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Third, experimental pitfalls that may result in bimodal killing should be ruled out. One of the most common reasons for a decrease in the killing rate is degradation of the drug with time. Therefore, it is important to test that the killing efficacy of the drug itself does not decrease with time because of natural degradation of the drug, uptake by bacteria or changes in the medium.

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Another reason for survival of some bacteria may be their adhesion to the walls of the culture vessel 38 , where the antibiotic may not efficiently kill them. Finally, in addition to clearly stating in which conditions the time-kill assay is performed, care should be given to the recovery conditions, when bacteria are allowed to grow after removal of the antibiotic. The precise conditions for the evaluation of survival after treatment should be described, such as the washing out of the antibiotics, the medium in which the bacteria are recovered and the time that has passed from the exposure to the antibiotics until the exposure to the recovery conditions.

For example, it has been shown that keeping the bacteria in non-growing conditions after treatment may increase their survival In addition, bacteria recovering from an antibiotic treatment may have a delayed regrowth either because they are in the tail of the lag time distribution 26 , 40 or because of the post-antibiotic effect 41 , 42 , which results in the delayed growth of bacteria after treatment. As the trigger is an integral part of triggered persistence, the trigger duration, intensity and exact conditions should be clearly mentioned and kept the same between experiments.

For example, one of the most common triggers of persistence is starvation. This overnight culture has been exposed to several stress signals during starvation, such as high cell density, stringent response and altered pH, that may trigger persistence, and therefore inevitably still contains bacteria that experienced a trigger.

In this example of triggered persistence, the persistence level will depend strongly on several parameters, including the size of the inoculum, the time that has elapsed since the inoculum was regrown and the duration of starvation during the previous overnight culture 26 , Typically, to obtain reproducible results, the time between the trigger for persistence and the exposure to antibiotics should be minimized to avoid the uncontrolled loss of persister bacteria that switch back to normal cells.

The conditions for measuring drug-induced persistence are the same as for measuring spontaneous persistence, namely, steady-state growth, as the trigger is the drug itself and should be applied in steady-state conditions to avoid stationary-phase-induced persistence. Without further characterizations, the spontaneous and drug-induced persistence are difficult to distinguish.

In this case, direct observation of single cells as they respond to the antibiotics is needed 43 , 44 , or a dissection of the molecular mechanism that allows the bacteria to respond to the drug by activating a stress response Earlier attempts to characterize drug-induced tolerance or drug-induced persistence made use of the minimum bactericidal concentration MBC The MBC is the concentration required to kill bacteria.

Some drugs may arrest the growth at the MIC but require a higher concentration to kill. If the drug itself induces persistence at the MIC, a higher concentration may be required to reach killing. In contrast to triggered persistence, which is determined by the history of the culture, the rare spontaneous persistence should be measured in conditions of steady-state also called balanced growth so as to avoid the effect of the past growth conditions. This measurement can be achieved in a chemostat or by subdiluting the culture several times 37 before performing the time-kill assay, making sure to dilute the inoculum to below the persistence level As spontaneous persistence is a steady-state phenomenon, care should be taken to evaluate whether the culture remains in steady-state growth, also after the inoculum influence has been ruled out.

For example, a common pitfall is to perform the time-kill assay without diluting and subculturing the bacteria for enough time to eliminate the persister bacteria triggered by past stationary phase growth. Another common pitfall is to perform the time-kill assay when the culture is too close to the next stationary phase, which again may trigger the formation of persister cells. Even if the culture seems to be growing exponentially, it may no longer be in balanced growth and persister formation may be already triggered at a cell density that is ten times lower than the maximal density The spontaneous persistence fraction should remain constant with time in steady-state growth conditions.

A simple way to test that the results do not depend on the cell density is to perform the same experiment at a twofold lower density and verify that the persistence fraction remains the same. An inherent part of the persistence phenomenon is the ability of persisters to eventually resume growth. As evidenced by the low killing rate displayed in the second phase of biphasic killing curves Fig. Only persisters resuming growth after cessation of the antibiotic treatment will give rise to a new population of susceptible bacteria.

