Table 2.
Selection of Published in vivo and in vitro evidence of CI cephalosporins.
| Study | Type of Study | Population | Comparator Arms/Groups | PK/PD Data and Outcomes |
|---|---|---|---|---|
| Cefazolin | ||||
| Howard GW, et al. [8] | Observational trial | n = 7; patients with uncomplicated cellulitis | No LD provided. CFZ 3 g/24 h IV for ≥5 d, adjusted at the discretion of the physician. | Mean (±SD) dose of CFZ 3.5 ± 1.1 g (36 ± 6.1 mg/kg) IV via CI. Total concentrations (mean ± SD) in plasma proved higher than interstitial fluid concentration in 6/7 patients (32 ± 17 mg/L vs. 17.4 ± 8.3 mg/L). Free drug concentrations were not significantly different between plasma and interstitial fluid. Positive correlation between free concentrations of plasma and interstitial fluid (p = 0.005). |
| Zeller V, et al. [9] | Retrospective cohort study | n = 100; patients with bone and joint infection | CFZ 1 or 2 g IV LD (for daily doses ≤ 4 g or >4 g, respectively) followed by CFZ 60–80 mg/kg/24 h IV. | Median CFZ serum concentration 63 mg/L on days 2–10 and 57 mg/L on days 11–21 (target 40–70 mg/L); median CFZ bone concentration of 13.5 µg/g (n = 8). Cure/probable cure in 93% of patients. One person died secondary to infection. |
| Adembri, et al. [64] | Prospective, randomized study | n = 20; cardiac surgery patients | CFZ 2 g IV LD, followed by either CFZ 1 g IV q6h x 3 doses (at 3, 9, and 15 h after the first dose) (n = 10) or CFZ 3 g/18 h IV (n = 10). | Mean total CFZ serum concentrations were significantly higher with CI compared to II at 14.5 h (51.3 ± 18.1 mg/L vs. 34.1 ± 19.2 mg/L, p < 0.05) and 24 h post dose (52.5 ± 19.4 mg/L vs. 14.9 ± 10.3 mg/L, p < 0.01). Mean total myocardial tissue CFZ concentrations higher for CI group (6.9 ± 1.1 mg/L vs. 3.28 ± 0.1 mg/L, p < 0.05). More patients in the CI group achieved free concentrations 90% T > MIC (assuming E. coli) (90% patients vs. 30% patients, p < 0.01). |
| Anlicoara R, et al. [65] | Observational trial | n = 18; patients undergoing bariatric surgery | CFZ 2 g IV LD followed by CFZ 1 g IV over 2 h during surgery. | Mean adipose tissue CFZ concentration at start of surgery = 6.66 ± 2.56 mg/L and at surgery conclusion = 7.93 ± 2.54 mg/L; higher initial and final tissue concentrations with BMI < 40 kg/m2. No SSIs in BMI ≥ 40 kg/m2. |
| Shoulders BR, et al. [66] | Retrospective quasi-experimental cohort study | n = 516; patients undergoing CABG on CPB | CFZ 2 or 3 g IV q2h (n = 284) vs. CFZ 2 or 3 g/24 h IV (n = 232) during cardiac surgery Initial dosage adjustments for CrCl. |
No statistically significant difference in the reduction in SSI in the CI group vs. II group (1.7% vs. 4.6%, p = 0.116). No statistically significant difference in safety outcomes, such as seizures, AKI, or need for postoperative dialysis, between groups. |
| Cefuroxime | ||||
| Broekhuysen et al. [67] | Controlled trial | n = 18; patients > 70 years old with acute pulmonary infection | CXM 1500 mg IV LD followed by CXM 4500 mg/24 h IV (n = 7) vs. CXM 4500 mg IV daily divided q8h or q12h (n = 11) (all doses adjusted for CrCl) for an average of 7 days. | Mean (range) Css in the CI group was 37 mg/mL (23–61 mg/L). Mean (range) Cmax and Cmin in the II group were 83 mg/L (44–118 mg/L) and 10 mg/L (1.6–29.5 mg/L), respectively. |
