Daptomycin synergistic properties from in vitro and in vivo studies: a systematic review

Abstract

Introduction

Daptomycin is a bactericidal lipopeptide antibiotic approved for the treatment of systemic infections (i.e. skin and soft tissue infections, bloodstream infections, infective endocarditis) caused by Gram-positive cocci. It is often prescribed in association with a partner drug to increase its bactericidal effect and to prevent the emergence of resistant strains during treatment; however, its synergistic properties are still under evaluation.

Methods

We performed a systematic review to offer clinicians an updated overview of daptomycin synergistic properties from in vitro and in vivo studies. Moreover, we reported all in vitro and in vivo data evaluating daptomycin in combination with other antibiotic agents, subdivided by antibiotic classes, and a summary graph presenting the most favourable combinations at a glance.

Results

A total of 92 studies and 1087 isolates (723 Staphylococcus aureus, 68 Staphylococcus epidermidis, 179 Enterococcus faecium, 105 Enterococcus faecalis, 12 Enterococcus durans) were included. Synergism accounted for 30.9% of total interactions, while indifferent effect was the most frequently observed interaction (41.9%). Antagonistic effect accounted for 0.7% of total interactions. The highest synergistic rates against S. aureus were observed with daptomycin in combination with fosfomycin (55.6%). For S. epidermidis and Enterococcus spp., the most effective combinations were daptomycin plus ceftobiprole (50%) and daptomycin plus fosfomycin (63.6%) or rifampicin (62.8%), respectively.

Future perspectives

We believe this systematic review could be useful for the future updates of guidelines on systemic infections where daptomycin plays a key role.

Introduction

Daptomycin is a semisynthetic cyclic lipopeptide first marketed in the USA in 2003 and in Europe in 2006.^1,2 Daptomycin acts with a unique mechanism of action causing depolarization of the bacterial cell wall and membrane reorganization in lipid and protein sites, determining a rapid, concentration-dependent bactericidal effect.^3–5 Due to its activity against clinically relevant Gram-positive cocci, including MRSA and VRE,² daptomycin is a milestone in the treatment of systemic infections, including severe skin and soft tissue infections (SSTIs), bloodstream infections (BSIs), catheter-related BSIs (CRBSIs) and infective endocarditis sustained by Gram-positive cocci.^6,7 In fact, besides prescription based on antimicrobial susceptibility testing, it is often prescribed pending microbiological results, if the patient has known rectal or nasal colonization by MDR Gram-positive bacteria.^8,9 Daptomycin is generally reported to have a good safety profile and its pharmacokinetics (PK) and pharmacodynamics (PD) allow once-a-day administration, making daptomycin a valuable option for outpatient treatments also.¹⁰

Ultimately, there are some methodological and ethical concerns that cannot be ignored in conducting clinical trials, in particular comparative trials between monotherapies and combination regimens, in life-threatening infections such as endocarditis. With this in mind, translational studies may be the most reasonable starting point.

We performed a systematic review to provide an updated overview of daptomycin synergistic properties from in vitro and in vivo studies.

Materials and methods

The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were considered for conception and design of the present systematic review (Table 1).¹¹

On 1 June 2022 we performed a PubMed/MEDLINE search including papers published starting from 1 January 2003 (year of first authorization of daptomycin for clinical purposes). The PubMed/MEDLINE search engine was chosen as it was a free and accessible option, with optimal update frequency, including online early articles, and the authors were more familiar with it than other search engines as they used it for previous systematic reviews. The complete search string was ‘((Daptomycin[Title/Abstract]) AND (((((((((((((((synergistic[Title/Abstract]) OR (synergic[Title/Abstract])) OR (synergism[Title/Abstract])) OR (antagonism[Title/Abstract])) OR (antagonistic[Title/Abstract])) OR (combination[Title/Abstract])) OR (combined[Title/Abstract])) OR (plus[Title/Abstract])) OR (together[Title/Abstract])) OR (time kill[Title/Abstract])) OR (time-kill[Title/Abstract])) OR (time killing[Title/Abstract])) OR (time-killing[Title/Abstract])) OR (checkerboard[Title/Abstract])) OR (chequerboard[Title/Abstract]))) AND ((‘2003/01/01’[Date—Publication] : ‘2022/05/31’[Date—Publication]))’.

