Peter B. Ward

Treatment Outcomes for Serious Infections Caused by Methicillin-Resistant Staphylococcus aureus with Reduced Vancomycin Susceptibility

Although infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility (SA-RVS) have been reported from a number of countries, including Australia, the optimal therapy is unknown. We reviewed the clinical features, therapy, and outcome of 25 patients with serious infections due to SA-RVS in Australia and New Zealand. Eight patients had endocarditis, 9 had bacteremia associated with deep-seated infection, 6 had osteomyelitis or septic arthritis, and 2 had empyema. All patients had received vancomycin before the isolation of SA-RVS, and glycopeptide treatment had failed for 19 patients (76%). Twenty-one patients subsequently received active treatment, which was effective for 16 patients (76%). Eighteen patients received linezolid, which was effective in 14 (78%), including 4 patients with endocarditis. Twelve patients received a combination of rifampicin and fusidic acid. Surgical intervention was required for 15 patients (60%). Antibiotic therapy, especially linezolid with or without rifampicin and fusidic acid, in conjunction with surgical debulking is effective therapy for the majority of patients with serious infections (including endocarditis) caused by SA-RVS.

Clinical Features Associated with Bacteremia Due to Heterogeneous Vancomycin-Intermediate Staphylococcus aureus

We assessed all episodes of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia at our hospital during a 12-month period (n=53) and compared those due to heterogeneous vancomycin-intermediate S. aureus (hVISA; n = 5, 9.4%) with those due to vancomycin-susceptible MRSA (n=48). Patients with hVISA bacteremia were more likely to have high bacterial load infections (P=.001), vancomycin treatment failure (persistent fever and bacteremia for >7 days after the start of therapy; P<.001), and initially low serum vancomycin levels (P=.006). These clinical markers of hVISA bacteremia may help focus diagnostic efforts and treatment.

Isolates with Low-Level Vancomycin Resistance Associated with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia

ABSTRACT Low-level vancomycin-resistant Staphylococcus aureus (vancomycin-intermediate S. aureus [VISA] and heterogenous VISA [hVISA]) is increasingly reported and leads to glycopeptide treatment failure. Various phenotypic features have been reported for these isolates, but the genetic changes leading to hVISA and VISA have yet to be clearly determined. We assessed phenotypic, antibiotic resistance, and genomic changes by using genomic DNA microarray comparison and sequencing of selected loci in five pairs of clinical hVISA/VISA strains and the initial methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained prior to vancomycin therapy. The isolates were from adult patients in Australia and New Zealand who had persistent MRSA bacteremia (>7 days) while receiving vancomycin therapy. In all cases, the initial isolates were found to be fully vancomycin-susceptible Staphylococcus aureus (VSSA). The hVISA/VISA phenotype was associated with increased cell wall thickness, reduced autolytic activity in four of five hVISA/VISA strains, and a striking reduction in biofilm formation compared to the parent strains in all pairs. All five pairs appeared to be isogenic, and genomic DNA microarray comparison suggested that major genetic changes are not required for the development of the resistant phenotype in these strains. No sequence differences were found in the agr locus or the tcaRA genes for any pair, but a marked reduction in RNAIII expression was found in four pairs. In summary, hVISA/VISA arises from fully VSSA during persistent infection that fails to respond to glycopeptide therapy and is associated with significant phenotypic changes, including a marked reduction in biofilm-forming ability. These clinically derived pairs of isolates will be a useful resource to elucidate the genetic mechanism of resistance in hVISA/VISA strains.

Genomic Analysis Reveals a Point Mutation in the Two-Component Sensor Gene graS That Leads to Intermediate Vancomycin Resistance in Clinical Staphylococcus aureus

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA), once restricted to hospitals, is spreading rapidly through the wider community. Resistance to vancomycin, the principal drug used to treat MRSA infections, has only recently emerged, is mainly low level, and characteristically appears during vancomycin therapy (vancomycin-intermediate S. aureus [VISA] and hetero-resistant VISA). This phenomenon suggests the adaptation of MRSA through mutation, although defining the mutations leading to resistance in clinical isolates has been difficult. We studied a vancomycin-susceptible clinical MRSA isolate (MIC of 1 μg/ml) and compared it with an isogenic blood culture isolate from the same patient, despite 42 days of vancomycin treatment (MIC of 4 μg/ml). A whole-genome sequencing approach allowed the nearly complete assembly of the genome sequences of the two isolates and revealed only six nucleotide substitutions in the VISA strain compared with the parent strain. One mutation occurred in graS, encoding a putative two-component regulatory sensor, leading to a change from a polar to a nonpolar amino acid (T136I) in the conserved histidine region of the predicted protein. Replacing the graS allele of the vancomycin-susceptible parent strain with the graS allele from the VISA derivative resulted in increased vancomycin resistance at a level between those of the vancomycin-susceptible S. aureus and VISA clinical isolates, confirming a role for graRS in VISA. Our study suggests that MRSA is able to develop clinically significant vancomycin resistance via a single point mutation, and the two-component regulatory system graRS is a key mediator of this resistance. However, additional mutations are likely required to express the full VISA phenotype.

Prospective comparison of the clinical impacts of heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-susceptible MRSA.