| Pass et al. [68] | Prospective, non-comparative trial | n = 54; patients undergoing CABG procedure | CXM 1500 mg IV 30 min preoperatively followed by 3000 mg/24 h IV (average duration 2.6 ± 2.1 days). | Mean (±SD) Css 21.6 ± 14.2 mg/L (range 6.56–59.5 mg/L). Significant inverse correlation between estimated CrCl and serum concentration (r = −0.5029; p = 0.0005). No patients experienced sternal wound infection within 30 days post-op or readmission for sternal wound infection within 6 months. |
| Carlier et al. [17] | Observational PK study | n = 20; patients in the ICU from which 160 blood samples were collected | CXM 1500 mg IV q8h (750 mg IV q8h for CrCl < 20 mL/min), with population PK analysis and Monte Carlo dosing simulations applied with non-linear mixed-effects modeling to evaluate EI (no LD, CXM 1500 mg q6-8 h over half of the dosing interval) and CI (CXM 750 mg IV LD followed by CXM 4500 mg–9000 mg/24 h IV). | Standard intermittent dosing of CXM resulted in inadequate PTA (87%) for MICs of 8 mg/L in patients with CrCl ≥ 50 mL/min. CrCl ranged 10–304 mL/min. The PTA decreases as CrCl increases; thus, standard II doses may be insufficient in critically ill patients. PTA was overall improved with simulated CI dosing strategies. PTA ≥87% for CI of 9 g daily and CrCl ≤ 200 mL/min. |
| Tøttrup M, et al. [69] | PK study in swine models | n = n/a; plasma, tissue, and bone concentrations were assessed | CXM 1500 mg IV once vs. CXM 500 mg IV LD followed by CXM 1000 mg/8 h IV. | Tissue penetration was incomplete in all groups except subcutaneous tissue penetration in the II group. Plasma concentrations consistently optimized in CI group with longer T > MIC. |
| Ceftriaxone | ||||
| Salvador P, et al. [23] | PK study | n = 35; patients with neutropenia | High variability in dosing strategies, up to CRO 6 g/24 h IV. Most commonly used was LD 1 g followed by 2 g/8 h (repeated). |
High variability in PK observations due to high variability in dosing regimens. Mean serum CRO concentration on day 2–8 was 135 mg/L (range 117–151 mg/L). |
| Roberts JA, et al. [24] | Open-label, randomized controlled pilot study | n = 57; patients in the ICU diagnosed with sepsis | CRO 2 g IV once daily vs. CRO 2 g/24 h IV. | No statistically significant difference in the intention-to-treat analysis for clinical response, clinical cure, or bacteriological response. Controlling for SOFA score and age demonstrated improved clinical outcomes among CI group (aOR 22.8, 95% CI 2.24–232.3, p = 0.008) and among those with low APACHE score (aOR 0.70, 95% CI 0.54–0.91, p = 0.008). |
| Ceftazidime | ||||
| Benko AS, et al. [70] | Prospective, randomized, crossover study | n = 14; patients with suspected gram- negative infection (mostly pneumonia) | CAZ 2 g IV LD followed by CAZ 3 g/24 h IV vs. CAZ 2 g IV q8h; participants received each regimen for 2 days prior to crossover to opposite regimen. | Mean serum Cmax for II was 124.4 ± 52.6 mg/L, mean serum Cmin was 25.0 ± 17.5 mg/L. Mean Css for CI was 29.7 ± 17.4 mg/L. Time > MIC was higher in CI group than II (T > MIC 100% vs. 92%). |
| Nicolau DP, et al. [71] | Open-label, randomized, steady-state, four-way crossover study | n = 12; healthy volunteers | CAZ 1 g IV q8h vs. CAZ 1 g IV q12h vs. CAZ 3 g/24 h IV vs. CAZ 2 g/24 h IV. | AUBCs for all organisms were the same for II and CI doses (p > 0.05). No statistically significant differences found for varying CAZ dosing schedules for any isolates obtained from blood samples (p > 0.05). |
