pneumonia [NP]). Of 1,830 baseline Enterobacteriaceae isolates, 88 (4.8%) were ESBLE and 238 (13.0%) were CIPRE. The incidence of ESBLE was greatest in Europe (7.8%); that of CIPRE was higher in South America (15.9%) and Europe (14.4%). ESBLE incidence was highest in NP (12.9%) cases; that of CIPRE was higher in cUTI (18.3%) and NP (14.9%) cases. Against ESBLE and CIPRE, carbapenems appeared more active than other antibiotic classes. Among carbapenems, doripenem and meropenem were most potent. Doripenem had low MIC90s for CIPRE (0.5 μg/ml) and ESBLE (0.25 μg/ml). Doripenem and comparators were highly clinically effective in infections caused by Enterobacteriaceae, irrespective of their ESBL statuses. The overall cure rates were the same for doripenem (82%; 564/685) and the comparators (82%; 535/652) and similar for ESBLE (73% [16/22] versus 72% [21/29]) and CIPRE (68% [47/69] versus 52% [33/64]). These findings indicate that doripenem is an important therapeutic option for treating serious infections caused by ESBLE and CIPRE.

Campylobacter bacteremia in children

OBJECTIVE To describe clinical and laboratory data for, and to propose pathogenesis and management of, children from impoverished communities with Campylobacter bacteremia. METHODS A retrospective review of patient data generated from laboratory records in an urban tertiary care hospital in Soweto and a rural mission hospital in Eastern Transvaal, South Africa. Participants were 19 children presenting to either hospital with Campylobacter bacteremia. Clinical and laboratory data were collated. RESULTS Nineteen children with Campylobacter bacteremia were identified; all isolates were Campylobacter jejuni. Sixteen (84%) had malnutrition; 13 of these were severely malnourished. Thirteen (68%) were febrile at the time of bacteremia. Four children (21%) did not have diarrhea. The case fatality rate was 16% and may not have been influenced by aminoglycoside administration. CONCLUSION Malnourished children may be more likely to have gastrointestinal C. jejuni infection. Immunodeficiency and intestinal mucosal compromise secondary to malnutrition may render such children at increased risk of C. jejuni bacteremia and its consequences. C. jejuni bacteremia is potentially life-threatening and should be managed accordingly.