Inclusion criteria were papers written in English, papers evaluating daptomycin in combination with another antibiotic against Gram-positive cocci in vitro or in vivo in animal models (no limitations on the site of infection) and full text available online. Exclusion criteria were papers evaluating daptomycin alone or in combination with molecules that are not antibiotics (i.e. antimicrobial peptides, phytotherapeutics), combinations tested against bacteria other than Gram-positive cocci, papers reporting clinical data (i.e. case reports, case series, clinical trials) or expert opinions, papers written in languages other than English and full text not available online.

A total of 796 published papers were identified and screened (Figure 1). Of these, 19 were excluded by language screening (written in languages other than English) and 481 by title/abstract screening. The remaining 296 papers and their pertinent references were jointly reviewed and discussed by authors. Ninety-two studies were finally included and considered for further analysis. Fifteen papers, though pertinent for the aim of the present review, had no extractable data, i.e. only general statements about synergistic interactions but no details on how the synergism was established. Studies evaluating daptomycin synergistic properties in bacteria other than Gram-positive cocci were not included in the data analysis but are considered in the Discussion section. The full database of articles screened and included in the present systematic review is available from the corresponding author.

To ensure homogeneous criteria of paper selection, analysis and data extraction, the following common definitions were established and adopted by all authors (R.M.A., D.C., N.R.), who reviewed the papers independently.

Synergistic effect

Chequerboard assay or Etest: FIC index (FICI) ≤0.5. FICI is defined as follows: A/MIC_A + B/MIC_B = FIC_A + FIC_B = FICI. Time–kill assay: ratio of effective concentrations concordant with FICI or ≥2 log kill.

Additive effect

Chequerboard assay or Etest: 0.5 < FICI ≤ 1. Time–kill assay: ratio of effective concentrations concordant with FICI or 1 < log kill <2.

Indifferent effect

Chequerboard assay or Etest: 1 < FICI < 4. Time–kill assay: ratio of effective concentrations concordant with FICI or 1 log kill.

Antagonistic effect

Chequerboard assay or Etest: FICI 4. Time–kill assay: ratio of effective concentrations concordant with FICI or <1 log kill.

For in vitro studies using a method different from chequerboard, Etest or time–kill assay (i.e. PK/PD models), synergism was evaluated according to the ratio of effective concentrations in combination or the log kill.

For studies performed in vivo, synergism was established with the same ratio of effective concentrations considered for chequerboard assays or with the same log kill considered for time–kill assays.

Studies in which there was no distinction between additive and indifferent effect were included and the interaction was considered indifferent (we remarked about this point in the note section for these studies).

For further analysis, i.e. descriptive statistics calculating percentages of synergism for daptomycin in combination with each antibiotic class, if a study evaluated daptomycin in combination with more than one antimicrobial agent belonging to the same antibiotic class, the most unfavourable association was considered.

The present systematic review was not registered and no specific protocol was written.

Results

A total of 92 studies and 1087 isolates (723 Staphylococcus aureus, 68 Staphylococcus epidermidis, 179 Enterococcus faecium, 105 Enterococcus faecalis, 12 Enterococcus durans) were included in the present systematic review. For better comprehension, a table with the included studies and a brief summary of the main findings is provided for each antibiotic class.

Penicillins and penicillins/β-lactamase inhibitors (BLIs)

Twenty-two studies evaluated daptomycin in combination with penicillins or penicillins/BLIs (Table 2).^12–33

S. aureus [MSSA, MRSA, VISA, glycopeptide-intermediate S. aureus (GISA)] and methicillin-resistant S. epidermidis (MRSE)

Two hundred and thirty-seven isolates of S. aureus (25 MSSA, 189 MRSA, 21 VISA, 2 GISA) were tested in vitro. Indifferent effect was observed against most isolates (145; 61.2%). The combination was synergistic against 77 (32.5%) isolates. Antagonistic effect was found only against one isolate of S. aureus when the combination was tested with Etest, but the result was not confirmed by time–kill assay (indifferent effect).¹⁴ Eight isolates of S. aureus were tested in vivo; synergistic effect was observed against five (62.5%) isolates, additive effect against two isolates (25%) and indifferent effect against one isolate (12.5%).

