Worldwide Control of Typhoid

World Health Organization. Typhoid vaccines: WHO position paper. Wkly Epidemiol Rec 2008; 83:49–59.

It is estimated that there are ∼21 million cases of typhoid fever annually in the world, with ∼90% occurring in Asia. Serious complications occur in 10% of cases, and as many as 4% of the infections are fatal, with most deaths occurring among children. The emergence of multidrug-resistant Salmonella enterica serotype Typhi (i.e., S. Typhi with resistance to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) has complicated the management of infection in countries where it is endemic. The more recent emergence of reduced susceptibility to fluoroquinolones is of further concern.

Two vaccines have replaced the older inactivated whole-cell vaccine: a live, orally administered Ty21 vaccine and an injectable Vi polysaccharide product. Each is capable of providing ∼70% protection. The Strategic Advisory Group of Experts on immunization of the World Health Organization has endorsed a position paper on the programmatic use of these vaccines to control endemic typhoid fever. This paper recommends consideration of implementation of a vaccine program with either the oral or injectable vaccine, with attention to high-risk groups and populations, as well as use of the vaccine for outbreak control. The decision to implement such a program should be based on knowledge of local epidemiology of typhoid and on the prevalence of antibiotic-resistant S. Typhi, as well as considerations of cost-effectiveness. School-aged and/or preschool-aged children are an important target population. Most importantly, “All typhoid vaccination programmes should be implemented in the context of other efforts to control the disease, including health education, water quality and sanitation improvements, and training of health professionals in diagnosis and treatment” (p. 51).

Doripenem Treatment of Ventilator-Associated Pneumonia

Chastre J, Wunderink R, Prokicimer P, et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study. Crit Care Med 2008; 36:1089–96.

Doripenem is a carbapenem with antipseudomonal activity that recently received the US Food and Drug Administration's approval for the treatment of complicated intraabdominal and urinary tract infections. It is also being considered as therapy for nosocomial pneumonia, including ventilator-associated pneumonia. In an open-label, multicenter trial, Chastre and colleagues randomized adults with ventilator-associated pneumonia to receive either doripenem (500 mg every 8 h via a 4-h infusion) or imipenem-cilastatin (100 mg every 8 h via a 30–60-min infusion) for 7–14 days. Vancomycin and/or an aminoglycoside could be added to the regimen at the discretion of the investigator but were to be discontinued if methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa were not subsequently identified. Among important reasons for exclusion from the study were infection with an organism resistant to either carbapenem, an APACHE II score at the extremes, adult respiratory distress syndrome, septic shock, end-stage renal failure, immunocompromise, and “any rapidly progressing disease or immediately life-threatening illness.”

Of the 525 randomized patients who received a study drug, 22.7% did not complete treatment, primarily because of the occurrence of adverse events or the need for nonstudy antibiotics. The APACHE II score was >15 for only 51.6% of the clinically evaluable population (only 47% of the randomized subjects), and the clinical pulmonary infection score (CPIS) was >7 for only 37.9% of patients. Doripenem was noninferior to imipenem, with clinical cure rates in the clinical modified intent-to-treat population (i.e., subjects who met entry criteria and received at least 1 dose of study drug) of 59.0% and 57.8%, respectively. Similarly, the clinical cure rate in the clinically evaluable population was 68.3% among doripenem recipients and 64.2% among imipenem recipients. A favorable microbiological response was achieved in 73.3% and 67.3% of doripenem and imipenem recipients, respectively.

Among the 20 patients with P. aeruginosa infection who received doripenem, 13 (65%) had a favorable clinical response, compared with 5 (35.7%) of the 14 who were given imipenem—a difference that was not statistically significant. It was not specifically stated whether these patients concomitantly used aminoglycosides, making the results difficult to interpret. A ⩾4-fold increase in the MIC was identified in subsequent P. aeruginosa isolates, with an MIC <8 µg/mL at baseline noted for 10 (35.7%) of 28 doripenem recipients and 10 (53%) of 19 imipenem recipients; most subsequent isolates were genotypically identical or closely related to their baseline counterparts.

Seizures occurred in 3 doripenem recipients (1.1%) and 10 imipenem recipients (3.8%) but were judged to be related to the study drug in only 1 subject, an imipenem-treated patient.

