Amoxicillin during pregnancy

The most realistic potential scenario might be scenario B or a scenario in which amoxicillin distributes in interstitial fluid plus part of the total bone fluid outside the interstitial space (a mix of scenarios B and C).

As total bone fluid likely includes fluid in small pores of the hydroxyapatite crystals from which interstitial fluid markers (e.g., sucrose) are excluded (45), distribution throughout total bone fluid (scenario C) seems less likely.

aureus to enter and survive in osteoblasts (31, 35) was suggested to be a possible reason for relapses of osteomyelitis (Table 4, scenario D). As beta-lactams are not expected to penetrate cells well, an intracellular bone infection might relapse (38). In any case, when bacteria reside in a part of the bone which is inaccessible to amoxicillin, treatment failure or relapse seems likely. The volumes described in Table 4 refer to those in healthy bone.

In patients with acute osteomyelitis, it has been suggested that the blood supply to the bone is increased, capillary permeability is higher, and potentially greater antibiotic concentrations reach bone (34).

In osteomyelitic canine bone, the volume of distribution of cefazolin was increased to 0.572 ml per ml bone, whereas in uninfected bone, it was 0.0662 ml per ml bone (17).

The results of few PK studies with patients with osteomyelitis are available. In patients with chronic osteomyelitis, dead bone (a location where bacteria may be sequestered) which is not reached by the blood circulation is often present. Beta-lactams most likely cannot penetrate into sequestered areas, and therefore, surgical debridement, in addition to antibiotic therapy, is necessary. Another limitation of our analysis is that the target for beta-lactams in bone is unknown. Data on the efficacies of amoxicillin and other beta-lactams for the treatment of osteomyelitis are sparse. Therefore, the present analysis could not apply reverse engineering to determine the PK-PD target, as was done previously (9, 37).

To consider a wide range of potential target values, we reported the results for fT > MIC targets of at least 30%, 50%, 70%, or 100% (Tables 2 and 3). Should a future study determine that amoxicillin needs to achieve a free concentration of greater than 4? the MIC for 50% of the time, for example, one can directly calculate the breakpoints on the basis of the results of our analysis by dividing our breakpoint (on the basis of fT > 1 ? MIC ) by 4, since amoxicillin displays linear PK after intravenous administration.

Although beta-lactams likely distribute mainly in the interstitial space in bone and the bacteria residing there might encounter concentrations similar to those that they would encounter in plasma, the time course of the concentration in bone is different from that in serum. For the beta-lactam target fT > MIC , the shape of the concentration-time curve affects the PTA, unless the drug is given by continuous infusion.

Simulations with our model confirmed that fT > MIC depends on the equilibration half-life between serum and bone, even for dosing at steady state.

For single doses, such as for perioperative prophylaxis, the equilibration half-life has an even greater impact.

Therefore, it is important to determine the half-life of equilibration by modeling and to derive breakpoints on the basis of the concentration-time profiles in bone. However, clinical trials are needed to determine the PK-PD target for bone.

Like virtually all studies of drug bone penetration whose findings have been published, we had one bone sample per patient.

The collection of multiple bone samples is not feasible in joint replacement studies.

In contrast to previous studies, we applied population PK analysis in which all data from all patients were considered simultaneously.

In addition, a full Bayesian analysis, which is the latest method for amoxicillin 875 for sinus infection data analysis and which is particularly valuable for use with sparse data, was applied.

Our

The latter method was also applied to amoxicillin bone penetration studies (3, 24, 36, 54) and was recently criticized by Mouton et al.

(47) as “meaningless,” and they also considered its use to be “potentially harmful in patient care.” Despite the activity of amoxicillin-clavulanic acid against pathogens commonly encountered in bone infections (28), its PK profile and PK-PD breakpoints in bone have not been determined by population PK and Monte Carlo simulations. used population PK and Monte Carlo simulations to analyze the penetration of levofloxacin into the prostate (21) and epithelial lining fluid (20).

We used these techniques, which consider the full time course of tissue and serum concentrations and their BSVs, to estimate the extent and rate of bone penetration and to evaluate the PK-PD profile. Even though the data were sparse, the estimates from NONMEM and S-ADAPT were comparable (Table 1).