Only one study evaluated daptomycin in combination with penicillins/BLIs (ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate) in vitro against S. epidermidis; the most effective combination was daptomycin + piperacillin/tazobactam, showing synergistic effect against 18 (50%) isolates and indifferent effect against 18 (50%) isolates.¹⁶

Enterococcus spp. [vancomycin-susceptible Enterococcus (VSE), VRE]

A total of 127 Enterococcus spp. isolates (28 VSE, 99 VRE) were tested: the most frequent interaction was synergism (65 isolates; 51.2%), followed by additive effect (31.5%) and indifferent effect (17.3%). No antagonistic effect was described. Only one study evaluated the combination in vivo against two isolates of E. faecalis in a rabbit infective endocarditis model; the combination was highly effective and acted synergistically against both isolates.³¹

Cephalosporins and cephalosporins/BLIs

Daptomycin in combination with cephalosporins or cephalosporins/BLIs was evaluated in 26 studies (Table 3).^{14,19,25–27,33–53}

S. aureus (MSSA, MRSA, hVISA, VISA) and S. epidermidis [methicillin-susceptible S. epidermidis (MSSE), MRSE]

A total of 228 S. aureus isolates (34 MSSA, 165 MRSA, 16 hVISA, 13 VISA) were tested. In in vitro studies (227 isolates tested), the combination had an indifferent effect against 82 isolates (36.1%). On the other hand, synergism was observed when the combination was tested against 75 (33%) isolates. One study evaluated one strain in an in vivo model of infective endocarditis with spleen and kidney dissemination, reporting an indifferent effect of the combination daptomycin + ceftriaxone on valve vegetations, but a synergistic effect on spleen septic emboli.⁴⁵

Against 16 isolates of S. epidermidis (5 MSSE, 6 MRSE, 5 linezolid-resistant S. epidermidis), the most frequent effect of the combination was synergistic (8 isolates; 50%), followed by indifferent effect (31.2%) and additive effect (18.8%).

Enterococcus spp. (VSE, VRE)

A total of 82 isolates of Enterococcus spp. (24 VSE, 58 VRE) were tested in vitro. Indifferent effect was observed in most cases (51 isolates; 62.2%), while synergism was observed against 23 isolates (28%). No antagonism was observed against any of the tested strains.

Carbapenems

Seven studies evaluated daptomycin + carbapenems in vitro (Table 4).^{14,17,22,25,27,42,45}

S. aureus (MSSA, MRSA, VISA)

Forty-four isolates of S. aureus (20 MSSA, 23 MRSA, 1 VISA) were tested in three in vitro studies, and the combination had an indifferent effect in most cases (90.7%). One study evaluated one strain in an in vivo model of infective endocarditis with spleen and kidney dissemination, reporting an indifferent effect of the combination daptomycin + ertapenem on valve vegetations, but a synergistic effect on kidneys.⁴⁵

Enterococcus spp. (VSE, VRE)

When daptomycin + carbapenems was tested against Enterococcus spp. (56 isolates; 21 VSE, 35 VRE), synergism was observed against 19 isolates (33.9%), additive effect against 1 isolate (1.8%) and indifferent effect against 36 isolates (64.3%). No antagonistic effect was reported.

Macrolides

S. aureus (MSSA, MRSA, hVISA) and S. epidermidis (MSSE, MRSE)

Four in vitro and one in vivo studies evaluated daptomycin + macrolides against 5 S. aureus isolates (1 MSSA, 3 MRSA, 1 hVISA) and 15 S. epidermidis isolates (10 MSSE, 5 MRSE) (Table 5).^54–58 Overall, the combination exerted indifferent effect against most S. aureus and S. epidermidis isolates. In fact, against 4 S. aureus isolates (80%), including 2 isolates tested in vivo, and against 14 S. epidermidis isolates (93.3%), the combination showed no significant enhanced activity compared with monotherapy. Synergism was reported sporadically (two isolates). One study reporting synergistic activity of the combination against one S. aureus isolate described enhanced antibacterial activity against both planktonic and biofilm bacteria.⁵⁵ No antagonistic effect was reported.