Single-cell observation often shows non-growing cells that remain intact during exposure to the drug. However, regrowth must be documented 30 to illustrate that bacteria have survived exposure to the drug before those can be dubbed persisters. There has been a sharp increase in the interest for antibiotic persistence in the past years in the background of growing concerns about antimicrobial resistance. The observation that triggered persistence evolves fast in vitro 46 , 47 and can be followed by the evolution of resistance 48 suggests that persistence may be evolving quickly in the host as well.

Indeed, even in the absence of any antibiotic resistance, many bacterial infections are hard to treat and tend to relapse such as tuberculosis, lung infections in people with cystic fibrosis, systemic infections with Salmonella , tonsillitis and urinary tract infections. The underlying reasons are most likely multifactorial, with suboptimal pharmacodynamics in the host probably playing a major role in some instances.

However, it is also clear that non-growing bacteria 29 and high-persister-forming mutants are selected over time in patients exposed to repeated doses of antibiotics 49 , Further work is needed to evaluate the possible impact of persister cells on the treatment outcome of bacterial infections and to find ways to fight them As seen above, many pitfalls exist even for in vitro analysis of persistence, and controlling the experimental conditions is crucial. The understanding of persistence in the host, in which our knowledge of the conditions is scarce, is orders of magnitude more challenging 51 , It is our hope that the guidelines outlined in this article will enable a consensus on in vitro measurements and pave the way for designing protocols adapted to the clinical evaluation of antibiotic persistence.

This has now been corrected in all versions of the Review. The publisher apologizes to the authors and to readers for this error. Hobby, G. Observations on the mechanism of action of penicillin. NY 50 , — Bigger, J. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet , — Brauner, A. Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nataro, J. Fisher, R. Persistent bacterial infections and persister cells. Ernst, J. Mechanisms of M. Cell Host Microbe 24 , 34—42 Blango, M.

Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Agents Chemother. Mulvey, M. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Lewis, K. Persister cells, dormancy and infectious disease. Jacoby, G. Du, D. Multidrug efflux pumps: structure, function and regulation. Blair, J. Molecular mechanisms of antibiotic resistance.

Wolfson, J. Mutants of Escherichia coli K exhibiting reduced killing by both quinolone and beta-lactam antimicrobial agents. El-Halfawy, O. Antimicrobial heteroresistance: an emerging field in need of clarity. Meylan, S. Targeting antibiotic tolerance, pathogen by pathogen. Cell , — Handwerger, S.


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Antibiotic tolerance among clinical isolates of bacteria. Ackermann, M. A functional perspective on phenotypic heterogeneity in microorganisms. Rotem, E. Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Natl Acad. USA , — Huang, G.

Accurate analytic solution of chemical master equations for gene regulation networks in a single cell. E 97 , Moyed, H. Levin, B. Persistence: a copacetic and parsimonious hypothesis for the existence of non-inherited resistance to antibiotics. Michiels, J. Molecular mechanisms and clinical implications of bacterial persistence. Drug Resist. Radzikowski, J. Bacterial persistence from a system-level perspective. Balaban, N. Bacterial persistence as a phenotypic switch. Science , — Joers, A. The frequency of persisters in Escherichia coli reflects the kinetics of awakening from dormancy.

Levin-Reisman, I. Paracetamol can be prescribed for analgesia; non-steroidal anti-inflammatory drugs NSAIDs or opioids are not recommended as they may increase the risk of complications and recurrence. Consider initiating antibiotic treatment at a follow-up assessment for patients with worsening or persistent symptoms.

Patients with suspected complicated diverticulitis, e. Referral to, or discussion with, a clinician in secondary care is appropriate for patients who are immunocompromised, pregnant, vomiting or unable to tolerate oral liquids, or have significant co-morbidities. Bacteroides fragilis, Escherichia coli, Clostridium and Fusobacterium species ; however, it is thought that uncomplicated diverticulitis may have a primarily inflammatory, rather than infectious, basis. Amoxicillin clavulanate. Antibiotic treatment is recommended for people who have tested positive for giardia, and for symptomatic contacts.

