Anders Lannergård

Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial

BACKGROUND Acute pyelonephritis is a common infection in adult women, but there is a paucity of controlled trials of its treatment and the optimum duration of antibiotic treatment has not been properly defined. We compared the efficacy of ciprofloxacin for 7 days and 14 days in women with community-acquired acute pyelonephritis. METHODS In a prospective, non-inferiority trial undertaken at 21 centres of infectious diseases in Sweden, women (aged ≥18 years) who were not pregnant and had a presumptive diagnosis of acute pyelonephritis were randomly assigned to oral treatment with ciprofloxacin 500 mg twice daily for 7 days or 14 days. The first week was open label. A computer-generated randomisation list in block sizes of two was used for treatment allocation in a 1:1 ratio. The study was double-blind and placebo-controlled during the second week of treatment, which was either continuation of ciprofloxacin 500 mg or placebo tablets twice daily according to the randomisation code. Patients, carers, site investigators, and trial coordinating centre staff were masked to group assignment. The primary endpoint was the clinical and bacteriological outcome 10-14 days after completion of treatment with active drug. Analysis was by per protocol. This trial is registered with EudraCT, number 2005-004992-39, and ClinicalTrials.gov, number ISRCTN73338924. FINDINGS 126 of 248 patients were randomly assigned to 7 days and 122 to 14 days of ciprofloxacin. 73 and 83 patients, respectively, were analysed. Short-term clinical cure occurred in 71 (97%) patients treated with ciprofloxacin for 7 days and 80 (96%) treated for 14 days (difference -0·9%; 90% CI -6·5 to 4·8; p=0·004; non-inferiority test). Cumulative efficacy at long-term follow-up was 93% in each group (68 of 73 vs 78 of 84; -0·3%; -7·4 to 7·2; p=0·015). Both regimens were well tolerated. Two patients discontinued ciprofloxacin because of myalgia with 7 days of treatment and itching exanthema with 14 days. Four (5%) of 86 patients assigned to 7 days of treatment who complied with study criteria and six (6%) of 93 assigned to 14 days reported an adverse event after the first week of treatment that was possibly or probably related to the study drug. In those assigned to 7 days, no patient had mucosal candida infection after the first week versus five treated for 14 days (p=0·036). INTERPRETATION Our results show that acute pyelonephritis in women, including older women and those with a more severe infection, can be treated successfully and safely with oral ciprofloxacin for 7 days. Short courses of antibiotics should be favoured in an era of increasing resistance. FUNDING Swedish Strategic Programme against Antibiotic Resistance (Strama).

Prevalence of polymorphisms with significant resistance to NS5A inhibitors in treatment-naive patients with hepatitis C virus genotypes 1a and 3a in Sweden

Abstract Background: The future treatment of hepatitis C virus (HCV) infection will be combinations of direct-acting antivirals (DAAs) that not only target multiple viral targets, but are also effective against different HCV genotypes. Of the many drug targets in HCV, one promising target is the non-structural 5A protein (NS5A), against which inhibitors, namely daclatasvir, ledipasvir and ombitasvir, have shown potent efficacy. However, since HCV is known to have very high sequence diversity, development of resistance is a problem against but not limited to NS5A inhibitors (i.e. resistance also found against NS3-protease and NS5B non-nucleoside inhibitors), when used in suboptimal combinations. Furthermore, it has been shown that natural resistance against DAAs is present in treatment-naïve patients and such baseline resistance will potentially complicate future treatment strategies. Methods: A pan-genotypic population-sequencing method with degenerated primers targeting the NS5A region was developed. We have investigated the prevalence of baseline resistant variants in 127 treatment-naïve patients of HCV genotypes 1a, 1b, 2b and 3a. Results: The method could successfully sequence more than 95% of genotype 1a, 1b and 3a samples. Interpretation of fold resistance data against the NS5A inhibitors was done with the help of earlier published phenotypic data. Baseline resistance variants associated with high resistance (1000–50 000-fold) was found in three patients: Q30H or Y93N in genotype 1a patients and further Y93H in a genotype 3a patient. Conclusion: Using this method, baseline resistance can be examined and the data could have a potential role in selecting the optimal and cost-efficient treatment for the patient.

Human serum amyloid A (SAA) and high sensitive C-reactive protein (hsCRP) in preterm newborn infants with nosocomial infections.

Human serum amyloid A (SAA) and high sensitive C‐reactive protein (hsCRP) and their relation to suggestive nosocomial infections (NIs) were investigated in very preterm (VPT) newborn infants.

