Beta-lactams bind to penicillin-binding proteins (PBPs) and affect enzymes that are involved in cell wall synthesis. This kills the bacterium. The minimum inhibitory concentration (MIC) is the smallest amount of antibiotic required to stop the bacterium growing. The optimum efficacy for beta-lactams is when they are above 4x MIC for 40-60% of the time, although it does vary between different types of beta-lactam:
- Penicillins 50%
- Cephalosporins 60%
- Carbapenems 40%
Beta-lactam antibiotics have time-dependent killing; that is the longer the bacterium is in contact with the beta-lactam the more effective the antibiotic is. There are three possible ways of increasing the time at which a concentration stays above a certain level:
- Give more antibiotic
- Give more frequent antibiotic
- Give the antibiotic over a longer period of time
Giving more antibiotic will still leave times when the amount of antibiotic falls below a therapeutic level and runs the risk of high peak concentrations that could be toxic. Whereas more frequent dosing may also leave times when the amount of antibiotic is not therapeutic but it also leads to more antibiotic being given per day, increased need for IV access and more staff time, and as a result is more expensive.
So what about giving antibiotics over a longer period? The theory is if you continuously infuse the antibiotic it will be more effective. This smooths out the peaks and therefore theoretically reduces toxicity issues. The normal daily dose is given over a longer period of time and so there are no increased drug or staff costs. There are some drawbacks but I’ll get to those later.
Are prolonged or continuous infusions safe and beneficial?
The studies that have been done show no difference between prolonged or continuous infusions compared to conventional intermittent dosing in terms of toxicity. This isn’t really a surprise; beta-lactams are usually well tolerated and bad side effects and toxicity are uncommon.
In addition to being safe from a toxicity point of view there is also a theoretical benefit in terms of safety with prolonged or continuous infusions in that they are less likely to select for antibiotic resistant bacteria. Most antibiotic resistance is thought to occur when levels become sub-therapeutic (in between doses) allowing slightly more resistant subpopulations of bacteria to grow again. The more often low levels occur the more likely increasingly resistant bacteria will be selected. Continuous or prolonged infusions mean there is less opportunity for these slightly resistant bacteria to survive and become more resistant later.
Ease of administration
Continuous infusions would be easy to give in an outpatient setting as the patients IV line only needs to be accessed once a day, rather than 6x/day to load the electronic pump. This also reduces the risk that someone might introduce bacteria into the line causing a new infection.
Narrow vs. broad spectrum
Current outpatient antibiotic strategies in the UK are often based around long acting, once a day, antibiotics such as Ceftriaxone and Ertapenem. Unfortunately these antibiotics are very broad spectrum and cause damage to the patient’s normal flora predisposing to secondary problems such as Clostridium difficile associated disease (CDAD). Continuous infusions allow for the use of narrower spectrum antibiotics such as Benzylpenicillin or Flucloxacillin. This would cause less damage to normal flora and less risk of CDAD.
This all sounds great, where’s the catch?
So other than the lack of strong clinical evidence to support prolonged or continuous infusions there are some other potential drawbacks.
Prolonged infusions may not give clinical benefit?
This is where it gets a bit difficult. There is no good evidence that prolonged or continuous infusions of beta-lactams are any better than conventional intermittent dosing. There are a number of poor quality, observational studies and non-randomised non-blinded small trials which suggest a benefit but there are also other trials that contradict this. What we need are large multicentre randomized double-blinded studies to compare different treatment strategies but so far these are not forthcoming.
One of the reasons why the studies might fail to show a difference is the heterogeneity in the study populations; that is the patient groups are too mixed. The patient groups most likely to benefit are the critically ill and those with more resistant bacteria. Patients in critical care have enhanced drug clearance, different volumes of distribution, abnormal fluid balance and altered protein binding. All of these influence the way antibiotics affect bacteria and often mean that critically ill patients do not have sufficient antimicrobial levels with conventional doses; they often need higher doses.
Patients who are not that unwell are not so reliant on the antibiotic to kill the bacterium causing their infection; their own immune system will be doing this as well. In addition they will metabolise and distribute antibiotics around the body very differently. Studies have shown that in non-critically ill patients, continuous or prolonged infusions make no difference to clinical care.
The Defining Antibiotic Levels in Intensive Care Unit Patients (DALI) study showed that critical care patients, with high severity of illness scores, who received prolonged infusions of beta-lactams where more likely to have antibiotic concentrations 4x MIC for >50% of the time as well as have a better clinical outcome. The study wasn’t randomised or blinded though, so the results could be susceptible to bias.
The other beneficial group are those patients with more resistant bacteria. Current clinical studies include patients with infections caused by variable bacteria some of which are more resistant than others. Prolonged infusions are not necessary for sensitive bacteria (low MIC) as normal conventional dosing keeps antibiotic levels 4x the MIC and are easily able to kill the bacteria. However, conventional dosing does not work as well for resistant bacteria (high MIC) as the antibiotic levels drop too quickly in between doses, so that a concentration 4x the MIC is not maintained for long enough for the antibiotic to kill the bacteria.
Pseudomonas aeruginosa and Enterococcus spp. are considered relatively resistant to beta-lactams compared to other Gram-negative bacilli (e.g. E.coli) or Viridans streptococcus spp. The MICs for Piptazobactam and Amoxicillin against these bacteria are shown below:
Antibiotic |
Organism |
MIC (mg/L) |
Piptazobactam |
P. aeruginosa |
16 |
" " |
E. coli |
8 |
Amoxicillin |
Enterococcus spp. |
8 |
" " |
Viridans streptococcus spp. |
2 |
Another drawback to continuous or prolonged infusions is that they require central venous catheter (CVC) access and this predisposes to possible CVC infection. Drugs need to be made up carefully to ensure concentrations are correct and IV trained nurses are required to administer the infusions. Also these patients run antibiotic levels just above 4x MIC all the time therefore if there is a need to replace the CVC or stop the infusion the patient will quickly become sub-therapeutic. Infusions may have to be stopped in order to give other medications especially if the other drug is not compatible with the antibiotic being infused.
A further problem is that not all beta-lactams are stable enough at room temperature to be given as prolonged infusions. Piptazobactam is stable for 24 hours but carbapenems such as Meropenem are only stable for 1-4 hours, which is not long enough for a continuous infusion.
So what do I think?
I have little experience of using continuous or prolonged infusions of beta-lactams but I have studied the literature a lot in recent times as it keeps coming up in conversations.
My opinion is that the most promising antibiotic to use is Piptazobactam and that there is probably some benefit to prolonged infusions or continuous infusions of this antibiotic in the treatment of critically ill patients with infections caused by P. aeruginosa or other Gram-negative bacilli with MICs at the higher end of the sensitive range. Otherwise I do not think these methods of antibiotic delivery will become more widespread because of the logistics of CVC insertion, care and risk of infection as well as the lack of stability of many of the currently used antibiotics which might provide narrower therapeutic options.
But what do you think? Do you use prolonged or continuous infusions and if so what do you use, when do you use them and how well do you think they work?