The crude mortality rates in the clinical modified intent-to-treat population for doripenem and imipenem recipients were 10.8% and 9.5%, respectively. These low mortality rates are consistent with the exclusion of high-risk patients and with the low APACHE II and CPIS scores in those enrolled. As a consequence, the applicability of these results to a sicker population can be questioned. However, analysis of clinically evaluable patients with APACHE II scores >20 (a score >29 was a criterion for exclusion from the study) at baseline identified clinical cure in 19 (70.4%) of 27 doripenem recipients and 15 (57.7%) of 26 imipenem recipients. Similarly, in a separate, apparently identically designed trial, clinical cure was achieved in 14 (78%) of 18 and 6 (43%) of 14 doripenem and imipenem recipients, respectively, with ventilator-associated pneumonia and APACHE II scores >22 [1].

The role of doripenem relative to the other 2 carbapenems with antipseudomonal activity (meropenem and imipenem) will be the subject of much discussion at Pharmacy and Therapeutics Committee meetings.

A New Mechanism of Resistance to Linezolid—And It's Transferable

Toh SM, Xiong L, Arias CA, et al. Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid. Mol Microbiol 2007; 64:1506–14.

Mendes RE, Deshpande LM, Castanheira M, et al. First report of cfr-mediated resistance to linezolid in human staphylococcal clinical isolates recovered in the United States. Antimicrob Agents Chemother 2008; 7 April [Epub ahead of print].

Mutations in the peptidyl transferase center of bacterial 23S rRNA result in reduced affinity of linezolid for the 50S subunit and thus interfere with the ability of this antibiotic to block the initiation of protein synthesis. Fortunately, resistance to linezolid among S. aureus isolates remains rare, at least in part because staphylococci carry 5–6 rRNA operons, and multiple copies must be mutated before significant resistance is expressed. The recent recognition of a novel mechanism of resistance to linezolid in staphylococcal isolates encoded by cfr on a transmissible plasmid raises concern of more-rapid spread of resistance to linezolid in this organism.

The cfr gene was originally described as encoding resistance to chloramphenicol. The gene product of cfr, a methyltransferase, adds a methyl group to bacterial 23S rRNA. This posttranslational methylation was previously demonstrated to cause resistance—not only to chloramphenicol, but also to antibiotics in other classes, including lincosamides, pleuromutilins, and streptogramin A. Although cfr had previously only been identified in staphylococci of animal origin, no human isolates with this gene had been identified. Unfortunately, 2 groups have now found this plasmid-mediated methyltranferase gene in staphylococcal isolates of human origin.

Toh and colleagues examined a linezolid-resistant S. aureus isolate recovered in 2005 from a hospitalized patient in Colombia. Although they were unable to identify the presence of mutations in either target site in the 23S rRNA, domain V, or protein L4, they did uncover the presence of a plasmid carrying cfr. They further demonstrated that introduction of cfr into a linezolid-susceptible methicillin-resistant S. aureus strain rendered it resistant to this oxazolidinone antibiotic.

More recently, linezolid-resistant S. aureus was isolated from an Ohio nursing home resident, and a similarly resistant Staphylococcus epidermidis isolate was recovered from an elderly resident of a long-term care facility in Arizona. Neither patient was known to have received linezolid. Examination of these isolates by Mendes and colleagues also identified the presence of cfr in each.

The emergence of staphylococcal resistance to linezolid, a totally synthetic antibiotic, has, to date, been slow to develop. The identification of cfr encoding a methyltransferase interfering with the activity of this and other antibiotics on 2 continents is worrisome, given the fact that it is present on a mobile genetic element capable of dissemination.

Effective Treatment Reduces the Incidence of Hepatic Failure in Patients with Advanced Chronic Hepatitis C Virus (HCV) Infection

Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007; 147:677–84.

Some evidence suggests that hepatic fibrosis in patients with chronic HCV infection may be diminished in patients with sustained virological response to treatment with pegylated IFN plus ribavirin. Although such responses have been found to be associated with a reduction in the incidence of hepatocellular carcinoma in Japan, similar benefit with regard to a reduction in the risk of hepatic failure has not been previously demonstrated. Veldt and colleagues retrospectively examined outcomes of 479 treated patients (59% of whom were infected with genotype 1) with biopsy-proven advanced fibrosis or cirrhosis, 29% of whom had a sustained virologic response to therapy. The median duration of follow-up was 2.1 years. Sustained virologic response was associated with a significant reduction in clinical events (i.e., death, hepatocellular carcinoma, and liver failure; adjusted hazard ratio, 0.21; 95% CI, 0.07–058; P=.003 with the benefit mostly the result of a reduction in the occurrence of hepatic failure.