ABSTRACT Although methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (RVS-MRSA; including vancomycin-intermediate S. aureus [VISA] and heterogeneous VISA [hVISA]) have been linked with vancomycin treatment failure, it is unclear whether they are more pathogenic than vancomycin-susceptible MRSA (VS-MRSA). We prospectively assessed patients with clinical MRSA isolates during a 10-month period to determine clinical status (infection versus colonization) and therapeutic outcome before correlating these findings with the results of detailed in vitro assessment of vancomycin susceptibility, including population analysis profile (PAP) testing. hVISA and VISA were defined by standard PAP criteria (area-under-the-curve ratio compared to that of the reference hVISA strain Mu3 [≥0.9]) and routine CLSI criteria (vancomycin MIC, 4 to 8 μg/ml), respectively. Among the 117 patients assessed, 58 had RVS-MRSA isolates (56 hVISA and 2 VISA) and 59 had VS-MRSA isolates; the patient demographics and comorbidities were similar. RVS-MRSA was associated with a lower rate of infection than VS-MRSA (29/58 versus 46/59; P = 0.003), including a lower rate of bacteremia (3/58 versus 20/59, respectively; P < 0.001). The cure rates in RVS-MRSA and VS-MRSA groups were not statistically different (16/26 versus 31/42; P = 0.43), but the post hoc assessment of treatment regimes and study size made detailed conclusions difficult. The results of the macro method Etest correlated well with the PAP results (sensitivity, 98.3%, and specificity, 91.5%), but broth microdilution and our preliminary RVS-MRSA detection method correlated poorly. All isolates were susceptible to linezolid and daptomycin. These data suggest that detailed prospective laboratory identification of RVS-MRSA isolates may be of limited value and that, instead, such in vitro investigation should be reserved for isolates from patients who are failing appropriate anti-MRSA therapy.

Daptomycin non-susceptibility in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA): implications for therapy after vancomycin treatment failure

OBJECTIVES The aim of this study was to establish the relationship between reduced vancomycin and daptomycin susceptibility among Australasian vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA) isolates from patients never exposed to daptomycin. METHODS Forty-seven stored clinical isolates of hVISA/VISA collected before November 2008 from around Australia and New Zealand were selected. Daptomycin and vancomycin MIC testing was performed using broth microdilution (BMD) and Etest methods. Daptomycin population analysis was performed on a subset of isolates. RESULTS The percentage of daptomycin non-susceptible isolates was 0% for vancomycin-susceptible S. aureus (VSSA) (Etest and BMD), for hVISA it was 26% by Etest and 15% by BMD, and for VISA 62% by Etest and 38% by BMD. Population analysis profile testing demonstrated daptomycin heteroresistance among the hVISA and VISA strains tested. CONCLUSIONS This is the highest rate of daptomycin non-susceptibility reported among hVISA isolates to date. Clinicians should exhibit caution when using daptomycin in situations where serious hVISA or VISA infection is a possibility.

Faecal microbiota transplantation for severe Clostridium difficile infection in the intensive care unit.

We describe a case of faecal microbiota transplantation (FMT) used for severe binary toxin-positive Clostridium difficile infection in an intensive care setting. The patient was admitted to the ICU of a tertiary hospital and failed traditional maximal pharmacological management. Adjunctive therapy with FMT given through gastroscopy resulted in resolution of the C. difficile-related symptoms. Although there is a growing experience with FMT for recurrent C. difficile infection, published evidence in severe disease is very limited. In a landscape of increasingly severe C. difficile infection, adjunctive FMT may be considered a useful early treatment option.

Severe Bordetella holmesii Infection in a Previously Healthy Adolescent Confirmed by Gene Sequence Analysis

We describe an immunocompetent adolescent who presented with exceptionally severe Bordetella holmesii infection, including previously undescribed manifestations. Sequelae included a severe restrictive lung defect due to pulmonary fibrosis.

Campylobacter upsaliensis gastroenteritis in childhood.

BACKGROUND Campylobacter upsaliensis can cause gastroenteritis and bacteremia. Data on its epidemiology and role in pediatric gastroenteritis are limited. OBJECTIVE To describe the incidence and clinical features of enteric C. upsaliensis infection in children and to compare these with similar data for Campylobacter jejuni. DESIGN AND METHODS Medical records of all patients with enteric C. upsaliensis infection between 1992 and 1999 at the Royal Childrens Hospital, Melbourne, were reviewed. A case-control study (age-matched 1:2) was performed to compare the severity of clinical disease and associated risk factors for infection with C. upsaliensis and C. jejuni. RESULTS Of 18,516 specimens 666 (3.6%) were positive for C. jejuni and 19 (0.1%) were positive for C. upsaliensis. Records were available for 18 patients with C. upsaliensis gastroenteritis (mean age, 1.6 years; median age, 1.3 years; range, 3 months to 7 years; 14 male). Eleven patients (61%) presented with acute and 7 (39%) with chronic or intermittent diarrhea. The case-control study showed that fever (P = 0.03), acute diarrhea (P = 0.05) and rectal bleeding (P = 0.0006) were significantly less common in C. upsaliensis than in C. jejuni infection. CONCLUSION C. upsaliensis is a rare cause of gastroenteritis in young children and, compared with C. jejuni infection, is associated with significantly lower rates of fever, acute diarrhea and rectal bleeding.

Brachyspira aalborgi infection in four Australian children

Aim: The clinical presentation of four children and adolescents (two males and two females with a mean age of 12.4 years; range 9–16 years) with colorectal spirochetosis is discussed.