| Riethmueller J, et al. [72] | Randomized, crossover study | n = 80; patients with cystic fibrosis colonized with P. aeruginosa | CAZ 200 mg/kg/day in 3 divided doses IV with TOB 10 mg/kg OR CAZ 100 mg/kg/24 h IV with TOB 10 mg/kg via a 30 min IV infusion. |
CI mean concentrations 32 ± 12 mg/L (target of >20 mg/L). Mean peak concentrations of II were 159 ± 44 mg/L (target < 180 mg/L) while mean trough concentrations were 8.5 ± 5 mg/L (target < 30 mg/L). |
| Vinks AA, et al. [73] | Observational cohort study | n = 17 patients with cystic fibrosis | CAZ CI 100 mg/kg/24 h IV given via infusion pump at home | 25 clinically evaluable courses among 12 patients were all considered effective over a mean duration of 21 days; Bacterial density and proportion of patients with positive cultures decreased significantly; Among 10 patients with TDM, mean serum concentrations were 28.4 ± 5.0 mg/L and sputum concentrations were 3.9 ± 4.0 mg/L |
| Rappaz I, et al. [74] | Observational cohort study | n = 14 pediatric patients with cystic fibrosis and chronic P. aeruginosa infections | CAZ CI 100 mg/kg/24 h IV given via infusion pump at home or CAZ standard II | Among 14 children (mean weight 38.8 kg, mean age 12.6 years), CAZ CI maintained mean serum concentrations of 29.7 ± 9.9 mcg/mL and 27.4 ± 6.6 mcg/mL on days 3 and 10., respectively which achieved target concentrations significant more frequently than II. Mean sputum concentrations were 2.1 ± 1.1 mcg/g in patients receiving CI, very similar to those achieved with II. No resistance was noted and CI was well tolerated. |
| Bosso JA, et al. [75] | Prospective, crossover pilot study | n = 5 patients with cystic fibrosis requiring IV therapy for exacerbation | CAZ II 2 g q8 for 10 days and crossed over at next hospitalization to CAZ CI adjusted via TDM to achieve concentrations 6.6 × the MIC of least susceptible isolate | No differences in laboratory values, clinical outcomes or bacterial density; the mean reduction in CAZ dosage needed to obtain target concentrations using the CI was 50% |
| Bulitta JB, et al. [29] | Pharmacokinetic study with Monte Carlo simulation | n = 15; 8 patients with cystic fibrosis and 7 healthy volunteers | Patients received 2 g IV over 5-min infusion; Monte Carlo simulation of multiple dosing strategies including standard II, EI over 5-h and CI of 6 g/24 h | Based on Monte Carlo simulations, standard II dosing (2g q8h) over 30 min achieved good PTA for MICs of ≤ 1 MIC in patients with CF; using EI of 2 g q8h over 5-h, PTA remained high for MICs approaching 12 mg/L; Use of CI 6 g/24 h resulted in high PTA for MICs ≤ 12 mg/L. All simulations assumed 2 g/70 kg. |
| Lipman J, et al. [30] | Randomized controlled trial | n = 18; critically ill patients | CAZ 12 mg/kg LD followed by CAZ 6 g/24 h IV CI vs. CAZ 2g q8h II | Target concentrations were to remain above 40 mg/L in the study; all patients except 1 receiving CI met the goal versus target attainment in only 20–30% of those receiving standard II dosing |
| El Haj C, et al. [28] | Pharmacokinetic analysis | n = n/a; CAZ susceptible and resistant P. aeruginosa isolates | CAZ 6 g/24 h OR CAZ 9 g/24 h. |