Aminoglycosides

The combination daptomycin + gentamicin was evaluated in 16 studies, and daptomycin + tobramycin in one study (Table 6).^{14–16,30,42,57,59–69}

S. aureus (MSSA, MRSA, GISA, VISA, VRSA) and S. epidermidis (MRSE)

The combination was tested against 238 isolates of S. aureus [37 MSSA, 188 MRSA, 2 GISA, 8 VISA, 3 vancomycin-resistant S. aureus (VRSA)] in vitro. The most frequent interaction was indifferent effect (99 isolates; 41.4%). One study evaluating daptomycin + gentamicin in a PK/PD model against two S. aureus isolates reported an antagonistic effect against both isolates.⁶³ Only one isolate of MRSA was tested in vivo (indifferent effect).⁶⁴

Four isolates of S. epidermidis were tested in vitro, resulting in indifferent effect in most cases (75%). The combination showed an antagonistic effect against one isolate.⁵⁷

Enterococcus spp. (VSE, VRE)

Against 89 isolates of Enterococcus spp. (22 VSE, 67 VRE), the combination had a synergistic effect against 16 isolates (18%), additive effect against 1 isolate only, and indifferent effect against 72 (80.9%) isolates. When tested in vivo (three isolates; two Galleria mellonella infection models and one Guinea pig foreign body infection model), additive effect was observed against one isolate (foreign body infection model) and indifferent effect against the other two isolates.^65,66

Glycopeptides

Five in vitro and one in vivo studies evaluated daptomycin in combination with glycopeptides (four studies included vancomycin, one study oritavancin, and one study dalbavancin) (Table 7).^15,70–74

S. aureus (MSSA, MRSA, GISA)

Fifty-eight isolates of S. aureus (1 MSSA, 55 MRSA, 2 GISA) were tested. In vitro, the most frequent interaction was additive effect (23 isolates; 82.1%). Four S. aureus isolates showed indifferent effect. One isolate of MSSA was evaluated in vivo in a mouse implant-associated osteomyelitis and the combination had an indifferent effect compared with monotherapy.⁷⁰ Daptomycin was tested in combination with dalbavancin, a novel glycopeptide, in one in vitro study, and synergistic effect was observed against 67% (20/30) of tested strains.⁷¹

Enterococcus spp. (VSE, VRE)

With regard to Enterococcus spp., nine isolates (eight vancomycin-resistant E. faecium, one vancomycin-susceptible E. faecalis) were evaluated in vitro. Daptomycin + vancomycin had a synergistic effect against four vancomycin-resistant E. faecium, and daptomycin + oritavancin was synergistic against one vancomycin-susceptible E. faecalis. Daptomycin + oritavancin showed antagonistic effect against two isolates of vancomycin-resistant E. faecium.

Oxazolidinones

Eight in vitro and one in vivo studies evaluating daptomycin in combination with oxazolidinones were included in the present systematic review (Table 8).^{15,19,30,70,71,75–78} Linezolid was evaluated in eight studies and tedizolid in one study only.

S. aureus (MSSA, MRSA, GISA)

One hundred and forty-two S. aureus (1 MSSA, 139 MRSA, 2 GISA) isolates were tested. With regard to S. aureus, in vitro the combination showed an additive effect against most isolates (75; 53.2%). Synergism occurred against 26 isolates (18.4%). Indifferent effect was reported against 36 isolates (25.6%) and antagonism against 4 isolates (2.8%). One study evaluated daptomycin + linezolid against one isolate of S. aureus in a mouse implant-associated osteomyelitis, exhibiting indifferent effect.⁷⁰

Enterococcus spp. (VRE)

When the combination was tested against Enterococcus spp. (seven isolates, all VRE), synergism was observed against four isolates (57.1%), while additive and indifferent effect was described against one (14.3%) and two (28.6%) isolates, respectively.