Given the limitations pointed out above, the PK-PD breakpoints (Table 2) predicted by population PK and Monte Carlo simulations compared favorably to the MICs for clinically relevant pathogens.

Amoxicillin achieved PTA expectation values of >90% against MSSA in bone and serum for 30-min infusions of 2,000/200 mg amoxicillin-clavulanic acid q4h and q6h and for both an fT > MIC of ?30% and an fT > MIC of ?50% (Table 3).

The susceptibility patterns of the local hospital should be used to determine if amoxicillin-clavulanic acid is a promising choice for the treatment of bone infections.

In conclusion, the median ratios of the AUC for bone/AUC for serum were 20% (80% prediction interval for BSV, 16% to 25%) for cortical bone and 18% (80% prediction interval for BSV, 11% to 29%) for cancellous bone for amoxicillin and 15% (80% prediction interval for BSV, 11% to 21%) for cortical bone and 10% (80% prediction interval for BSV, 5.1% to 21%) for cancellous bone for clavulanic acid. Equilibration between serum and bone was rapid for both drugs. For dosing q4h, amoxicillin achieved robust (?90%) PTAs for MICs of ?12 mg/liter in serum and 2 to 3 mg/liter in cortical and cancellous bone for the nearly maximal kill target ( fT > MIC , ?50%). Amoxicillin achieved PTA expectation values of >90% against MSSA for both targets in bone and serum for 30-min infusions of 2,000/200 mg amoxicillin-clavulanic acid q4h and q6h ( fT > MIC , ?50%).

The PTA

expectation

As the PK-PD target in bone will need to be established in future studies, we considered a wide range of PK-PD targets, and our simulation results should be interpreted conservatively. Antibiotics save lives, but antibiotics can have negative effects. When patients have bacterial infections, we want to treat them to prevent complications of the bacterial amoxicillin red and yellow capsule infection, but not treat them for an excessive duration.

So we have a Goldilocks problem — we want antibiotic duration to be just right — neither too short or too long.

Some clinical conditions have adequate research to define the Goldilocks duration. Community acquired pneumonia only requires five days of antibiotics, if the patient is clinically stable at three days. We know that five days is sufficient, so if we give antibiotics for 7 or 10 days, the patient gets exposed to unnecessary antibiotics. We have learned antibiotic duration without the teaching (and guidelines) having an evidence base.

So a new movement suggests that we should tell patients to stop the antibiotics

when

The concept of an antibiotic course ignores the fact that patients may respond differently to the same antibiotic, depending on diverse patient and disease factors.

Currently, we largely ignore this fact and instead make indication specific recommendations for antibiotic duration that are based on poor evidence. This situation is changing in hospital practice, where biomarkers of treatment response

such

Outside hospital, where repeated testing may not be feasible, patients might be best advised to stop treatment when

they

So this interesting idea got published in the British Medical Journal.

But does subjectivity get us to the Goldilocks duration?

So this article argues against the BMJ opinion piece: Why you really should take your full course of antibiotics. So, knowing what you now know, do you think stopping a course of antibiotics when you feel better as opposed to completing the course is a good idea?

It may be the case that your infection is completely clear by day two of your five-day course, but it’s equally possible that a small population remains that can grow back and reinfect you. More research and clinical trials (as also noted in the BMJ article) are required in order to fully understand and adjust the lengths of antibiotic courses, but, in my opinion as a microbiologist, the risks of taking an insufficient course significantly outweigh the benefits.

As you might imagine, I do not think this opinion gets us to the Goldilocks duration. In 2000, Zwart and colleagues published a study of placebo versus three days penicillin versus seven days penicillin for severe adult pharyngitis (defined as a Centor score of 3 or 4). Their results are instructive: Patients who took penicillin for seven days showed a permanent resolution of sore throat 1.9 and 1.7 days sooner than those who took penicillin for three days or placebo respectively. During the first three days of treatment, patients in the three-day penicillin group showed a similar resolution of symptoms to those in the seven-day penicillin group.

However, 40 percent (77 of 194) of the three-day penicillin group had a temporary resolution of symptoms, which recurred amoxicillin on empty stomach later that week, against 5 percent (10 of 190) of the seven-day penicillin group. This finding accounts for the difference between the two penicillin

groups