CAZ exhibited dose-dependent antibiofilm activity in vitro; administration of CAZ by CI may provide benefits over intermittent bolus infusion. |
| Ceftazidime/Avibactam | ||||
| Goncette V, et al. [35] | Retrospective case series | n = 10; MDR P. aeruginosa (n = 6) and K. pneumoniae (n = 4) (multi-site/source) | CAZ/AVI 2.5 g IV LD followed by CAZ/AVI 5 g/12 h IV given q12h (i.e., 10 g/24 h CI); Initial dosage adjustments for CrCl and subsequent dosage adjustments based on TDM. |
Median CAZ plasma Css was 63.6 mg/L (range 47.6–80 mg/L). Moreover, 100% of patients met goal of ≥4× MIC in plasma and/or site infection., and 40% of patients received additional antibiotics. Clinical cure was 80%, and microbiological eradication was 90%. The 30-day mortality was 10% (1 patient death attributed to unrelated cause of ventilator-associated tracheobronchitis). |
| Lodise TP, et al. [34] | Hollow-fiber infection model | n = n/a; MBL-producing strains of E. coli and K. pneumoniae | Staggered vs. simultaneous administration of CAZ/AVI plus aztreonam; 16 unique dosing strategies, of which 6 included CAZ/AVI CI: CAZ/AVI 7.5 g/24 IV + various aztreonam dosing strategies. | Simultaneous administration was superior to staggered administration against MBL-producing organisms. Longer infusion durations (2 h infusions and CI) demonstrated enhanced bacterial killing compared to standard infusion. |
| Cefotaxime | ||||
| Buijk SE, et al. [44] | Non-randomized, block design, observational study | n = 15; patients undergoing elective orthotopic liver transplantation | CTX 4 g/24 h IV vs. 1 g IV q6h as an II, aimed to determine the PK of CTX in serum, bile and urine. | Mean concentration in serum after CI was 18 mg/L. Serum concentrations of ≥4 mg/L were achieved for 100% of the CI dosing interval and for 60% of the II interval. |
| van Zanten, et al. [45] | Randomized controlled, prospective, non-blinded study | n = 93; patients with acute exacerbations of chronic obstructive pulmonary disease | CTX 1 g IV LD followed by CTX 2 g/24 h IV vs. CTX 1 g IV three times daily. | Clinical cure did not differ between groups (93%). Time ≥ 5x MIC was 100% in the CI group and 55% in the intermittent group (p < 0.001). |
| Seguin P, et al. [46] | Prospective observational study | n = 11; patients in the ICU with secondary peritonitis | CTX 4 g/24 h IV, aimed to determine SS plasma and peritoneal concentration of CTX. | CI of CTX at 4 g/day provided mean plasma and peritoneal concentrations well above MIC for the gram-negative bacteria discovered (24.0 ± 21.5 on day 2 and 22.1 ± 20.7 on day 3). |
| Cefepime | ||||
| Burgess DS, et al. [76] | Randomized crossover study | n = 12; healthy volunteers | FEP 2 g IV q12h via II vs. FEP 3–4 g/24 IV. | Intermittent infusion regimen achieved serum concentrations above the MIC for P. aeruginosa and E. cloacae in 11 patients for ≥70% of the dosing interval when MIC was ≤4 mcg/mL. Steady state concentrations for both CI regimens (i.e., 3 and 4 g/24 h) were above the MIC for P. aeruginosa, E. cloacae, and S. aureus, but Css was ≥4x MIC only if the MIC was ≤2 mcg/mL. |
| Boselli E, et al. [77] | Prospective, open-label study | n = 20; patients with severe VAP | FEP 2 g IV LD followed by FEP 4 g/24 h IV. | Mean plasma Css was 13.5 ± 3.3 mg/L, and mean epithelial lining fluid Css was 14.1 ± 2.8 mg/L. Mean percentage penetration to epithelial lining was 100%. |