Rifampicin

We included 31 studies evaluating daptomycin in combination with rifampicin (Table 9).^{13,15–17,30,33,42,55,56,58,61,63,64,66,68,70,79–93}

S. aureus (MSSA, MRSA, GISA, hVISA, VRSA) and S. epidermidis (MRSE)

Twenty-one studies (11 in vitro, 4 in vitro and in vivo, 6 in vivo) evaluated the combination against S. aureus (273 isolates; 27 MSSA, 233 MRSA, 2 GISA, 1 hVISA, 7 VISA, 3 VRSA). Two hundred and sixty-six isolates were tested in vitro. The combination exerted a synergistic effect against only 13 (4.9%) isolates, while the most frequent interaction was indifferent effect, which was observed against 138 (51.9%) isolates. Three studies (two time–kill assay, one PK/PD model) reported an antagonistic effect of the combination against the tested strains.^63,64,81 Daptomycin + rifampicin was tested in vivo against 11 isolates, and synergistic effect was observed against 6 isolates (54.5%), thus suggesting a higher synergism rate than observed in vitro. One study reported an antagonistic effect of the combination against one isolate of S. aureus in a rabbit infective endocarditis model.⁶⁴

With regard to S. epidermidis, one isolate was tested in vitro (PK/PD biofilm model, synergistic effect), and one isolate was tested in vivo (osteitis model in rats, additive effect).^56,93

Enterococcus spp. (VSE, VRE)

A total of 129 isolates of Enterococcus spp. (8 VSE, 121 VRE) were tested in eight in vitro studies and one in vitro and in vivo study. Synergism was observed in most cases (81 isolates; 62.8%), while additive and indifferent effects occurred for 10.9% and 25.6% of tested strains, respectively. Antagonism was observed in vitro against one isolate of E. faecium evaluated in a PK/PD model.⁶⁶ Only two isolates (one E. faecalis, one E. faecium; G. mellonella infection model) were tested in vivo and the combination exerted an antagonistic effect against both isolates.⁶⁶

Fosfomycin

We included 14 studies evaluating daptomycin in combination with fosfomycin in the present systematic review (Table 10).^{29,30,32,33,68,85,88,92,94–99}

S. aureus (MSSA, MRSA, GISA)

A total of 153 isolates of S. aureus (12 MSSA, 139 MRSA, 2 GISA) were tested (147 in vitro, 3 in vitro and in vivo, 3 in vivo). In vitro, the combination was synergistic against most isolates (55.4%). Additive effect accounted for 31.3% of interactions, while indifferent effect accounted for 13.3% of interactions. In vivo (two infective endocarditis, two osteomyelitis, two foreign body infection model), the combination acted synergistically against four isolates (66.7%), while indifferent effect was observed against two isolates (33.3%; one infective endocarditis and one osteomyelitis model).

Enterococcus spp. (VSE, VRE)

Five in vitro studies evaluated 22 isolates of Enterococcus spp. (14 E. faecalis, 8 E. faecium). The most frequent interaction was synergism (14 isolates; 63.6%). The combination had an additive effect against four isolates (18.2%) and an indifferent effect against four isolates (18.2%). No antagonistic effect was observed, either in vitro or in vivo.

Miscellanea

Table 11 summarizes the studies evaluating daptomycin in combination with other antimicrobial agents not belonging to the previously discussed antibiotic classes. The following daptomycin combinations were evaluated in three or fewer studies: aztreonam (one study),¹⁴ quinolones (three studies),^69,90,100 trimethoprim/sulfamethoxazole (three studies),^19,101,102 tigecycline (two studies),^42,103 fusidic acid (one study)⁶⁸ and quinupristin/dalfopristin (one study).¹⁵ Due to the limited number of studies and tested strains, it appears inappropriate to reach any conclusion.

Aztreonam

Forty S. aureus (20 MSSA, 20 MRSA) and 40 Enterococcus spp. (20 VSE, 20 VRE) isolates were tested, resulting in indifferent effect in 78 out of 80 cases (97.5%). Synergistic effect was observed against two isolates of S. aureus.