The time course of body temperature, serum amyloid A protein, C-reactive protein and interleukin-6 in patients with bacterial infection during the initial 3 days of antibiotic therapy

The accuracy of using body temperature, serum amyloid A (SAA), C-reactive protein (CRP) and interleukin-6 (IL-6) in the work-up for early or late step-down therapy after an initial course of intravenous cefuroxime was investigated. Eighty-one hospitalized patients with an initial course of cefuroxime were retrospectively classified with one of the following diagnoses: bacterial infection without known focus, pneumonia, bronchitis, pyelonephritis, skin and soft-tissue infections or fever of other origin. The majority of the patients had sepsis (91% or 74/81) of whom 6 patients had severe sepsis. The inter-individual variability of body temperature, SAA, CRP and IL-6 was considerable. The time course of SAA and CRP during the first 24 h in patients with sepsis with a short duration of illness but without septic shock showed increasing levels during the initial course of intravenous therapy. In contrast, body temperature and IL-6 decreased, regardless of illness duration. Beyond 24 h, all 4 biomarkers declined, again regardless of the duration of illness. After the initial course of cefuroxime, biomarkers were non-distinguishing in terms of guidance in the judgement of early or late step-down therapy. Further studies are proposed for biomarker guidance antibiotic therapy in sepsis patients without septic shock.

Serum pentraxin 3 concentrations in neonates

Dear Editor, C-reactive protein (CRP) is one of the most commonly used diagnostic biomarkers in the clinical setting for diagnosing and monitoring of inflammatory and infectious diseases. However, in neonates several questions remain, regarding the interpretation of an increased serum CRP concentration during the first days of life in otherwise healthy newborns, especially in preterms (1). Pentraxins are endogenous substances that neutralize or eliminate a variety of pathogenic agents in concert with the complement system and macrophages. These complex biological responses to tissue injury, necrosis, infections, or immune-related diseases are part of the natural innate defence system (2). The pentraxin family consists of proteins with cyclic multimeric structures. The well-known acute-phase protein CRP belongs to the short members of the family, while pentraxin 3 (PTX3) belongs to the long counterparts. PTX3 is released from macrophages and endothelial cells among a great variety of other cell types in which the protein is synthesized and stored. On stimuli from primary inflammatory signal proteins, as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-α), and microbial lipopolysaccharides (LPS) as well as toll-receptor-mediated signals, PTX3 will be synthesized, and the serum concentration will increase up to 100-fold in 6–8 hours. Interleukin-6 (IL-6) is a weak inducer for PTX3 (3,4). PTX3 synthesis is thus produced close to the site of inflammation and is not dependent on cytokine production or liver function. All subjects in our study were recruited from the Department of Womens and Childrens Health, Uppsala University Hospital, Uppsala, Sweden. Three groups were included: umbilical venous cord blood collected from term healthy newborns (n = 36), venous blood from term healthy newborns at 3–7 days of age at phenylketonuria (PKU) testing (n = 11), and venous blood from very preterm (VPT) newborns at the neonatal supportive care unit (n = 40). The median gestational age and postnatal age were 26 weeks (range 23–31, IQR 4) and 27 days (range 4–103, IQR 26), respectively. The median birth weight was 954 g (range 422–2244, IQR 400). The study was approved by the local Ethical Review Board of Uppsala University. Serum PTX3 was determined by a commercial sandwich ELISA kit (DY1826, R&D Systems, Minneapolis, MN, USA), as described elsewhere (5). Serum concentrations of PTX3 in term healthy newborns were lower than in term healthy newborns at 3–7 days of age and VPT newborns at the supportive care unit (P < 0.0001) (Figure 1). VPT newborns showed a lower serum concentration of PTX3 than term healthy newborns at 3–7 days of age (P < 0.0001) (Figure 1). To our knowledge, no studies have presented such data before. Previous studies on serum amyloid A and high-sensitivity (hs) CRP reported gestational age-related differences, with higher concentrations in VPT compared with full-term healthy babies, during the neonatal period (6-8). A similar pattern seems to apply to PTX3. Because PTX3 may be a faster acute-phase protein that is not liver-dependent, it is probable that it is superior to traditional biomarkers for mirroring rapid inflammatory courses. Compelling indications are present that a high serum concentration of PTX3 predicts shock, poor outcome, and organ failure in meningococcal disease and severe sepsis, respectively, in children and adults (9,10). Figure 1. Serum concentrations in term healthy newborns (n = 36), term healthy newborns at 3-7 days of age (n = 11), and very preterm newborns (n = 40). A Kruskal–Wallis test was used for continuous three-group comparisons. Data were computed by Statistica ... The serum concentration of PTX3 in the cohort should be interpreted with care because a part of the sample was likely to have its origin from infants treated with antibiotics or with inflammatory reactions. It is important to remember that there is an extremely rapid foetal development up to the expected day of delivery. This means that there will be differences between a prematurely born child with a gestation age of 30 weeks from a child with a gestation age of 36 weeks. The cause of the prematurity may also involve inflammatory reactions which will further increase the variability in PTX3 values in samples from prematurely born babies. Nevertheless, the prematurely born cohort, despite the existence of possible factors that may influence the serum PTX3 concentration, could be representative for this group of newborn infants. In summary, serum PTX3 may be a promising acute-phase protein for interpretation of affected newborns with symptoms and signs of sepsis. Serum PTX3 is measurable in both term and preterm babies in similarity with other acute-phase proteins. Considering the promising results from studies in adult patients with sepsis, PTX3 might represent a helpful tool in diagnosis of sepsis in the neonate as well. The predictive value of PTX3 may thus be higher compared with conventionally used acute-phase proteins. However, regarding serum PTX3 concentrations in infants with infection we propose a prospective study on neonatal sepsis with well-defined established criteria.