| Al-Shaer MH, et al. [47] | Monte Carlo simulation | n = 266; critically ill pediatric and adult patients | A total of 8 unique dosing strategies evaluated via Monte Carlo simulation, 3 of which included CI: FEP IV 6 g/24 h, 7 g/24 h, and 8 g/24 h. EIs of FEP 4 g IV via 4 h infusion as LD to CI regimens were also evaluated. | CI dosing strategies were most likely to achieve targets of Time > 4×MIC, with only FEP 8 g/24 h IV achieving >90% PTA (MIC = 1 mg/L). Assuming higher MIC (8 mg/L), the regimen with the highest PTA was LD provided over EI followed by CI. |
| Alvarez JC, et al. [48] | Open-label, non-randomized, prospective, observational, and descriptive study | n = 15; patients with hematological malignancies treated for febrile neutropenia | 12 unique dosing strategies evaluated via Monte Carlo simulations, 3 of which included CI: FEP IV 4 g/24 h, 6 g/24 h, and 8 g/24 h. | PTA was higher among CI regimens. FEP 6 g/24 h IV obtained the highest cut-off MIC value. |
| Reese A, et al. [78] | Monte Carlo simulation | n = 10,000; non-duplicate ESBL isolates | Intermittent bolus and CI of PIP/TZB and FEP (1 g q8h, 1 g q12h, 2 g q12h, 3 g/24 h and 4 g/24 h). | FEP 4 g CI had the highest PTA (T > MIC = 77%); no CI regimen achieved an adequate (>90%) T > MIC. |
| Ceftaroline | ||||
| Fresán D, et al. [50] | Retrospective, observational study | n = 12; patients receiving treatment for confirmed gram-positive infections | 1800 mg/24 h, 1200 mg/24 h, and 600 mg/24 h. All doses adjusted based on renal function. |
Six of seven patients who received CI achieved 100% fT > 4×MIC. Based on TDM, two patients receiving 1800 mg/24 h via continuous infusion had the dose decreased, while others were maintained. |
| Ceftobiprole | ||||
| Cojutti PG, et al. [54] | Retrospective pharmacokinetic study with Monte Carlo simulation | n = 132; patients with gram-positive infections | The following CI dosing strategies were evaluated via Monte Carlo simulation: 3000 mg/24 h for eGFR > 130 mL/min/1.73 m2; 2000 mg/24 h for eGFR 51–130 mL/min/1.73 m2; 1500 mg/24 h for eGFR 30–50 mL/min/1.73 m2; 750 mg/24 h CI for eGFR < 30 mL/min/1.73 m2. |
Monte Carlo simulations of CI, using standard doses based on GFR, were needed to achieve optimal PD targets against MRSA. This remained the case for patients with renal impairment and augmented renal clearance. |
| Ceftolozane/Tazobactam | ||||
| Jones BM, et al. [79] |
Case report | n = 1; MDR P. aeruginosa pulmonary infection | C/T 4.5 g/24 h. | Clinical and microbiological resolution; no TDM performed. |
| Stewart A, et al. [80] | Case report | n = 1; MDR P. aeruginosa cavitating pulmonary infection | C/T 4.5 g/24 h. | Clinical resolution; improvement of lesion on imaging; inpatient and outpatient TDM demonstrated unbound plasma (and assumed epithelial lining) ceftolozane concentrations well above 4–5 times the MIC value associated with maximal bacterial killing for the full dosing interval. |
| Davis SE, et al. [81] |
Case report | n = 1; cystic fibrosis patient with P. aeruginosa and ESBL E. coli | C/T 3 g IV LD followed by C/T 6 g/24 h. | TDM confirmed adequate exposure: observed concentrations exceeded the established CLSI susceptibility breakpoints for P. aeruginosa and E. coli (≤4/4 μg/mL and ≤2/4 μg/mL, respectively). |