Fusidic acid

Only one study evaluated daptomycin in combination with fusidic acid against 25 MRSA isolates, resulting in synergistic effect against 4 (16%) isolates, additive effect against 7 (28%) and indifferent effect against 14 (56%) isolates.

Quinupristin/dalfopristin

One study evaluated daptomycin + quinupristin/dalfopristin against two isolates of GISA, and indifferent effect was observed against both isolates.

Trimethoprim/sulfamethoxazole

A total of 23 isolates of S. aureus were tested with daptomycin + trimethoprim/sulfamethoxazole; synergistic effect was observed against 19 (82.6%) isolates, while additive effect was observed against 4 (17.4%) isolates.

Tigecycline

The daptomycin + tigecycline combination was tested against 13 isolates of S. aureus and 44 isolates of Enterococcus spp. Synergistic effect was observed in most cases in vitro (75% isolates of S. aureus and 60.5% isolates of Enterococcus spp.). Antagonistic effect was observed against two isolates of Enterococcus spp. (4.5%) in vitro. Daptomycin + tigecycline was evaluated in vivo (wound infection model in mice) against one MSSA and one vancomycin-susceptible E. faecalis and resulted in synergistic effect against both isolates.

Quinolones

Daptomycin in combination with moxifloxacin, levofloxacin and ciprofloxacin was evaluated in three studies (two in vitro studies, one in vitro and in vivo study). Four isolates of S. aureus were tested and synergistic effect accounted for 75% of interactions. Antagonistic effect was observed against one isolate of S. aureus in vitro. In vivo, daptomycin + levofloxacin exerted an additive effect against one isolate of S. aureus.⁹⁰

Overview

Overall, synergism accounted for 30.9% of total interactions, while indifferent effect was the most frequently observed interaction (41.9%). Antagonism accounted for 0.7% of total interactions. Against S. aureus isolates, the highest synergistic rates were observed when daptomycin was tested in combination with fosfomycin (55.6%). For S. epidermidis and Enterococcus spp., the most effective combinations were daptomycin plus cephalosporins (50%) and daptomycin plus fosfomycin (63.6%) or rifampicin (62.8%), respectively. Against S. epidermidis, daptomycin plus rifampicin could also be a valuable therapeutic option, but the extremely limited number of tested isolates (only two isolates) does not allow us to make generalistic considerations. Figure 2 provides an overview of the activity of daptomycin in combination with different antibiotic classes against isolates of S. aureus, S. epidermidis and Enterococcus spp.

Discussion

To the best of our knowledge, this is the first systematic review on daptomycin synergistic properties including in vitro and in vivo studies, including all antibiotic classes previously tested. Compared with a narrative review on daptomycin synergistic combination, where no antagonism was reported, our study reported antagonistic effect for some daptomycin combinations, like daptomycin + glycopeptides against Enterococcus spp. and daptomycin + aminoglycosides against S. epidermidis (Figure 2).¹⁰⁴ Our systematic review suggests that a tailored approach is strongly recommended, taking into account not only the causative agent and clinical aspects that might limit prescription (i.e. drug allergies, comorbidities, drug–drug interactions), but also the site of infection. In fact, the same can act differently in different in vivo models of infection (the number of in vivo studies for each combination is too limited to make general statements about the superiority of a combination regimen compared with others in a specific model of infection).^{45,64,82,83,96}

Although some meta-analyses have been conducted on daptomycin in combination with β-lactams in clinical settings, none was performed investigating the efficacy of daptomycin in combination with molecules belonging to other antibiotic classes. Three meta-analyses on daptomycin in combination with β-lactams for the treatment of MRSA BSI reported superiority of the combination compared with monotherapy, though with an alert on the combination therapy for the increased risk of Clostridioides difficile infection.^105–107 In particular, one of these studies underlined that the combination showed no significant improvement of survival, but was associated with a shorter duration of bacteraemia, a lower risk of persistent bacteraemia and of recurrence within 60–90 days, suggesting careful evaluation of both harms and benefits of daptomycin plus β-lactam combinations.¹⁰⁷