Secondary lactose intolerance often occurs after giardiasis; patients with ongoing symptoms after treatment can consider temporarily avoiding lactose-containing foods e. Nitazoxanide hospital treatment may be considered for recurrent treatment failures. Antibiotic treatment is usually unnecessary and may prolong excretion. Antibiotic treatment is, however, recommended for adults with severe disease, those who are immunocompromised and those with prosthetic vascular grafts. Discuss appropriate treatment for infants with a paediatrician; those aged months may not, depending on clinical state.

People typically remain infectious to others for several days to weeks after onset of symptoms; children may remain infectious for up to one year. However, with or without antibiotic treatment, spread to others is very rare. Antibiotic treatment is recommended for women who are symptomatic, pregnant or if an invasive procedure is planned, e. Approximately half of women found to have bacterial vaginosis are asymptomatic; antibiotic treatment is not necessary in these cases if there are no other risk factors.

Treatment of male sexual contacts is not usually necessary. Adult: mg, twice daily, for seven days, or 2 g, stat, if adherence to treatment is a concern although this dose is associated with a higher relapse rate. Advise avoidance of unprotected sexual intercourse for seven days after treatment has been initiated, and for at least seven days after any sexual contacts have been treated, to avoid re-infection. A test of cure should be done five weeks after initiation of treatment in pregnant women, if a non-standard treatment has been used, e.

Repeat STI screen in three months. Doxycycline if symptomatic urethritis, rectal or oral infection or alternative required. Do not use in women who are pregnant or breastfeeding. Amoxicillin alternative for pregnant women if azithromycin contraindicated. Antibiotic treatment is required for all patients with suspected epididymo-orchitis and their sexual contacts within the last three months. Epididymo-orchitis may occur due to a variety of pathogens; STI pathogens are more likely in males aged Test for chlamydia, gonorrhoea and urinary tract infection; empirical treatment should be given while awaiting results.

If symptoms are initially severe or signs and symptoms do not resolve or worsen after 24 to 48 hours, refer to hospital. Advise avoidance of unprotected sexual intercourse for two weeks after treatment has been initiated, and for at least seven days after any sexual contacts have been treated, to avoid re- infection. Majority due to Chlamydia trachomatis or Neisseria gonorrhoeae. Also E. Advise avoidance of unprotected sexual intercourse for seven days after treatment has been initiated, and for at least seven days after any sexual contacts have been treated, to avoid re- infection.

A test of cure should be done five weeks after initiation of treatment in pregnant women, or if a non-standard treatment has been used or if symptoms do not resolve.

National Antibiotic Guideline (NAG), 2nd Edition

As co-infection with chlamydia is very common, azithromycin is also routinely given. Hospital admission may be required for IV antibiotics. Advise abstinence from sexual intercourse until abdominal pain has settled and avoidance of unprotected sexual intercourse for 14 days after treatment has been initiated, and for at least seven days after any sexual contacts have been treated, to avoid re-infection.

Adult: mg, twice daily, for 14 days metronidazole may be discontinued if not tolerated. Empiric treatment may be commenced while awaiting laboratory results. Due to low sensitivity, culture of urethral swabs is rarely positive in males, even if infection is present. Antibiotic treatment is required for males who are symptomatic and their sexual contacts within the last three months.

Non-specific urethritis is a diagnosis of exclusion. A urethral swab and first void urine sample should be taken to exclude gonorrhoea and chlamydia or use combination testing if available. Patients with symptoms persisting for more than two weeks, or with recurrence of symptoms, should be referred to a sexual health clinic or urologist. Urethritis not attributable to Neisseria gonorrhoeae or Chlamydia trachomatis is termed non-specific urethritis and there may be a number of organisms responsible, e.

Ureaplasma urealyticum, Mycoplasma genitalium, Trichomonas vaginalis. If purulent discharge, treat as for gonorrhoea, i. Azithromycin if adherence is a concern or an alternative is required. Antibiotic treatment is indicated for adults with symptoms and signs of cystitis lower urinary tract infection. Urine culture is not necessary to diagnose cystitis. Urine culture is most useful for confirming the presence of significant bacteriuria and reporting on bacterial susceptibility to antibiotics in infections that are considered to be complicated due to an abnormality of the urinary tract or an underlying condition or clinical circumstance; this includes:.

