A forgotten antibiotic, temocillin, led to lower selection of resistant bacteria than the standard treatment for febrile urinary tract infection, in a study published in The Lancet Infectious Diseases.
Thus, temocillin may be useful in treating severe urinary tract infections that give rise to fever, and contribute to a reduced spread of resistant bacteria in hospitals.
The bacterial species Escherichia coli (E. coli) constitutes a large fraction of the normal bacterial flora in the intestine. But if E. coli gets into the wrong places in the body, such as the blood or urinary tract, it can cause serious illness. E. coli is the most common cause of urinary tract infections.
These can often be treated with antibiotics in tablet form, but some patients become so ill that they must be admitted to hospital and treated with intravenous antibiotics.
“It has long been standard procedure to use the antibiotic cefotaxime for such intravenous treatment. But as time has passed, an increasing fraction of bacteria have become less susceptible to this antibiotic, both in Sweden and the rest of the world, and this has made it necessary to seek an alternative,” says Håkan Hanberger, professor at Linköping University and consultant in infectious diseases at Linköping University Hospital. He has been principal investigator and medically responsible for the study.
The study now published is the result of the Public Health Agency of Sweden being requested by the Swedish government to study how already existing antibiotics can be used in the best way. The researchers have investigated temocillin, a member of the penicillin group of antibiotics that has been known for several decades.
It is used in some other European countries, but is not marketed in Sweden. Temocillin acts specifically against E. coli and other intestinal bacteria that can cause urinary tract infections. It is positive that temocillin does not have a broad effect against many different bacteria, since it reduces the risk that the treatment will act against the normal intestinal bacterial flora.
This led the researchers to investigate whether temocillin gives less resistance among intestinal bacteria than treatment with the standard antibiotic, cefotaxime.
They studied 152 patients with urinary tract infection that gave rise to fever, also known as pyelonephritis, that required intravenous antibiotics.
“We saw clearly that the intestinal flora was less affected in the group treated with temocillin. The main reason for this is that temocillin gives less selection of resistant intestinal bacteria,” says Charlotta Edlund, professor of microbiology and specialist investigator at the Public Health Agency of Sweden.
The clinical effect of temocillin was as good as the standard treatment with cefotaxime, and the undesired effects were equivalent. The fact that temocillin is less aggressive against the bacterial flora in the intestine suggests that starting to use this forgotten antibiotic for urinary tract infections will have advantages for both patients and society.
“The consequence will be that we see less selection of resistant intestinal bacteria in hospitals, which may contribute to reducing hospital-related infections from these bacteria,” says Håkan Hanberger.
Enterobacterales commonly cause serious community-acquired and healthcare-associated infections. ESBLs are major causes of β-lactam (penicillin and cephalosporin) resistance in Enterobacterales. ESBLs are often expressed with other genes that confer fluoroquinolone and aminoglycoside resistance, further reducing treatment options. ESBLs are a growing problem globally, with dramatic increases in these resistant organisms occurring in both community and hospital settings.1
As a result, carbapenems are often used as treatment options for ESBL-producing Enterobacterales, but resistance to carbapenems among Gram-negative bacteria has also increased over the last decade. Outbreaks of carbapenem-resistant Enterobacterales (CRE) are associated with high costs and high mortality.2 It is therefore essential to consider non-carbapenem antimicrobial agents where possible.
Temocillin, a 6-alpha-methoxy derivative of ticarcillin, is a narrow spectrum β-lactam with activity against many Gram-negative bacteria, but not Gram-positive bacteria, anaerobes or Pseudomonas aeruginosa.3 It is licensed in the UK for the treatment urinary tract infections (UTIs) and lower respiratory tract infections (LRTIs) where susceptible Enterobacterales are suspected or confirmed.4
Temocillin is licensed at doses of 4–6 g/day (in 2–3 divided doses or via continuous infusion).5 A 2011 review of temocillin highlighted that the modal MIC for Enterobacterales was 4–8 mg/L (range 2–32 mg/L) with 90% of isolates susceptible at 16 mg/L, and that temocillin is stable against a variety of β-lactamases, including ESBLs (TEM, SHV, CTX-M), AmpC β-lactamases and KPC carbapenemases.6,7 Where susceptible, temocillin offers a useful alternative to carbapenems.
In 2020, EUCAST published clinical breakpoints for temocillin based on WT distribution, reducing the breakpoint for susceptible isolates to <0.001 mg/L. Those with an MIC of 0.001–16 mg/L are reclassified as ‘susceptible, increased exposure’ (I) and high-dose temocillin regimens are recommended (6 g/day).8 Previously BSAC guidance advised a breakpoint of 8 mg/L for systemic infection (or 32 mg/L for urine infections),9 which should be overcome by 4 g/day temocillin.
Implementation of the 2020 EUCAST breakpoint would necessitate high-dose temocillin (6 g/day) for the majority of clinical cases. This has significant financial impact on healthcare providers and may cause many centres in the UK to revert to low-cost carbapenems, driving further development of CRE. To understand current clinical utility at 4 g/day dosing, we undertook a single-centre retrospective observational analysis of the outcomes of patients prescribed temocillin.
At the study centre temocillin is included within the guidelines as empirical therapy for the treatment of UTIs; when the patient has a history of ESBL organisms susceptible to temocillin or is at high risk of such organisms. Other use is based on targeted therapy once a causative organism resistant to first line agents is known or based on the advice of the antimicrobial stewardship team when empirical therapy is failing.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210019/
More information: The clinical and microbiological efficacy of temocillin versus cefotaxime in adults with febrile urinary tract infection, and its effects on the intestinal microbiota: a randomised multicentre clinical trial in Sweden, The Lancet Infectious Diseases (2021). DOI: 10.1016/S1473-3099(21)00407-2