Daptomycin is a milestone for systemic infections caused by MDR Gram-positive cocci and its administration is on the rise due to increased antimicrobial resistance worldwide and its manageable profile. Firstly, it has a good safety and tolerability profile (the most frequent side effect is rhabdomyolysis, mainly occurring in patients with acute kidney injury, end-stage renal disease, or who are taking statins) and can also be administered in children and neonates.^108–110 Secondly, it exerts its bactericidal activity rapidly (in vitro, up to 90% of tested bacteria killed after 1 h) and it is also active against biofilm-embedded bacteria, therefore being a valuable therapeutic option in infections involving prosthetic materials.^111,112 Thirdly, as it is active against MDR Gram-positive cocci and its PK/PD properties allow its administration once a day, its administration has also grown in recent years in outpatient settings.¹¹³ This consideration strengthens the necessity of avoiding the emergence of daptomycin non-susceptible strains.

The clinical superiority of daptomycin-containing regimens compared with monotherapy is still under debate. It is reasonable to hypothesize that the benefits of prescribing daptomycin in combination mainly depend on the partner drug, the infection site, the microbial burden and the type of microorganism involved, as emerged in the ‘Penicillins and penicillin/BLIs’ to ‘Miscellanea’ sections. Some case reports documented clinical failure when daptomycin was administered as monotherapy for BSI or endocarditis, while the infection was cleared by a daptomycin-containing regimen, thus supporting the superiority of the combination compared with monotherapy in the prevention of resistance emergence, enhanced bactericidal effect and subsequent better clinical outcomes.^{108,114–117} In a pilot study, the combination of daptomycin plus ceftaroline was associated with such a reduction in in-hospital mortality (0% versus 26%) compared with daptomycin monotherapy that it caused the study to be halted.¹¹⁸ In two cohorts of 597 and 229 patients with MRSA BSI, combination therapy (daptomycin + β-lactams) was associated with better clinical outcomes (lower 60 day mortality, 60 day recurrence and persistent bacteraemia rates).^119,120 In agreement with the high synergism between daptomycin and fosfomycin that emerged in the present review, in a randomized clinical trial evaluating daptomycin plus fosfomycin and daptomycin monotherapy for MRSA BSI and endocarditis, higher treatment success rates (although not statistically significant; 54.1% versus 42.0%) were reported for combination treatment, although a higher occurrence of adverse events (17.6% versus 4.9%) was observed.¹²¹ In addition, the combination of daptomycin plus fosfomycin successfully treated a total femoral replacement infection sustained by S. epidermidis.¹²² A systematic review on fosfomycin synergistic properties reported consistent results.¹²³ On the other hand, a randomized clinical trial reported daptomycin monotherapy as non-inferior to vancomycin plus gentamicin for the treatment of MRSA BSI and right-sided endocarditis.¹²⁴ In another randomized clinical trial involving MRSA bacteraemic patients, daptomycin in combination with an antistaphylococcal β-lactam (IV flucloxacillin, cloxacillin or cefazolin) was non-superior to daptomycin monotherapy.¹²⁵ Non superiority of the daptomycin + β-lactam (ceftaroline) combination compared with daptomycin monotherapy was also reported in a cohort of patients admitted with MRSA BSI.¹²⁶ For MSSA BSI, a randomized, double-blind, placebo-controlled trial reported no significant advantages of daptomycin + cefazolin or cloxacillin compared with β-lactam monotherapy in terms of both duration of the bacteraemia (primary outcome of the study) and 90 day mortality.¹²⁷

With regard to enterococcal systemic infections, although high-dose daptomycin (10–12 mg/kg/day) is generally considered effective based on available PK/PD data, EUCAST warned about the insufficient clinical evidence of the role of daptomycin in enterococcal endocarditis and BSI.¹²⁸

Our systematic review suggests great heterogeneity in daptomycin synergistic properties according to the antibiotic class tested in combination. As stated in the Materials and methods section, when no distinction was possible between additive and indifferent effect, the combination was considered to exert an indifferent effect compared with monotherapy. This should be stressed, as slightly higher percentages of additive effect against some strains could be possible (see Tables 2–10 for studies that did not make this distinction). Of note, in some PD models, the little benefit observed from the combination of daptomycin with other antimicrobials is mainly due to the extremely effective and rapid bactericidal effect that daptomycin exerted alone.^34,59