Urine culture is not recommended in asymptomatic people. However, if bacteriuria is incidentally found to be present, this only requires antibiotic treatment in pregnant women. Escherichia coli, Staphylococcus saprophyticus, Proteus spp. Adult: mg, once daily, for three days avoid during the first trimester of pregnancy.


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  • Cefalexin - only if infecting organism known to be susceptible, and resistant to the other choices. If susceptibility testing indicates resistance to commonly available antibiotics, discuss treatment with a clinical microbiologist or infectious diseases specialist; alternative antimicrobials may be available in some DHBs.


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    • Antibiotic treatment oral is indicated for children aged over six months, without known renal tract abnormalities, and who do not have acute pyelonephritis. Refer children aged under six months, those with severe illness, or those with recurrent infection, to hospital for treatment. All children with suspected urinary tract infection should have a urine sample for culture collected clean catch, catheter, midstream urine as it may be a marker for previously undetected renal malformations, particularly in younger children.

      For information on collecting a urine specimen in children, see: " Managing urinary tract infections in children ", BPJ 44 May, Antibiotic treatment oral is required for all patients with mild symptoms of pyelonephritis upper urinary tract infection ; patients with more severe symptoms e. Urine culture is recommended for all patients with suspected pyelonephritis. Renal tract ultrasound may also be appropriate depending on the clinical situation. In most cases, patients with severe infection would be referred to hospital for treatment. The information in this publication is specifically designed to address conditions and requirements in New Zealand and no other country.

      BPAC NZ Limited assumes no responsibility for action or inaction by any other party based on the information found in this publication and readers are urged to seek appropriate professional advice before taking any steps in reliance on this information. What's changed? If you would like to know what changes were made when the article was updated please contact us. We have now added the ability to add replies to a comment. Simply click the "Reply to comment" button and complete the form. Your reply, once signed off, will appear below the comment to which you replied if multiple replies to a comment, they will appear in order of submission.

      Purely Paediatrics – Basis for Recommendations

      You can still add a fresh comment by scrolling to the bottom of the discussion and clicking the "Add a comment" button. If someone adds a reply to one of your comments or replies you will recieve an email notifying you of this. You can opt out of or into if currently out all comment notification emails by clicking the button below. Made with by the bpac nz team. Hello there! Remember me. Antibiotic resistance and stewardship Infections. Log in. General principles of antimicrobial stewardship: In most cases, only prescribe antibiotics for bacterial infections if: Symptoms are significant or severe There is a high risk of complications The infection is not resolving or is unlikely to resolve Select the first-line indicated antibiotic at the recommended dose and duration Reserve broad spectrum antibiotics for indicated conditions only Prioritise consideration of antibiotic resistance over palatability issues and convenience of dosing regimens when deciding which antibiotic to prescribe Educate patients about responsible use of antibiotics, including when an antibiotic is not indicated Information on national antimicrobial resistance patterns is available from the Institute of Environmental Science and Research Ltd ESR , Public Health Surveillance: www.

      Dental infections Due to popular request, we have created a new chapter in the Guide for dental infections. Diverticulitis We have added a new topic in the gastrointestinal chapter of the Guide on the management of diverticulitis. Genito-urinary chapter update The New Zealand Sexual Health Society has recently released an update of its management guidelines for sexually transmitted infections September, Common pathogens.

      Antibiotic treatment - Pertussis symptoms. However, the benefits of treating pertussis outweigh this risk; azithromycin is the preferred macrolide during pregnancy, lactation and in infants aged. Antibiotic treatment is appropriate for all adults with suspected pneumonia. Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, Staphylococcus aureus , respiratory viruses N.

      Antibiotic treatment - Suspected or confirmed pneumonia. Amoxicillin Adult: mg - 1 g, three times daily, for five to seven days If atypical organisms are suspected, e. Antibiotic treatment is appropriate for all children with suspected pneumonia. Erythromycin Child: 10 — Ear, nose and throat Otitis externa - acute Management. Antibiotic treatment topical should only be considered if secondary infection is present. First-line management is gentle cleansing of the external ear canal, e.

