Synergistic Meropenem/Vaborbactam Plus Fosfomycin Treatment of KPC Producing K. pneumoniae Septic Thrombosis Unresponsive to Ceftazidime/Avibactam: From the Bench to the Bedside

Abstract

Gram-negative bacilli septic thrombosis (GNB-ST) represents a subtle and often misleading condition, potentially fatal if not recognized early and requiring prolonged antimicrobial therapy and anticoagulation. Herein, reported for the first time, is a very challenging case of Klebsiella producing carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) ST unresponsive to ceftazidime/avibactam (CZA) relapsed first with meropenem/vaborbactam (MVB) monotherapy and subsequently cured with MVB plus fosfomycin (FOS) combination. The present case highlights the possibility of CZA underexposure on the infected thrombus and the risk of in vivo emergence of CZA resistance in the setting of persistent bacteremia and sub-optimal anticoagulation. Pharmacokinetic analyses showed that both MVB and FOS were in the therapeutic range. In vitro studies demonstrated a high level of MVB + FOS synergism that possibly allowed definitive resolution of the endovascular infection.

Effect of ceftazidime/avibactam plus fosfomycin combination on 30 day mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae: results from a multicentre retrospective study

“… 1 Nowadays, the treatment of KPC- Kp infections is mainly based on ceftazidime/avibactam, which undoubtedly represented a therapeutic advance in the field and contributed to the reduction of mortality rates compared with traditional therapies. 2 Nevertheless, its efficacy may be reduced in particular conditions, such as pneumonia, continuous renal replacement therapy, 3 delayed source control 4 and septic thrombosis, 5 where a risk of underexposure and, therefore, clinical failure exists, raising the question of the optimal use of this drug.…”

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

“…Shields et al found that pneumonia was an independent risk factor for CZA clinical failure, while the receipt of renal replacement therapy (RRT) predicted microbiological failure and CZA resistance development [ 39 ]. Recently, clinical and microbiological failures with CZA have combined to the development of decreased susceptibility/resistance to this agent, as described in a case of septic thrombosis, a high clinical complexity condition [ 43 ], and in a case of delayed source control [ 44 ].…”

Oral Fosfomycin Formulation in Bacterial Prostatitis: New Role for an Old Molecule-Brief Literature Review and Clinical Considerations

“…Although oral fosfomycin administration dates back to the 1970s and some mechanisms of resistances are unknown—as aforementioned—fosfomycin-resistant E. coli are still rare, testifying the slow adaptation rate of the bacteria to this molecule, a clear advantage for the physician. Moreover, the mechanism of action of fosfomycin, affecting the early steps involved in bacterial cell wall formation [ 48 ], suggests an additive or synergistic action in combination with other antibiotics; in fact, fosfomycin shows important synergistic effects with many other antibiotics, e.g., piperacillin/tazobactam, ceftazidime/avibactam, meropenem, colistin, and daptomycin, as well as linezolid [ 14 , 44 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ].…”