| Pilmis B, et al. [82] | Prospective cohort study | n = 72; patients with MDR P. aeruginosa infections (primarily respiratory) | C/T 3 g IV q8h infused over 1 h (n = 44) vs. C/T 3 g IV q8h via 4 h EI (n = 13) vs. C/T 9 g/24 h (n = 15). | No difference in PTA for MICs < 4 mg/L; intermittent dosing inadequate for MICs ≥ 4 mg/L, but prolonged and CI of C/T (dosed 6 g/day) achieved >90% PTA. |
| Sime FB, et al. [83] |
Prospective observational study with Monte Carlo Simulation | n = 12; critically ill patients without renal impairment | C/T 1.5 g IV or 3 g IV q8h infused over 1 h (n = 1000 Monte Carlo Simulations). | CI C/T dosing regimens associated with higher PTAs particularly in patients with augmented renal clearance (85% for directed therapy with MICs up to 4 mg/L; 84 and >85%, for empirical coverage with MICs up to 64 mg/L with 1.5 g and 3 g dosing regimens, respectively). |
| Jones BM, et al. [84] |
Retrospective, case series | n = 7; Outpatients with P. aeruginosa infections (multi-site/source) | C/T 4.5 g/24 h (n = 6) and C/T 9 g/24 h (n = 1) (labeled dosing converted to 24 h dosing, e.g., patients eligible for 1.5 g q8h received 4.5 g CI). | 6 of 7 patients had symptom resolution; 3/3 patients had microbiological clearance. |
| Otero JA, et al. [59] |
Case report | n = 1; MDR P. aeruginosa osteomyelitis | C/T 1.5 g IV LD followed by 2.25 g/24 h (adjusted for renal dysfunction, glomerular filtration rate 40 mL/min). | Clinical resolution (both antibiotic and surgical management employed). |
| Sheffield M, et al. [58] |
Retrospective, case series | n = 7; deep-seated MDR P. aeruginosa infections | C/T 3 g IV LD for all patients; 1 patient treated with C/T 3 g/24 h (n = 1, suppression dosing); C/T 4.5 g/24 h (n = 1, adjusted for renal function; C/T 6 g/24 h (n = 5, 3 patients had q12h infusions over 12 h). | 7/7 patients had clinical resolution, and 1/1 patients had partial microbiological clearance; TDM in 4 cases confirmed adequate exposure with observed concentrations 100% fT > 4×MIC. |
| Winans SA, et al. [85] |
Case report | n = 1; P. aeruginosa meningitis | C/T 3 g IV LD followed by C/T 9 g/24 h. | Serum TDM obtained 3 and 6.75 h after the 3 g LD of C/T and 15 h after CI started. CSF TDM obtained 4 h after the third serum concentration was obtained and 6 d after starting CI to confirm steady state. Ceftolozane CSF concentrations were 83% of serum. Clinical resolution with C/T + IV and intraventricular gentamicin. |
| Cefiderocol | ||||
| No clinical data available | ||||
| Cefoxitin | ||||
| Suffoletta TJ, et al. [76] | Retrospective, cohort-matched pilot study | n = 116; patients undergoing colorectal surgery stratified into low and medium risk groups | FOX 1 g IV if ≤80 kg or 2 g IV if >80 kg q8h for three doses 3 h after surgery vs. FOX 3 g/20 h IV if ≤80 kg or 6 g/20 h IV if >80 kg started immediately after surgery. | 30-day postoperative SSI rate showed a 50% relative risk reduction in medium-risk patients while it was equal between continuous and intermittent regimens in the low-risk group. |
CI: continuous infusion; EI: extended infusion; II: intermittent infusion; SSI: surgical site infection; IV: intravenous; TDM: therapeutic drug monitoring; LD: loading dose; h: hour; PTA: probability of target attainment; CSF: cerebrospinal fluid; MIC: minimum inhibitory concentration; ICU: intensive care unit; ESBL: Extended-spectrum beta-lactamase.