      Antibiotic treatment - Otitis externa with secondary infection. Antibiotic treatment is usually unnecessary as most infections are self-limiting. Antibiotic treatment - Otitis media in child with risk factors or recurrent infection. Antibiotic treatment is not required in the majority of cases. Antibiotic treatment - Persistent or severe sinusitis. Eyes Conjunctivitis Management. Antibiotic treatment - Severe bacterial conjunctivitis. Dental Dental abscess Management. People with any of the following are considered to be at high risk of developing infective endocarditis: A prosthetic heart valve, either biological or mechanical Rheumatic valvular heart disease Previous endocarditis Unrepaired cyanotic congenital heart disease or a repair procedure within the last six months Cardiac shunts or conduits for palliation People at high-risk of endocarditis do NOT require prophylactic antibiotic if they are undergoing any of the following: Routine dental anaesthetic injections through non-infected tissue Dental x-rays Placement of removable prosthodontic or orthodontic appliances Adjustment of orthodontic appliances Placement of orthodontic brackets Losing deciduous teeth Treatment of bleeding caused by trauma to the lips or oral mucosa People at high risk of developing infective endocarditis who are undergoing general anaesthesia will generally be managed in a secondary care setting.

      Meningococcal disease is notifiable on suspicion. Antibiotic treatment - Suspected meningitis or meningococcal septicaemia. Skin Bites — human and animal Management.

      Summary of antimicrobial prescribing guidance - managing common infections

      Clean and debride the wound thoroughly and assess the need for tetanus immunisation. Refer to hospital if there is bone or joint involvement. Antibiotic treatment - Infected bite or prophylaxis if risk factors. Staphylococcus aureus Consider MRSA if there is a lack of response to flucloxacillin, another penicillin or cephalosporin. Flucloxacillin Child: Antibiotic treatment - Mild to moderate cellulitis. Antibiotic treatment is not recommended for prevention of diabetic foot infections.

      Antibiotic treatment - Infected foot wound in adult with diabetes. Streptococcus pyogenes, Staphylococcus aureus. Antibiotic treatment is required for severe, worsening or persistent symptoms. Antibiotic treatment - Severe or non-resolving mastitis. Flucloxacillin Adult: mg, four times daily, for days. Erythromycin Adult: mg, four times daily, for days Cefalexin Adult: mg, four times daily, for days N. Gastrointestinal Campylobacter enterocolitis Management.

      Mechanisms and Classification of Antibiotics (Antibiotics - Lecture 3)

      Campylobacter enterocolitis is a notifiable disease. Antibiotic treatment - Severe or prolonged campylobacter enterocolitis or high risk. Ciprofloxacin Adult: mg, twice daily, for five days not recommended for children. Antibiotic treatment - Confirmed C. Metronidazole Adult: mg, three times daily, for 10 days. Vancomycin If patient has not responded to two courses of metronidazole; discuss with an infectious diseases physician or clinical microbiologist. Antibiotic treatment - persistent uncomplicated diverticulitis. People can remain infectious to others for up to several months after onset of symptoms.

      Resistance to antimicrobials is complex and increasing. Combined with a lack of new antimicrobial medicines, there is a growing risk that infections may not be treatable in the future. The Department of Health and Social Care asked us to develop guidelines to help slow antimicrobial resistance. These guidelines are evidence-based and clinical syndrome specific. We're beginning a project with NHS England and NHS Improvement to develop and test innovative models for the evaluation and purchase of antimicrobials.

      People should take honey or cough medicines instead but speak to their GP if it persists for longer than three weeks. View all our latest news on antimicrobials and antibiotics. Guidance Our guidelines offer evidence-based antimicrobial prescribing information for all care settings.

      An example of the draft visual summary for our sinusitis guideline. Topics added to the table: community-acquired pneumonia replaces PHE guidance from November hospital-acquired pneumonia. Advice Our antimicrobial evidence summaries provide commissioners, providers and health professionals with a summary of the best available evidence for antimicrobials.