The challenges of antibiotic resistance: Key findings from recent studies

The emergence of antimicrobial resistance has increasingly impeded the management of a number of clinically important infections. Noteworthy examples include infections caused by penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), antibiotic resistant Pseudomonas aeruginosa, vancomycin-resistant enterococci (VRE), and fluoroquinolone-resistant Clostridium difficile.

Infections caused by MRSA, for instance, are occurring more frequently-in the community as well as in the hospital setting. Compared with infections caused by methicillin-susceptible S aureus (MSSA), MRSA infections are associated with longer hospital stays, higher mortality rates, and increased costs.^1-3 Similar adverse consequences have been observed in patients with other antimicrobial-resistant infections.

This Clinical Update sums up the findings of several recent studies on MRSA and other antibiotic resistant pathogens and discusses the antibiotic options.

RECENT STUDIES

CA-MRSA skin infections

According to a recent study, community-associated MRSA (CAMRSA) infection has emerged among the urban poor in Chicago.⁴ It appears to have occurred in addition to (rather than instead of) MSSA infection.

Hota and associates⁴ analyzed the risk factors for CA-MRSA skin and soft tissue infections (SSTIs) at a public hospital in Chicago. Of the 73 strains tested, 79% were type USA300 on pulsed-field gel electrophoresis. The incidence of CAMRSA SSTIs increased from 24 cases per 100,000 persons in 2000 to 164.2 cases per 100,000 in 2005 (relative risk, 6.84). The incidence of MSSA infections was stable during this period.

The risk factors for CA-MRSA infections included recent incarceration, African American ethnicity, and residence at certain public housing complexes. Overcrowding was not a risk factor. Older age was inversely associated with the risk of MRSA infections. The authors note that CA-MRSA may become endemic as it disseminates within communities.

CA-MRSA pneumonia

A report from the CDC emphasizes the importance of being on the alert for CA-MRSA pneumonia, particularly during the influenza season.⁵ This type of pneumonia often occurs in young, previously healthy persons, and it can be quickly fatal.

In December 2006 and January 2007, 10 cases of severe CA-MRSA pneumonia occurred in Louisiana and Georgia. These cases involved previously healthy persons, 5 of whom were younger than 15 years. MRSA was documented by specimens (usually sputum or blood) that were obtained from the patients less than 48 hours after hospitalization or arrival at the emergency department (ED). Its association with influenza was established by either laboratory testing or a diagnosis of influenza-like illness, which was defined as a temperature of 37.8°C (100°F) or higher, with cough and/or sore throat, in the absence of a known cause other than influenza.

Four of the patients had a documented history of MRSA SSTI or close contact with someone with an MRSA SSTI before the onset of pneumonia. Respiratory symptoms began a median of 3 days before recovery from MRSA, and 4 of the 6 patients who died did so within 4 days of the onset of respiratory symptoms. This suggests that influenza and MRSA infection probably occurred concomitantly.

MRSA bacteremia

Shurland and coworkers⁶ retrospectively studied 438 adults who had S aureus infection complicated by bacteremia. MRSA was documented in 193 (44%) of the patients. One hundred fourteen (26%) of the patients died of S aureus– related infection within 90 days of diagnosis. The mortality risk was higher for those with MRSA infection than for those with MSSA infection (relative risk, 1.7).

Patients with MRSA infections were older, had more comorbidities, and were more likely to have severe sepsis than those with MSSA infections. After adjusting for age, comorbidities, and the presence of pneumonia, the risk of S aureus–related death was higher among patients with MRSA infections (hazard ratio, 1.8).

Mupirocin resistance

The intranasal administration of mupirocin has been considered as a method of preventing nosocomial MRSA infections. However, a recent study of patients in a surgical ICU has documented a high rate of mupirocin resistance among MRSA isolates.⁷

Jones and colleagues⁷ analyzed 302 MRSA isolates from nasal swabs obtained from patients in a surgical ICU in St Louis. The incidence of resistance to mupirocin was 13.2%. The incidence of high level resistance was 8.6%. Patients colonized with mupirocin-resistant MRSA were more likely to have been admitted to the hospital in the previous year and were older, compared with patients colonized with mupirocin-susceptible MRSA. In addition, the in-hospital mortality rate was higher for those with mupirocin-resistant MRSA (33% vs 16%).

The investigators noted that the rate of mupirocin use in the hospital during the study period was fairly low-6.08 treatment-days per 1000 patient-days.

Pseudomonas pneumonia

P aeruginosa is a major cause of nosocomial infections, including ventilator-associated pneumonia (VAP). Effective management of pneumonia caused by this pathogen has been hindered by the increased incidence of multidrug resistance and limited treatment options.

Garnacho-Montero and associates⁸ conducted a retrospective, multicenter study that included 183 adults with VAP and respiratory cultures positive for P aeruginosa. The initial empirical antibiotic therapy was inappropriate in 40 patients. Compared with combination therapy, monotherapy was more likely to be inappropriate.

The mortality rate was significantly higher in patients who received inappropriate antibiotics, compared with those who received at least 1 antibiotic with in vitro activity against P aeruginosa (72.5% vs 23.1%; P < .05). Regression analysis indicated that the independent risk factors for mortality were inappropriate antibiotic therapy, age, and chronic cardiac insufficiency.