Conflicting results are reported about the avoidance of emergence of daptomycin resistance when daptomycin is co-administered with another active agent; one in vitro study reported that co-administration of gentamicin or rifampicin was not able to prevent daptomycin resistance, while amoxicillin/clavulanic acid or ampicillin greatly delayed the emergence of daptomycin resistance in S. aureus and Enterococcus spp. isolates.¹²⁹ Similar results, and in particular the prevention of daptomycin resistance in the presence of β-lactams, clarithromycin or rifampicin, was also confirmed in other studies.^130–133

Daptomycin also has antibiofilm properties, which is particularly relevant when prosthetic materials are present in the site of infection (e.g. CRBSI, prosthetic valve or prosthetic joint infection).^112,134,135 When biofilm-related infections are diagnosed or strongly suspected, association with another antimicrobial agent with antibiofilm properties could be an effective treatment. In in vitro biofilm models of staphylococcal infection, daptomycin in combination with rifampicin or tigecycline was more effective than either agent tested alone.^{82,112,136,137}

Treatment failure is often due to the development of daptomycin resistance, especially in MRSA isolates. When daptomycin was tested in vitro with β-lactams, the ‘seesaw effect’ was observed; the development of daptomycin resistance was accompanied by a concomitant restoration of β-lactam susceptibility.^18,138 Taking this into account, co-administration of daptomycin and a β-lactam could offer the advantage of preventing daptomycin resistance, and in case it develops, somehow taking advantage of the seesaw effect and counting on an eventually restored susceptibility to β-lactams.

Limitations and strengths

Neither clinical studies nor abstracts presented in congresses and preprint papers were included in the current review, nor databases other than PubMed/MEDLINE were consulted. Indeed, because they did not meet inclusion criteria, studies evaluating in vitro daptomycin in combination with another active agent (e.g. aztreonam, ceftazidime, colistin) against Gram-negative bacteria, including MDR Acinetobacter baumannii isolates, even with promising results, were not included in the present review.^139–142

On the other hand, this is the first evaluation of daptomycin synergistic properties carried out with rigorous methods and including all antibiotic classes. It could help clinicians define the best treatment strategy, which should however always be guided by the bacterial species isolated, antimicrobial susceptibility testing, patient allergies and comorbidities and drug–drug interactions. This systematic review also highlighted the combinations and the pathogens less tested, suggesting the fields where further research is particularly needed (e.g. in vivo studies comparing different combination regimens, daptomycin combination regimens against S. epidermidis, daptomycin plus oxazolidinones or glycopeptides against Enterococcus spp.). The updated overview of PD interactions between daptomycin and molecules of other antibiotic classes could also be useful for the future updates of guidelines on systemic infections where daptomycin plays a key role.

Conclusions

Daptomycin is a valuable therapeutic option for systemic infections caused by Gram-positive cocci. Current guidelines for the treatment of systemic infections such as infective endocarditis, SSTI, BSI and CRBSI suggest evaluating co-prescription of daptomycin with another active drug.^6,7 Despite this, clinical evidence is limited and mainly based on case series rather than on randomized clinical trials regarding the superiority of combination regimens compared with monotherapy. Our systematic review presented an updated overview of most synergistic combinations, suggesting that a tailored approach is needed evaluating both clinical characteristics of the patient and the causative agent. In particular, against S. aureus, daptomycin in combination with fosfomycin, glycopeptides or oxazolidinones seems to be particularly beneficial compared with monotherapy. When treating infections by S. epidermidis, daptomycin plus penicillins, penicillins/BLIs, cephalosporins or cephalosporins/BLIs could be valuable options. Finally, daptomycin plus fosfomycin or rifampicin resulted as the most beneficial combinations compared with monotherapy against Enterococcus spp. isolates.

Funding

We carried out the study as part of our routine work without any internal or external financial support.

Transparency declarations

None to declare.

References