ESBL-producing Enterobacteriaceae

In-patient screening for colonization with extended-spectrum -lactamase (ESBL)-producing Enterobacteriaceae may be warranted in light of the considerable mortality and hospital costs associated with bacteremia caused by this pathogen. However, screening only high-risk patients may not be sufficient, according to a recent study by Reddy and colleagues.⁹

Over a 6-year period, they screened 17,872 hospitalized patients for rectal colonization with VRE and ESBL-producing Enterobacteriaceae. The patients were in units that were designated as high-risk.

The researchers found that the incidence of ESBL-producing Enterobacteriaceae colonization more than doubled during the study period, from 1.33% in 2000 to 3.21% in 2005. About 50% of the patients colonized with ESBL-producing Enterobacteriaceae were also colonized with VRE. The incidence of bacteremia associated with ESBL producing Enterobacteriaceae increased more than 4-fold during the study. Of the patients colonized with ESBL-producing Enterobacteriaceae, bacteremia subsequently developed in 8.5%.

The investigators also studied other patients at their hospital who had bacteremia due to ESBL-producing Enterobacteriaceae during the study period. They found that more than 50% of the cases of bacteremia occurred in patients who had not been screened. In these patients, bacteremia was diagnosed while they were hospitalized in low-risk medical units, when they were in the ED, or when they were transferred from an acute-care facility or long-term–care facility.

ADVANCES IN ANTIBIOTIC THERAPY

The emergence and escalation of antimicrobial resistance and the significant consequences of treatment failures have prompted the development of alternative therapies. Vancomycin has been widely used in the management of MRSA infections. However, vancomycin's limited tissue penetration, the emergence of isolates with reduced susceptibility, and reports of treatment failure underscore the need for other antibiotic choices.^10,11

Of equal importance is the need for new therapies for Gram-negative pathogens that have become increasingly resistant, such as P aeruginosa,Escherichia coli, and Enterobacter. Below is a brief summary of some of the newer treatment alternatives.

Daptomycin

This cyclic lipopeptide can be used to treat complicated skin and skin structure infections and bacteremia, including bacteremia with right-sided endocarditis, that are caused by MRSA (as well as those caused by other pathogens). Daptomycin has been demonstrated to be as effective as vancomycin in the treatment of these infections.^12,13 However, this antibiotic is not appropriate for the treatment of MRSA pneumonia.¹⁰

Doripenem

This parenteral carbapenem provides broad-spectrum coverage of Gram-positive, Gram-negative, and anaerobic pathogens, and-importantly-it provides coverage of some strains of P aeruginosa that are resistant to other antipseudomonal antibiotics. In addition, doripenem has been demonstrated to be more potent than imipenem against Enterobacteriaceae.¹⁴

Doripenem recently received approval for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. The use of doripenem in the treatment of nosocomial pneumonia, including VAP, is currently under regulatory review.

Ceftobiprole

This cephalosporin has a broad spectrum of activity against Gram-positive and Gram-negative bacteria. Ceftobiprole has been shown to be effective in the management of SSTIs caused by MRSA.^15,16 In one study of complicated SSTIs, the cure rate of ceftobiprole was 93.3%, with a cure rate of 91.8% against MRSA.¹⁵

Data presented at the 2007 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago demonstrated that ceftobiprole was active against daptomycin-resistant S aureus, CA-MRSA, and hospital-acquired MRSA isolates.^17,18 Ceftobiprole appears to have a low potential to select for resistance.¹⁹

Ceftobiprole is under regulatory review for the treatment of complicated skin and skin structure infections, including those caused by MRSA. The FDA has granted ceftobiprole fast-track status for the treatment of nosocomial pneumonia, including VAP, caused by suspected or proven MRSA.

Linezolid

This agent belongs to the oxazolidinone class of antimicrobials and is available for oral and intravenous administration. Linezolid is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections; nosocomial pneumonia caused by S aureus (including MRSA); complicated skin and skin structure infections caused by S aureus (including MRSA), Streptococcus pyogenes, or Streptococcus agalactiae; and some forms of community-acquired pneumonia. Recently, Micek¹⁰ suggested that linezolid might be considered for the treatment of CA-MRSA pneumonia.

In patients who have complicated SSTIs caused by MRSA, treatment with linezolid results in higher clinical cure rates and shorter duration of hospitalization, compared with the use of vancomycin. ^20,21 There is evidence that the survival rate is higher in patients with MRSA nosocomial pneumonia who are treated with linezolid than in patients who are treated with vancomycin.²²

Tigecycline

This intravenous antibiotic is in the class of glycylcyclines. It has broadspectrum activity against Gram-negative organisms, including enterococci and Enterobacteriaceae, and resistant Gram-positive organisms, including MRSA. Tigecycline has been shown to be effective in the treatment of intra-abdominal infections and complicated SSTIs.

Garrison and Nuemiller²³ recently reported that tigecycline has in vitro activity against fluoroquinolone-resistant S pneumoniae, MRSA, and VRE. Bouchillon and associates²⁴ evaluated the minimal inhibitory concentration (MIC) of tigecycline in more than 34,000 clinical isolates obtained from sites in 30 countries. Over a 3-year period, there was no shift in MIC values from tigecycline's pre-marketing values. Activity was maintained even against strains that were resistant to other antimicrobials, including MRSA, VRE, and penicillin-resistant S pneumoniae.

Tigecycline has been approved for the treatment of complicated skin and skin structure infections caused by MRSA (as well as for complicated skin and skin structure infections caused by other pathogens and for complicated intra-abdominal infections).^25,26

References:

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